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WO2025123055A1 - Non-naturally occurring melanocortin analogs and associated methods for modulating weight gain - Google Patents

Non-naturally occurring melanocortin analogs and associated methods for modulating weight gain Download PDF

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Publication number
WO2025123055A1
WO2025123055A1 PCT/US2024/059247 US2024059247W WO2025123055A1 WO 2025123055 A1 WO2025123055 A1 WO 2025123055A1 US 2024059247 W US2024059247 W US 2024059247W WO 2025123055 A1 WO2025123055 A1 WO 2025123055A1
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arg
trp
dpro
lys
seq
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French (fr)
Inventor
Russell Potterfield
Jordan DELEV
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Endevica Bio Inc
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Endevica Bio Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin

Definitions

  • the present technology comprises non-naturally occurring melanocortin analogs and uses thereof for increasing body weight in a subject.
  • the present technology comprises a method of increasing body weight in a subject in need thereof, including administering to the subject a non-naturally occurring melanocortin analog including a sequence of Formula (I): X1 -X2-X3- R1 -R2-R3-R4-R5-R6-R7-R8-R9-Y1 -Y2-Y3-Y4-Y5-Y6-Y7 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (d
  • the present technology comprises use of a non- naturally occurring melanocortin analog for increasing body weight in a subject in need thereof, the non-naturally occurring melanocortin analog including a sequence of Formula (I): X1 -X2-X3-R1 -R2-R3-R4-R5-R6-R7-R8-R9-Y1 -Y2-Y3-Y4-Y5-Y6-Y7 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D- arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-
  • Formula (I) X
  • the method further includes reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject.
  • the lean mass is lean muscle mass.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 0.5 mg/kg to about 10 mg/kg per body weight of the subject once daily.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 1 mg/kg or 3 mg/kg per body weight of the subject once daily.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily.
  • the non-naturally occurring melanocortin analog is an antagonist of a melanocortin 4 receptor.
  • the non-naturally occurring melanocortin analog is a partial antagonist of the melanocortin 4 receptor.
  • the non-naturally occurring melanocortin analog is an antagonist of a melanocortin 3 receptor.
  • the non-naturally occurring melanocortin analog is a full antagonist of the melanocortin 3 receptor.
  • the non-naturally occurring melanocortin analog is a partial antagonist of the melanocortin 3 receptor.
  • the non-naturally occurring melanocortin analog is an agonist of the melanocortin 3 receptor.
  • the non-naturally occurring melanocortin analog is a full agonist of the melanocortin 3 receptor.
  • the non-naturally occurring melanocortin analog is a partial agonist of the melanocortin 3 receptor.
  • the non-naturally occurring melanocortin analog has no melanocortin 3 receptor activity.
  • the method or the use further includes preventing or reducing one or more side effects associated with a metabolic disorder, relative to a control.
  • the present technology comprises a method of preventing or reducing cachexia in a subject in need thereof relative to a control, including administering to the subject: a non-naturally occurring melanocortin analog including a sequence of Formula (I): X1 -X2-X3-R1 -R2-R3-R4-R5-R6-R7-R8-R9-Y1 -Y2-Y3-Y4-Y5-Y6- Y7 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Rhe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (d
  • the present technology comprises use of a non- naturally occurring melanocortin analog for preventing or reducing cachexia in a subject in need thereof relative to a control
  • the non-naturally occurring melanocortin analog including a sequence of Formula (I): X1 -X2-X3-R1 -R2-R3-R4-R5-R6-R7-R8-R9-Y1 -Y2-Y3-Y4-Y5-Y6- Y7 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methi
  • the present technology comprises a method of preventing or reducing anorexia in a subject in need thereof relative to a control, including administering to the subject: a non-naturally occurring melanocortin analog including a sequence of Formula (I): X1 -X2-X3-R1 -R2-R3-R4-R5-R6-R7-R8-R9-Y1 -Y2-Y3-Y4-Y5-Y6- Y7 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine
  • the present technology comprises use of a non- naturally occurring melanocortin analog for preventing or reducing anorexia in a subject in need thereof relative to a control
  • the non-naturally occurring melanocortin analog including a sequence of Formula (I): X1 -X2-X3-R1 -R2-R3-R4-R5-R6-R7-R8-R9-Y1 -Y2-Y3-Y4-Y5-Y6- Y7 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-
  • the present technology comprises a method of increasing, maintaining, or reducing a loss in a body mass index (BMI) level in a subject in need thereof relative to a control, including administering to the subject: a non-naturally occurring melanocortin analog including a sequence of Formula (I): X1 -X2-X3-R1 -R2-R3- R4-R5-R6-R7-R8-R9-Y1 -Y2-Y3-Y4-Y5-Y6-Y7 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic
  • R3 is not His or (ii) R3 is His and R2 is Glu.
  • the present technology comprises use of a non- naturally occurring melanocortin analog for increasing, maintaining, or reducing a loss in a
  • the non-naturally occurring melanocortin analog including a sequence of Formula (I): X1 -X2-X3-R1 -R2-R3-R4-R5-R6- R7-R8-R9-Y1 -Y2-Y3-Y4-Y5-Y6-Y7 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (d
  • the method or the use reduces increases a fat mass level after administration of the non-naturally occurring melanocortin analog, relative to a control.
  • the method or the use maintains or increases brain mass in the subject during or after administration of the non-naturally occurring melanocortin analog, relative to a control.
  • the non-naturally occurring melanocortin analog includes a sequence according to Formula (I): X1 -X2-X3-R1 -R2-R3-R4-R5-R6-R7-R8-R9- Y1 -Y2-Y3-Y4-Y5-Y6-Y7 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-a
  • the non-naturally occurring melanocortin analog includes a sequence according to Formula (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro
  • the non-naturally occurring melanocortin analog includes a sequence according to Formula (IA): X1 -X2-X3-R1 -R2-R3-R4-R5-R6-R7-R8-Y1 - Y2-Y3-Y4-Y5-Y6-Y7 (IA), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alan
  • the non-naturally occurring melanocortin analog includes a sequence according to Formula (IA), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (d
  • the non-naturally occurring melanocortin analog includes a sequence according to Formula (IA), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent or Nle; X3 is absent or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert- leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cysteine (Cys), D-cystein
  • the non-naturally occurring melanocortin analog includes a sequence according to Formula (IA), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent or Nle; X3 is absent or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert- leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cysteine (Cys), D-cystein
  • the non-naturally occurring melanocortin analog includes a sequence according to Formula (IB): X1 -X2-X3-R1 -R2-R3-dNal(2')-R5-R6-R7- R8-Y1 -Y2-Y3-Y4-Y5-Y6-Y7 (IB), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal),
  • the non-naturally occurring melanocortin analog includes a sequence according to Formula (IB), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (d
  • the non-naturally occurring melanocortin analog includes a sequence according to Formula (IC): X1 -R1 -R2-R3-R4-R5-R6-R7-Y1 -Y2-Y3-Y4 (IC), wherein: X1 is absent or norleucine (Nle) R1 is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys); R2 is aspartic acid (Asp) or cysteine (Cys); R3 is His or proline (Pro); R4 is selected from the group consisting of para-chloro-D-phenylalanine (p(CI)dPhe), para- iodo-D-phenylalanine (p(l)dPhe), para-brom
  • IC X1
  • the non-naturally occurring melanocortin analog includes a sequence according to Formula (IC), wherein: X1 -R1 -R2-R3-R4-R5-R6-R7-Y1 - Y2-Y3-Y4 (IC), wherein: X1 is absent or norleucine (Nle) R1 is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys); R2 is aspartic acid (Asp) or cysteine (Cys); R3 is His or proline (Pro); R4 is selected from the group consisting of para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-
  • the non-naturally occurring melanocortin analog includes a sequence according to Formula (ID): X1 -R1 -R2-R3-R4-R5-R6-R7-Y1 -Y2-Y3-Y4 (ID), wherein: X1 is absent or norleucine (Nle); R1 is absent or is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys) R2 is aspartic acid (Asp) or cysteine (Cys); R3 is selected from the group consisting of His, D-histidine (dHis), proline (Pro), phenylalanine (Phe), tryptophan (Trp), tyrosine (Tyr), glutamine (Gin), and biphenyla
  • the non-naturally occurring melanocortin analog includes a sequence according to Formula (ID), wherein: R1 is absent or is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys) R2 is aspartic acid (Asp) or cysteine (Cys); R3 is selected from the group consisting of His, D-histidine (dHis), proline (Pro), phenylalanine (Phe), tryptophan (Trp), tyrosine (Tyr), glutamine (Gin), and biphenylalanine (Bip); R4 is selected from the group consisting of dPhe, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenyla
  • an N-terminus of the non-naturally occurring melanocortin analog if present, is modified by an acyl group.
  • the acyl group is an acetyl group.
  • an N-terminus of the non-naturally occurring melanocortin analog if present, is not modified.
  • a C-terminus of the non-naturally occurring melanocortin analog is modified by an amide group.
  • a C-terminus of the non-naturally occurring melanocortin analog is not modified.
  • R4 is dNal(2').
  • the non-naturally occurring melanocortin analog includes a sequence cyclized.
  • R3 is Pro, Hyp, or His.
  • the sequence of any one of Formulae (l)-( I D) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro (SEQ ID NO: 2); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 3); Ac-Nle- c[Asp-Hyp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 4); Ac-Nle-c[Asp-Pro-His- dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 5); Ac-Nle-c[Asp-Phe-His-dNal(2’)-
  • R9 is present. [0057] In some embodiments, wherein the sequence of any one of Formulae (l)-(ID) is: Ac-Nle-c[Asp-Phe-Phe-Pro-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 11 ), wherein c represents cyclization through R1 and R9 via a lactam bond.
  • R9 is absent and X1 -X3 are present.
  • sequence of any one of Formulae (l)-(ID) is: Ac-Nle-
  • the non-naturally occurring melanocortin analog includes a sequence cyclized between R2 and R7 via a lactam bond or a disulfide bond.
  • the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 38); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-dLys]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-Nle-c[Cys-Pro-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 40); Ac-Nle- c[dCys-Pro-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 41 ); Ac-Nle-c[Cys-Pro-dNal(2')-Arg-Trp-Cys]-d
  • R1 is selected from the group consisting of dArg, dMet, dlle, dLeu, dVal, dAla, Ala, Tie, dTle, dNIe, Nva, Gly, dPro, dCys, dPhe, dGIn, dAsn, transPro(guan), cisPro(guan), dTyr, Tyr, and Dmt.
  • the sequence of any one of Formulae (l)-( I D) is selected from the group consisting of: Ac-dArg-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 15); Ac-dMet-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 16); Ac-dlle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 17); Ac-dLeu- c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 18); Ac-dVal-c[Asp-Pro- dNal(2')-Arg-Trp-Lys]-d
  • R3 is absent or selected from the group consisting of Ala, dAla, dMet, Gly, Leu, He, Vai, dLeu, dlle, dVal, Trp, transPro(guan), cisPro(guan), b- Ala, Mamb, Acpc, Aba, Aia, Aic, Ope, Che, Oic, Tic, and Glu.
  • the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 68); Ac-Nle-c[Asp-Ala-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 69); Ac-Nle- c[Asp-dAla-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 71 ); Ac-Nle-c[Asp-dMet- dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Nle-c[Asp-Pro-Gly-dNal(2’
  • the sequence of any one of Formulae ( l)-( I D) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-dNal(2')-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 86); Ac-Nle-c[Asp-Pro-dNal(2’)-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 87); Ac-Nle- c[Asp-Pro-dNal(2')-Orn-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 90); Ac-Nle-c[Asp-Pro- dNal(2')-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 92); Ac-Nle-c[Asp-Pro-dNal(2')-Trp-Lys]
  • R6 is selected from the group consisting of Nal(1 '), dNal(1 '), Aia, Phe, dPhe, Tyr, dTyr, dNal(2'), dTrp, Aba, and Ata.
  • the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Nal(1 ')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 102); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Aia-Lys]-dVal-dPro-NH2 (SEQ ID NO: 103); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Phe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 104); Ac-Nle- c[Asp-Pro-dNal(2')-Arg-Tyr-Lys]-dVal-dPro-NH2 (SEQ ID NO: 105); Ac-Nle-c[Asp-Pro- dNal(2')-Arg-Tyr-Ly
  • Y1 is selected from dPro, Vai, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, Lys, dLys, Trp, and dTle and Y2 is absent or selected from dVal, Vai, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, and dTle; or (ii) Y1 is dVal, Y2 is dPro, and the C-terminus of the non-naturally occurring melanocortin analog is not modified.
  • the sequence of any one of Formulae ( l)-( I D) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-Val-Pro-NH2 (SEQ ID NO: 1 15); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 116); Ac- Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 117); Ac-Nle-c[Asp-Pro- dNal(2')-Arg-Trp-Lys]-dVal-Hyp-NH2 (SEQ ID NO: 118); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg- Trp-
  • one or more of Y3-Y7 are present and are each independently dVal or dPro.
  • the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 179); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 180); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 181 ); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys
  • one or more of X1 -X3 are present and are Nle.
  • the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 184); Ac-Nle-Nle-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 185); and Ac-Nle-Nle-Nle-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 186), wherein c represents cyclization through R2 and R7 via a lactam bond.
  • the non-naturally occurring melanocortin analog includes a sequence cyclized through a lactam bond between (i) Asp at R1 and Lys at R7, (ii) Asp at R2 and Lys at R8, or (ii) Asp at R1 and Lys at R8.
  • R2 is selected from Asp, Trp, Pro, and Glu
  • R3 is selected from Pro
  • Glu and His
  • R7 is selected from Lys, Pro, and Gly.
  • the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 194); Ac-Nle-c[Asp-Trp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 195); Ac-Nle-c[Asp-Pro-Glu-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 257); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 245); Ac-Nle- c[Asp-Glu-dN
  • one of R2 and R3 is Ala or dAla.
  • the sequence of any one of Formulae (l)-( I D) is selected from the group consisting of: Ac-Nle-c[Asp-dAla-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 266); Ac-Arg-c[Asp-dAla-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 267); Ac-Arg-c[Cys-dAla-His-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 269); Ac-dArg-c[Asp-dAla-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 270); Ac-Arg- c[Asp-dAla-
  • the non-naturally occurring melanocortin analog includes a sequence cyclized through a disulfide bond between dPen at R2 and dPen at R7 or R8.
  • R1 is selected from the group consisting of Nle, dLeu, dNIe, dArg, Arg, dPhe, dTyr, Ala, dHis, His, dLys, and Lys.
  • the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-dl_eu-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 327); Ac-dNle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 328); Ac-dArg-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 329); Ac-Arg-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 330); Ac-dPhe- c[dPen-Pro-dNal(2')-Arg-Trp-dP
  • the non-naturally occurring melanocortin analog is linear.
  • sequence of any one of Formulae (l)-(ID) is: Ac-Nle- Asp-Pro-dNal(2')-Arg-Trp-Lys-dVal-dPro-NH2 (SEQ ID NO: 13); or Ac-Nle-Pro-dNal(2')-Arg- Trp-dVal-dPro-NH2 (SEQ ID NO: 14).
  • R4 is selected from the group consisting of dPhe, p(CI)dPhe p(l)dPhe, p(Br)dPhe, p(F)dPhe, or p(CF3)dPhe.
  • the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 215); Ac-Nle-c[Asp-Pro-p(l)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 216); Ac-Nle-c[Asp-Pro-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 217); Ac-Nle- c[Asp-Pro-p(CF3)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 219); Ac-Nle-c[Asp-His- p(CI)dPhe-Arg-Arg-Trp-L
  • the non-naturally occurring melanocortin analog includes any one of the sequences of SEQ ID NOs: 2-7, 9-12, 13-23, 24-27, 28-30, 31 -43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-1 11 , 1 15-122, 123-138, 139-157, 158-164, 165-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219- 222, 224, 236-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327- 337, 344-350, 369, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-510, 514, 5
  • the non-naturally occurring melanocortin analog includes any one of the sequences of SEQ ID NOs: 2-7, 9-10, 12-23, 24-27, 28-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-11 1 , 115-138, 139-157, 158- 162, 164-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219, 221 -222, 224, 236-242, 244-245, 247-248, 250-257, 259-267, 269-275, 282-283, 327-337, 344-350, 509- 510, 525-527, 531 , 533-535, 538, 545-549, 551 -553, 555, 562-569, 571 -572.
  • the non-naturally occurring melanocortin analog includes any one of the sequences of SEQ ID NOs: 2-4, 13, 15-23, 24-32, 35-43, 48-55, 59, 64-69, 71 -76, 77-82, 86-87, 90, 92-93, 96, 102, 104-105, 108-111 , 1 15-138, 139-162, 164, 165-186, 195-197, 199-201 , 203, 215-217, 219, 221 -222, 224, 240-242, 244, 255-256, 259- 267, 269-275, 327-328, 331 , 344-350, 525-527, 531 , 533-535, 538, 545, 547-549, 551 -553, 555, 562-569, 571 -572.
  • the non-naturally occurring melanocortin analog includes any one of the sequences of SEQ ID NOs: 2-7, 9-10, 12-43, 48-55, 59, 64-69, 71 - 76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-111 , 115-138, 139-162, 164, 165-186, 194- 197, 199-201 , 203-206, 239-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, 344-350.
  • the non-naturally occurring melanocortin analog includes any one of the sequences of SEQ ID NOs: 215-217, 219-222, 224, 236-238, 497, 500, 507-510, 514, 516-517, 535, 538-561 .
  • the non-naturally occurring melanocortin analog includes any one of the sequences of SEQ ID NOs: 220, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-508, 514, 516-517, 524, 529, 539-544, 550, 554, 556-561.
  • the non-naturally occurring melanocortin analog includes a sequence of SEQ ID NO: 3.
  • the non-naturally occurring melanocortin analog is present in a pharmaceutical composition.
  • the pharmaceutical composition includes one or more pharmaceutically acceptable excipients and/or carriers.
  • the one or more pharmaceutically acceptable excipients and/or carriers of the pharmaceutical composition include water.
  • the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg/kg to about 20 mg/kg administered once a day for about 5 days to about 10 days; (ii) at a second dose of about 10 mg/kg to about 40 mg/kg administered once a day after administration of the first dose for about 5 days to about 10 days; (iii) at a third dose of about 5 mg/kg to about 30 mg/kg administered twice a day after administration of the second dose for at least about 5 days to about 10 days.
  • the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg/kg administered once a day for about 7 days; (ii) at a second dose of about 15 mg/kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 10 mg/kg administered twice a day after administration of the second dose for at least about 7 days.
  • the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 10 mg/kg administered once a day for about 7 days; (ii) at a second dose of about 20 mg/kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 15 mg/kg administered twice a day after administration of the second dose for at least about 7 days.
  • the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 15 mg/kg administered once a day for about 7 days; (ii) at a second dose of about 25 mg/kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 20 mg/kg administered twice a day after administration of the second dose for at least about 7 days.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 0.5 mg/kg to about 10 mg/kg per body weight of the subject once daily.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 1 mg/kg or 3 mg/kg per body weight of the subject once daily.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily.
  • the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.
  • the non-naturally occurring melanocortin analog crosses a blood-brain-barrier of a subject.
  • the non-naturally occurring melanocortin analog includes a sequence of SEQ ID NO: 3 and is administered at least once daily in an amount ranging from 0.001 mg/kg to 25 mg/kg per body weight of the subject.
  • the non-naturally occurring melanocortin analog includes a sequence of SEQ ID NOs: 3 and is administered at least once daily in an amount ranging from 0.5 mg/kg to 10 mg/kg per body weight of the subject.
  • the non-naturally occurring melanocortin analog is administered to a subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.
  • the non-naturally occurring melanocortin analog is administered to a subject for 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 1 10 days, or 120 days.
  • the method or the use further includes maintaining muscle mass or promoting muscle mass gain in the subject.
  • the present technology comprises non-naturally occurring melanocortin analogs, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, collectively referred to herein as melanocortin analogs, for modulating weight in subjects in need thereof.
  • the non-naturally occurring melanocortin analog is a non-naturally occurring melanocortin analog.
  • the non-naturally occurring melanocortin analogs may be useful in treating, preventing, or reducing one or more symptoms or conditions associated with weight loss.
  • the non-naturally occurring melanocortin analogs may be used to treat, prevent, or otherwise ameliorate one or more of anorexia, cachexia, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.
  • Cachexia may include cancer-induced cachexia or drug-induced cachexia.
  • the method comprises promoting weight loss in a subject, comprising administering a weight loss agent and a non-naturally occurring melanocortin analog to the subject, wherein the subject’s weight is decreased by loss of fat mass while maintaining or increasing muscle mass.
  • the non-naturally occurring melanocortin analogs may prevent or reduce the loss of lean mass, e.g., muscle and bone mass, associated with weight loss.
  • the term “about” means a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by acceptable levels in the art. Typically, such variation may be as much 10% above and below a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length and such variation may be influenced by standard applicable measurement practices. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth.
  • administering include delivery of therapies (e.g., non-naturally occurring melanocortin analogs (also referred to herein as peptides)) of the present technology to a subject either by local or systemic administration.
  • Administration may be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer), intratracheal, intranasal, epidermal and transdermal, oral or parenteral.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • active ingredient and “active compound” refer to a biologically active substance, whether naturally or non-naturally occurring, that is the main component of the pharmaceutical composition which elicits the intended effect of an administered therapeutic. This may be any component that drives the pharmacological activity or direct effect in the diagnosis, cure, mitigation, treatment, or prevention of the conditions associated with the present technology, such as but not limited to, reduced appetite and weight loss.
  • composition or a “pharmaceutical composition” refers to a mixture of the active ingredient with other chemical components, such as pharmaceutically acceptable carriers and/or excipients.
  • a “pharmaceutically acceptable carrier” of the first or the second pharmaceutical composition refers to a carrier or diluent that does not cause significant irritation to an organism, does not abrogate the biological activity and properties of the administered active ingredient, and/or does not interact in a deleterious manner with the other components of the composition in which it is contained.
  • carrier encompasses any excipient, binder, diluent, filler, salt, buffer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations. The choice of a carrier for use in a composition will depend upon the intended route of administration for the composition.
  • physiologically acceptable carriers include antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEN® (ICI, Inc.; Bridgewater, N.J.), polyethylene glycol (PEG), and PLURONICSTM (BASF; Florham Park, N.J.).
  • antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglob
  • excipient of the first or the second pharmaceutical composition refers to an inert substance added to a composition to further facilitate administration of a compound.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • the terms “treat,” “treatment,” and “treating” refer to a manner of providing a pharmaceutical composition and/or melanocortin analog to alleviate disease outcomes. This includes utilizing administration techniques as described in the context of the present technology. Efficacy of treatment may be determined by various assessment methods as described in the context of the present technology (e.g., assessment of appetite, food consumption, body weight, muscle mass, fat mass, and measurement of biomarkers).
  • biomarker refers to a biological output that is used as a measure of cellular response, whether that be to assess response to therapeutics, disease status, such as cachexia, or as a predictor of clinical outcomes. Biomarkers evaluated in the context of cells, tissue, or whole organisms.
  • the term “disease” herein refers to any disorder adversely affecting biological status. This includes weight-related disorders, such as cachexia. Disease also may be in the context of human and animal health.
  • treat may also refer to the reduction or inhibition of the progression and/or duration of a disease or disorder (e.g., metabolic disease, including, but not limited to, cachexia), the reduction or amelioration of the severity of the disease or disorder, and/or the amelioration of one or more symptoms thereof resulting from the administration of one or more therapies.
  • a disease or disorder e.g., metabolic disease, including, but not limited to, cachexia
  • these terms may refer to: (1 ) a stabilization, reduction, or elimination of the disease or disorder, (2) inhibiting exacerbation of the disease or disorder, (3) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with a pathology related to or caused in part by unregulated or aberrant metabolism, (4) an increase in disease-free, relapse-free, progression-free, and/or overall survival, duration, or rate, (5) a decrease in hospitalization rate, and (6) a decrease in hospitalization length.
  • the terms “treat,” “treatment,” and “treating” include prophylactic and/or therapeutic treatments. If it is administered prior to clinical manifestation of a condition, the treatment is considered prophylactic.
  • Therapeutic treatment includes, e.g., ameliorating or reducing the severity of a disease or disorder, or shortening the length or frequency of the disease or disorder.
  • the terms “effective amount” or “therapeutically effective amount,” refer to that amount of the active ingredient being administered which will relieve to some extent one or more of the symptoms of the disease or disorder being treated. The result may be a reduction and/or alleviation of the signs, symptoms, or causes of a disease or disorder, or any other desired alteration of a biological system.
  • An appropriate “effective amount” may differ from one individual to another.
  • An appropriate “effective amount” in any individual case may be determined using techniques, such as a dose escalation study.
  • after administration refers to any duration of time after the non- naturally occurring melanocortin analog or pharmaceutical composition thereof has been administered to a subject. “After administration” may also refer to the duration of time after one dose has been completed or after more than one dose has been completed, such as two doses, three doses, four doses, and the like. In some embodiments, “after administration” refers to completion of dosing regimen that includes one or more doses. Likewise, the term “prior to” refers to any duration of time before the non-naturally occurring melanocortin analog or pharmaceutical composition thereof has been administered to a subject. Unless otherwise specified, durations of time encompassed by “after administration” or “prior to administration” may include seconds, minutes, hours, days, weeks, months, and years.
  • appetite in a subject and/or patient is typically assessed by their desire to eat and/or the amount of food they consume. As used herein, appetite may be assessed through a daily questionnaire given at specified or random times of the day. In the questionnaire, subjects or patients rate their hunger and/or desire to eat greater varieties of food using scales ranging from 0 (not at all) to 100 (extremely).
  • Cachexia refers to a state of general ill health and malnutrition characterized by loss of body mass including loss of weight, loss of muscle mass (skeletal, smooth, and/or cardiac muscle), loss of fat mass, or a combination thereof, and wasting. It is often associated with and induced by certain diseases or conditions such as, but not limited to, cancer, cystic fibrosis, or AIDS.
  • cancer cachexia refers to cachexia induced by cancer.
  • Diagnostic criterion for cachexia may include (i) weight loss of greater than 5% over past 6 months; (ii) weight loss of greater than 2% in patients with a body mass index (BMI) less than 20 kg/m 2 ; or (iii) weight loss of greater than 2% in patients with sarcopenia (or appendicular skeletal muscle index consistent with sarcopenia). See Fearon K, et al., Lancet Oncol. 12(5):489-95 (2011 ). Cachexia may be used interchangeably with the term “Protein- Energy Wasting” (i.e., PEW).
  • PEW Protein- Energy Wasting
  • Anorexia refers to a loss of appetite, whether brought on by medical, physiological, or psychological factors. Anorexia is often closely associated with, and generally contributes to, cachexia seen in patients with advanced cancers and other conditions.
  • BMI Body Mass Index
  • subject and “patient” refer to anyone being evaluated for disease, disorder, or condition or being administered a therapeutic or pharmaceutical composition. This includes people without diagnosed or confirmed disease or condition. This also includes people with diagnosed or confirmed disease or condition, such as cancer, loss of appetite, nausea, emesis, anorexia, or cachexia.
  • control subject refers to any subject used as a basis for comparison to the subject (e.g., test subject).
  • a control subject includes, but is not limited to, any subject who has not been administered the therapeutic or pharmaceutical composition (e.g., the non-naturally occurring melanocortin analog, a therapeutically effective amount of the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof) or administered a placebo.
  • the therapeutic or pharmaceutical composition e.g., the non-naturally occurring melanocortin analog, a therapeutically effective amount of the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof
  • Melanocortin analogs are used interchangeably and refer to melanocortin-receptor ligands, which are macromolecules containing at least one melanocortin pharmacophore. Melanocortin analogs are typically peptides that bind melanocortin receptors under physiological conditions.
  • Melanocortin analogs include naturally occurring non-naturally occurring melanocortin analogs (i.e., “synthetic peptides” or “synthetic analogs”) and truncated and/or modified versions of melanocortin full-length protein or peptides.
  • synthetic peptides or “synthetic analogs”
  • truncated and/or modified versions of melanocortin full-length protein or peptides For example, the full-length proopiomelanocortin protein (POMC), prior to proteolytic cleavage of “sub-peptides,” consists of 241 amino acids. Tissue-specific proteolytic cleavage of POMC yields peptides ranging in size from 13 amino acids to 76 amino acids. See Bicknell and Lawry, Encyclopedia of Stress, vol. 3, 257-265, Academic Press (2000).
  • POMC proopiomelanocortin protein
  • Synthesized, non-naturally occurring melanocortin analogs having increased melanocortin receptor activity as discussed herein are approximately 7-12 amino acids in size. Melanocortin analogs exhibit binding functionality with melanocortin receptors. The binding to the melanocortin receptor is inhibitory (antagonist).
  • the non-naturally occurring melanocortin analogs include small molecule analogs of melanocortin or portions thereof comprised of organic compounds, inorganic compounds, or combinations of peptide and small molecule — i.e., peptide mimetics, or various combinations thereof.
  • Non-naturally occurring melanocortin analogs may be structurally similar and/or functionally similar to biological melanocortin proteins in their ability to bind melanocortin receptors. Further, the melanocortin analogs generally contain the pharmacophore: His-Phe-Arg-Trp (SEQ ID NO: 1 ) or a modified version thereof, or a structural or functional peptide mimetic thereof.
  • a “pharmacophore” is the minimum set of amino acid residues necessary to achieve a physiological effect; or a small molecule that is (with respect to a receptor) a structural mimic of the amino acid residues required for binding to and activation of a receptor.
  • non-naturally occurring melanocortin pharmacophore analogs may be small peptides or organic molecules designed to mimic the appearance or function (including activation or deactivation of receptor activity) of the melanocortin pharmacophore core sequence peptide.
  • a melanocortin receptor “agonist” is a naturally occurring substance or manufactured drug substance or composition that may interact with a melanocortin receptor and initiate a pharmacological response characteristic of the melanocortin receptor.
  • a melanocortin receptor “antagonist” is a naturally occurring substance or manufactured drug substance or composition that opposes the melanocortin receptor- associated responses normally induced by a melanocortin receptor agonist agent.
  • “Potentiated therapeutic activity” refers to an increase in melanocortin activity in a non-naturally occurring melanocortin analog that has undergone derivatization at the N- and/or C-terminus. Such derivatizations do not necessarily involve the pharmacophore, but do imply a relative increase in in vivo biological half-life.
  • binding refers to all types of physical and chemical binding, reactions, complexing, attraction, chelating and the like.
  • the “peptides” of the present technology may be (a) naturally-occurring, (b) produced by chemical synthesis, (c) produced by recombinant DNA technology, (d) produced by biochemical or enzymatic fragmentation of larger molecules, (e) produced by methods resulting from a combination of methods (a) through (d) listed above, or (f) produced by any other means for producing peptides.
  • peptide as used herein includes any structure comprised of two or more amino acids, including chemical modifications and derivatives of amino acids.
  • the amino acids forming all or a part of a peptide may be naturally occurring amino acids, stereoisomers and modifications of such amino acids, non-protein amino acids, post- translationally modified amino acids, enzymatically modified amino acids, constructs or structures designed to mimic amino acids, and the like, so that the term “peptide” includes pseudopeptides and peptidomimetics, including structures which have a non-peptidic backbone.
  • peptide also includes dimers or multimers of peptides.
  • a “manufactured” peptide includes a peptide produced by chemical synthesis, recombinant DNA technology, biochemical, or enzymatic fragmentation of larger molecules, combinations of the foregoing or, in general, made by any other method.
  • the term “peptide” includes peptides containing a variable number of amino acid residues, optionally with nonamino acid residue groups at the N- and C-termini, such groups including acyl, acetyl, alkenyl, alkyl, N-alkyl, amine, or amide groups, among others.
  • amino acids are molecules containing an amine group, a carboxylic acid group, and a side-chain that is specific to each amino acid.
  • the key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen and have the generic formula H2N — CHR — COOH, wherein R represents a side chain group.
  • the various a-amino acids differ in the side-chain moiety that is attached to the a-carbon.
  • the “amino acids” of the present technology include the known naturally occurring protein amino acids, which are referred to by both their common three letter abbreviation and single letter abbreviation. See generally Synthetic Peptides: A User’s Guide, G. A. Grant, editor, W.H.
  • amino acid also includes stereoisomers and modifications of naturally occurring protein amino acids, nonprotein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs or structures designed to mimic amino acids, and the like. Modified and unusual amino acids are described generally in Synthetic Peptides: A User’s Guide, supra; Hruby et al., Biochem. J. 268:249-262 (1990); and Toniolo, Int. J. Peptide Protein Res. 35:287-300 (1990); the teachings of all of which are incorporated herein by reference.
  • amino acid side chain moiety used herein, including as used in the specification and claims, includes any side chain of any amino acid, as the term “amino acid” is defined herein. This thus includes the side chain moiety present in naturally occurring amino acids. It further includes side chain moieties in modified naturally occurring amino acids, such as glycosylated amino acids. It further includes side chain moieties in stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs, or structures designed to mimic amino acids, and the like. For example, the side chain moiety of any amino acid of the present technology is included within the definition. A “derivative” of an amino acid side chain moiety is included within the definition of an amino acid side chain moiety.
  • the “derivative” of an amino acid side chain moiety includes any modification to or variation in any amino acid side chain moieties, including a modification of naturally occurring amino acid side chain moieties.
  • derivatives of amino acid side chain moieties include straight chain or branched, cyclic or noncyclic, substituted or unsubstituted, saturated or unsaturated, alkyl, aryl or aralkyl moieties.
  • L-Phe is L-phenylalanine
  • D-Phe is D-phenylalanine
  • D-/L-Phe is D-phenylalanine, L-phenylalanine, or combinations thereof
  • Phe is also D-phenylalanine, L-phenylalanine, or combinations thereof, and so on.
  • An alpha (a)-amino acid has the generic formula H2N — CaHR — COOH, where R is a side chain moiety and the amino group is attached to the carbon atom immediately adjacent to the carboxylate group (i.e. , the a-carbon).
  • R is a side chain moiety and the amino group is attached to the carbon atom immediately adjacent to the carboxylate group (i.e. , the a-carbon).
  • Other types of amino acids exist when the amino group is attached to a different carbon atom.
  • beta (P)-amino acids the carbon atom to which the amino group is attached is separated from the carboxylate group by one carbon atom, Cp.
  • p-amino acids When p-amino acids are incorporated into peptides, two main types of p- peptides exist: those with the side chain residue, R, on the carbon next to the amine are called 3 peptides and those with the side chain residue on the carbon next to the carbonyl group are called p 2 amino acids.
  • Gamma (y)-amino acids are amino acids with the carbon atom to which the amino group attaches is separated from the carboxylate moiety by two carbon atoms.
  • Nle is norleucine
  • Nal(2’) is 2'- naphthylalanine
  • Nal(1 ') is 1 '-naphthylalanine
  • Tie is tert-leucine
  • Nva is norvaline
  • Orn is ornithine
  • Bip biphenylalanine
  • Hyp is hydroxyproline
  • Mamb is 3-aminomethyl-benzoic acid
  • Pen is Penicillamine
  • Tic is 1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid
  • Aba is 4- amino-1 ,2,4,5-tetra-hydro-2-benzazepin-3-one
  • Oic is octohydroindole-2-carboxylic acid
  • Ate is 2-aminotetraline-2-carboxylic acid
  • APC is 1 -amino-4-phenylcyclohexane-carboxylic acid
  • APPC is 4-amin
  • a peptide is most usually acylated at the N-terminus.
  • An “amine” includes compounds that contain an amine group ( — NH2).
  • An “amide” includes compounds that have a trivalent nitrogen attached to a carbonyl group (i.e., — CO — NH2), such as for example methylamide, ethylamide, propylamide, and the like.
  • a peptide is most usually amidated at the C-terminus by the addition of an amine ( — NH2) moiety to the C-terminal carboxyl group.
  • Amino acids including stereoisomers and modifications of naturally occurring amino acids, protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs, or structures designed to mimic amino acids (peptide mimetics), and the like, including all of the foregoing, are sometimes referred to herein as “residues.”
  • “Substantial degradation” refers to the degradation of the N-terminal extension, the C-terminal extension, both N- and C-terminal degradation or degradation to other regions of the non-naturally occurring melanocortin analog by physiological enzymes and other factors, in such a manner or to a degree that side effects appear.
  • a non-naturally occurring melanocortin analog having a C-terminal extension that resists substantial degradation is one where no more than 50% of the administered peptide causes side effects and/or displays a low half-life. In some aspects, no more than 25% of the administered peptide causes side effects and/or displays a low half-life. More preferably, in some aspects, less than 10% of the administered peptide causes side effects and/or displays a low half-life, as compared to a non-naturally occurring melanocortin analog that lacks a C-terminal extension.
  • weight loss agent refers to a therapeutic agent useful for the treatment or prevention of metabolic dysfunction or one or more symptoms associated with metabolic dysfunction in a subject.
  • weight loss agents may be effective to treat, reduce, prevent, or otherwise be useful for a subject having a disease or condition that is not metabolic dysfunction, or besides metabolic dysfunction.
  • the present technology is expected to be useful for subjects that may receive, have received, or are receiving one or more doses of a weight loss agent regardless of the underlying disease or condition that the subject has or develops.
  • the non-naturally occurring melanocortin analogs of the present technology may comprise a non-naturally occurring melanocortin analog or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • Non-naturally occurring melanocortin analogs of the present technology may be selective for the melanocortin 4 receptor (MC4R) and/or melanocortin 3 receptor (MC3R) over other melanocortin receptors, i.e., the melanocortin 1 receptor (MC1 R), the melanocortin 2 receptor (MC2R), and the melanocortin 5 receptor (MC5R).
  • non-naturally occurring melanocortin analogs may bind only the MC3R or the MC4R.
  • some of the non-naturally occurring melanocortin analogs may bind the MC3R with greater affinity than the MC4R, whereas other melanocortin analogs may bind the MC4R with greater affinity than the MC3R.
  • Certain melanocortin analogs may bind the MC3R with the same or generally similar affinity as the MC4R.
  • the non-naturally occurring melanocortin analogs of the present technology may be full agonists or full antagonists for one or more melanocortin receptors.
  • a full agonist may comprise a non-naturally occurring melanocortin analog having a maximum effect (Emax) agonist value of greater than or equal to 85%.
  • a full antagonist may comprise a non-naturally occurring melanocortin analog having an Emax antagonist value of greater than or equal to 85%.
  • the non-naturally occurring melanocortin analogs of the present technology may be partial agonists or partial antagonists
  • a partial agonist may comprise a non-naturally occurring melanocortin analog having a maximum effect E ma x agonist value of less than 85%.
  • a partial antagonist may comprise a non-naturally occurring melanocortin analog having an Emax antagonist value of less than 85%.
  • a non-naturally occurring melanocortin analog may be classified as an agonist (e.g., a full agonist or a partial agonist).
  • a non-naturally occurring melanocortin analog may be classified as an antagonist (e.g., a full antagonist or a partial antagonist).
  • the non-naturally occurring melanocortin analogs of the present technology may be one or more of (i) a full MC4R antagonist and a full MC3R antagonist; (ii) a full MC4R antagonist and a partial MC3R antagonist; (iii) a full MC4R antagonist and a full MC4R agonist; (iv) a full MC4R antagonist and a partial MC3R agonist; (v) a full MC4R antagonist having no MC3R activity; (vi) a partial MC4R antagonist and a full MC3R antagonist; (vii) a partial MC4R antagonist and a partial MC3R antagonist; a partial MC4R antagonist and a full MC4R agonist; (viii) a partial MC4R antagonist and a partial MC3R agonist; (ix) a partial MC4R antagonist having no MC3R activity; (x) a partial MC4R agonist and a
  • the non-naturally occurring melanocortin analogs in accordance with the present technology may have certain structural features that impart specific properties on the analogs, such as, for example, degradation resistance, enhanced epithelial, gastrointestinal, and/or blood brain barrier transport, and binding affinity for the melanocortin 4 receptor and/or melanocortin 3 receptor. Accordingly, in some embodiments, the non- naturally occurring melanocortin analogs have one or more beta hairpin (p-hairpin) and/or beta turn (p-turn) structures.
  • p-hairpin beta hairpin
  • p-turn beta turn
  • amino acids that are structurally rigid such as, for example, Aia, Aba, Ata, Hyp, dHyp, Pro, dPro, transPro(guar ⁇ ), and c/'sPro(guan)
  • D-Met and disulfide bridges e.g., cyclization via disulfide bond
  • Pro-Gly and Gly-Gly linkers may induce and/or stabilize beta-turn structures of the non-naturally occurring melanocortin analogs.
  • melanocortin analogs include D-valine-D-proline (dVal-dPro) chain as their C-terminus, which may provide enhanced transport and resistance to degradation.
  • the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I),
  • X 1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
  • X 3 is absent, Phe, or Nle
  • R 1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), trans-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyros
  • R 3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), tra/?sPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]tria
  • R 4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
  • R 5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fransPro(guan);
  • R 7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
  • R 8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
  • R 9 is absent or Lys
  • Y 1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro,
  • Hyp D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
  • Y 2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
  • Y 3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
  • Y 4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp; [0187] Y 5 is absent or dVal;
  • Y 6 is absent or dVal
  • Y 7 is absent or dPro
  • the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
  • R 2 and R 7 or R 8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
  • a lactam bridge between R 2 and R 7 or R 8 when R 2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH CH-CO and R 7 or R 8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and
  • R 3 is dTrp or Phe, then R 4 is not dNal(2’) and R 6 is not dPhe;
  • R 4 is p(F)dPhe, then (i) R 3 is selected from Phe, Bip, Trp, and Tyr or (ii)
  • R 3 is Pro and R 5 is Lys, R 6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R 2 and Cys at R 7 ;
  • R 4 when R 4 is dPhe, then (i) R 3 is dBip or (ii) R 3 is Pro, R 2 is not Trp, and either R 5 is Lys or R 6 is dNal(2’) or Nal(2’);
  • R 4 when R 4 is p(CI)dPhe, then R 1 is Nle or Ala, R 3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R 2 is not Trp, Y 4 -Y 7 are absent, and either X 1 and Y 3 are both present or X 1 and Y 3 are both absent;
  • the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein:
  • X 1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
  • X 2 is absent, phenylalanine (Phe), or Nle;
  • X 3 is absent, Phe, or Nle
  • R 1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), tra/?s-4-guanidinyl-proline (f/'ansPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr)
  • R 3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), tra/?sPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]tria
  • R 4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Bi dPhe), para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
  • R 5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), czsPro(guan), and transP ro (guan);
  • R 6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
  • R 7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
  • R 8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
  • R 9 is absent or Lys
  • Y 1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro,
  • Hyp D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
  • Y 2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
  • Y 3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
  • Y 4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
  • Y 5 is absent or dVal
  • Y 6 is absent or dVal
  • Y 7 is absent or dPro
  • the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: [0221] a disulfide bond between R 1 or R 2 and R 7 or R 8 when each of R 1 or
  • R 2 and R 7 or R 8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
  • a lactam bridge between R 2 and R 7 or R 8 when R 2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH CH-CO and R 7 or R 8 is selected from the group consisting of Lys, dLys, Orn, and dOrn;
  • non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:
  • R 9 is absent.
  • the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA): X 1 -X 2 -X 3 - R 1 - R 2 - R 3 - R 4 - R 5 - R 6 - R 7 - R 8 - Y 1 - Y 2 -Y 3 - Y 4 - Y 5 -Y 6 - Y 7 ( I A) ,
  • X 1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
  • X 2 is absent, phenylalanine (Phe), or Nle;
  • X 3 is absent, Phe, or Nle
  • R 1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), frans-4-guanidinyl-proline (fransPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-
  • R 3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, Tyr, dTyr, c/sPro(guan), fransPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]d
  • R 5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fransPro(guan);
  • R 6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
  • R 7 is absent or is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
  • R 8 is Lys or dPen
  • Y 1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
  • Y 2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
  • Y 3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
  • Y 4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
  • Y 5 is absent or dVal
  • Y 6 is absent or dVal
  • Y 7 is absent or dPro
  • the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: [0536] a disulfide bond between R 1 or R 2 and R 7 or R 8 when each of R 1 or
  • R 2 and R 7 or R 8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
  • a lactam bridge between R 2 and R 7 or R 8 when R 2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH CH-CO and R 7 or R 8 is selected from the group consisting of Lys, dLys, Orn, and dOrn;
  • R 4 when R 4 is p(Br)dPhe, then R 1 is Nle or Ala, Y 4 -Y 7 are absent, and at least one of X 1 and Y 3 is absent;
  • R 4 when R 4 is p(CI)dPhe, then (i) R 3 is selected from Phe, dPhe, Bip, Trp, Tyr, dTyr, and Pro or (ii) R 3 is His and R 6 is not Trp;
  • the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA), wherein:
  • X 1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
  • X 2 is absent, phenylalanine (Phe), or Nle;
  • X 3 is absent, Phe, or Nle
  • R 1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), frans-4-guanidinyl-proline (fransPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-
  • R 3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, Tyr, dTyr, c/sPro(guan), fransPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]d
  • R 4 is selected from the group consisting of 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF 3 )dPhe);
  • R 5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and transPro(guan);
  • R 6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and T- naphthylalanine (Nal(1 ’));
  • R 7 is absent or is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
  • R 8 is Lys or d Pen;
  • Y 1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
  • Y 2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
  • Y 3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
  • Y 4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
  • Y 5 is absent or dVal
  • Y 6 is absent or dVal
  • Y 7 is absent or dPro
  • the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
  • R 2 and R 7 or R 8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
  • a lactam bridge between R 2 and R 7 or R 8 when R 2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH CH-CO and R 7 or R 8 is selected from the group consisting of Lys, dLys, Orn, and dOrn;
  • non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:
  • the non-naturally occurring melanocortin analog is a full antagonist on the melanocortin 4 receptor and the melanocortin 3 receptor. In some embodiments, when the non-naturally occurring melanocortin analog is a full antagonist on the melanocortin 4 receptor and the melanocortin 3 receptor, then R 4 is not dPhe. In further embodiments, R 4 is selected from dNal(2’), p(CI)dPhe, p(l)dPhe, p(Br)dPhe, and p(CF3)dPhe. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA), wherein:
  • X 1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
  • X 2 is absent or Nle
  • X 3 is absent or Nle
  • R 1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), and glutamic acid (Glu);
  • R 3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, fFalanine (P-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, Tyr, dTyr, 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 1 -amino-1 -cyclopentane carboxylic (C
  • R 5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, and ornithine (Orn);
  • R 6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
  • R 7 is selected from the group consisting of Gly, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
  • R 8 is Lys or dPen
  • Y 1 is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
  • Y 2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
  • Y 3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
  • Y 4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
  • Y 5 is absent or dVal
  • Y 6 is absent or dVal
  • Y 7 is absent or dPro
  • the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: [0654] a disulfide bond between R 1 or R 2 and R 7 or R 8 when each of R 1 or
  • R 2 and R 7 or R 8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
  • a lactam bridge between R 2 and R 7 or R 8 when R 2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH CH-CO and R 7 or R 8 is selected from the group consisting of Lys, dLys, Orn, and dOrn;
  • R 4 when R 4 is p(Br)dPhe, then R 1 is Nle or Ala, R 5 is Arg, Y 4 -Y 7 are absent, and at least one of X 1 and Y 3 is absent;
  • R 4 when R 4 is p(CI)dPhe, then R 3 is selected from Phe, dPhe, Bip, Trp, Tyr, dTyr, and Pro;
  • the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA), wherein:
  • X 1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
  • X 2 is absent or Nle
  • X 3 is absent or Nle
  • R 1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), and glutamic acid (Glu); [0666] R 2 is absent or is
  • R 3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, Tyr, dTyr, 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 1 -amino-1 -cyclopentane carboxylic (C
  • R 4 is selected from the group consisting of 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF 3 )dPhe);
  • R 5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, and ornithine (Orn);
  • R 6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, dNal(2’), 2’-naphthylalanine (Nal(2’)), T-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
  • R 7 is selected from the group consisting of Gly, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
  • R 8 is Lys or dPen
  • Y 1 is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
  • Y 2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn; 10675] Y 3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
  • Y 4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
  • Y 5 is absent or dVal
  • Y 7 is absent or dPro
  • the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
  • R 2 and R 7 or R 8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
  • a lactam bridge between R 2 and R 7 or R 8 when R 2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH CH-CO and R 7 or R 8 is selected from the group consisting of Lys, dLys, Orn, and dOrn;
  • non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:
  • R 4 is dNal(2’).
  • the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB):
  • X 1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
  • X 2 is absent, phenylalanine (Phe), or Nle;
  • X 3 is absent, Phe, or Nle
  • R 1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), frans-4-guanidinyl-proline (fransPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-
  • R 3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, c/'sPro(guan), transPro(guan), 4-amino- 1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 - aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5- a][1 ,4]diazepin-6(5H)-one
  • R 5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and transP ro (guan);
  • R 6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’-naphthylalanine (Nal(1 ’));
  • R 7 is absent or is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
  • R 8 is absent or is Lys or dPen
  • Y 1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
  • Y 2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
  • Y 3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
  • Y 4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
  • Y 5 is absent or dVal;
  • Y 6 is absent or dVal
  • Y 7 is absent or dPro
  • the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
  • R 2 and R 7 or R 8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
  • a lactam bridge between R 2 and R 7 or R 8 when R 2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH CH-CO and R 7 or R 8 is selected from the group consisting of Lys, dLys, Orn, and dOrn;
  • R 7 when R 7 is Pro or Gly, then (i) R 3 is not His or (ii) R 3 is His and R 2 is Glu.
  • the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB), wherein:
  • X 1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
  • X 2 is absent, phenylalanine (Phe), or Nle;
  • X 3 is absent, Phe, or Nle
  • R 1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), frans-4-guanidinyl-proline (fransPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-
  • R 3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, c/sPro(guan), fransPro(guan), 4-amino- 1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 - aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5- a][1 ,4]diazepin-6(5H)-
  • R 5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fra/?sPro(guan);
  • R 6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’-naphthylalanine (Nal(T));
  • R 7 is absent or is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
  • R 8 is absent or is Lys or dPen
  • Y 1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
  • Y 2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
  • Y 3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
  • Y 4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
  • Y 5 is absent or dVal
  • Y 6 is absent or dVal
  • Y 7 is absent or dPro
  • the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
  • R 2 and R 7 or R 8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
  • a lactam bridge between R 2 and R 7 or R 8 when R 2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH CH-CO and R 7 or R 8 is selected from the group consisting of Lys, dLys, Orn, and dOrn;
  • non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:
  • R 4 is not dNal(2’).
  • R 4 is selected from p(CI)dPhe, p(l)dPhe, p(Br)dPhe, and p(CF3)dPhe.
  • the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC):
  • X 1 is absent or norleucine (Nle)
  • R 1 is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys);
  • R 2 is aspartic acid (Asp) or cysteine (Cys);
  • R 3 is His or proline (Pro);
  • R 4 is selected from the group consisting of para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);
  • R 5 is Arg or His
  • R 6 is selected from the group consisting of tryptophan (Trp), 4-amino-1 ,2,4,5- tetrahydro-2-benzazepin-3-one (Aba), 3- 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5- a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), 2’-D-naphthylalanine dNal(2’), and 2’-naphthylalanine (Nal(2’));
  • R 7 is Lys or Cys
  • Y 1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle);
  • Y 2 is selected from the group consisting of dVal, dPro, and dTle;
  • Y 3 is absent or is dVal or dPro
  • Y 4 is absent or dPro
  • the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of:
  • R 4 when R 4 is p(CI)dPhe, then R 1 is Nle or Ala, Y 4 -Y 7 are absent, and either X 1 and Y 3 are both present or X 1 and Y 3 are both absent.
  • the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC), wherein:
  • X 1 is absent or norleucine (Nle)
  • R 1 is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys);
  • R 2 is aspartic acid (Asp) or cysteine (Cys);
  • R 3 is His or proline (Pro);
  • R 4 is selected from the group consisting of para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);
  • R 5 is Arg or His
  • R 6 is selected from the group consisting of tryptophan (Trp), 4-amino-1 ,2,4,5- tetrahydro-2-benzazepin-3-one (Aba), 3- 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5- a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), 2’-D-naphthylalanine dNal(2’), and 2’-naphthylalanine (Nal(2’));
  • R 7 is Lys or Cys
  • Y 1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle);
  • Y 2 is selected from the group consisting of dVal, dPro, and dTle;
  • Y 3 is absent or is dVal or dPro
  • Y 4 is absent or dPro
  • the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of:
  • non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:
  • R4 when R 4 is not dNal(2’), then R4 is selected from dPhe, p(CI)dPhe, p(Br)dPhe, and p(F)dPhe.
  • the non-naturally occurring melanocortin analog comprises a sequence of Formula (ID):
  • X 1 is absent or norleucine (Nle);
  • R 1 is absent or is selected from the group consisting of Nle, arginine (Arg), D- arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys)
  • R 2 is aspartic acid (Asp) or cysteine (Cys);
  • R 3 is selected from the group consisting of His, D-histidine (dHis), proline (Pro), phenylalanine (Phe), tryptophan (Trp), tyrosine (Tyr), glutamine (Gin), and biphenylalanine (Bip);
  • R 4 is selected from the group consisting of dPhe, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
  • R 5 is selected from the group consisting of Arg, Lys, and His;
  • R 6 is selected from the group consisting of Trp, 2’-D-naphthylalanine (dNal(2’)), and 2’-naphthylalanine (Nal(2’));
  • R 7 is Lys or Cys
  • Y 1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle);
  • Y 2 is dVal or dPro
  • Y 3 is absent, dVal, or dPro
  • Y 4 is absent or dPro
  • the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
  • R 4 when R 4 is p(F)dPhe, then (i) R 3 is selected from Phe, Bip, Trp, and Tyr or (ii) R 3 is Pro and R 5 is Lys, R 6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R 2 and Cys at R 7 ; [0877] when R 4 is dPhe, then R 3 is Pro and either R 5 is Lys or R 6 is dNal(2’) or Nal(2’); and
  • R 4 when R 4 is p(CI)dPhe, then R 1 is Nle or Ala, R 3 is selected from His, dHis, and Gin, R 6 is Trp, and either X 1 and Y 3 are both present or X 1 and Y 3 are both absent.
  • the non-naturally occurring melanocortin analog comprises a sequence of Formula (ID), wherein:
  • X 1 is absent or norleucine (Nle);
  • R 1 is absent or is selected from the group consisting of Nle, arginine (Arg), D- arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys)
  • R 2 is aspartic acid (Asp) or cysteine (Cys);
  • R 3 is selected from the group consisting of His, D-histidine (dHis), proline (Pro), phenylalanine (Phe), tryptophan (Trp), tyrosine (Tyr), glutamine (Gin), and biphenylalanine (Bip);
  • R 4 is selected from the group consisting of dPhe, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
  • R 5 is selected from the group consisting of Arg, Lys, and His;
  • R 6 is selected from the group consisting of Trp, 2’-D-naphthylalanine (dNal(2’)), and 2’-naphthylalanine (Nal(2’));
  • R 7 is Lys or Cys
  • Y 1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle);
  • Y 2 is dVal or dPro
  • Y 3 is absent, dVal, or dPro
  • Y 4 is absent or dPro; and [0892] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
  • non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:

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Abstract

Provided herein are methods of increasing body weight and/or fat mass in a subject in need thereof, comprising administering to the subject a non-naturally occurring melanocortin analog. The methods may promote lean mass gain in the subject.

Description

NON-NATU RALLY OCCURRING MELANOCORTIN ANALOGS AND
ASSOCIATED METHODS FOR MODULATING WEIGHT GAIN
CROSS-REFERENCE TO RELATED APPLICATION(S)
[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/607,500, filed December 7, 2023, U.S. Provisional Patent Application No. 63/618,843, filed January 8, 2024, U.S. Provisional Patent Application No. 63/557,385, filed February 23, 2024, U.S. Provisional Patent Application No. 63/573,429, filed April 2, 2024, U.S. Provisional Patent Application No. 63/650,705, filed May 22, 2024, U.S. Provisional Patent Application No. 63/656,583, filed June 5, 2025, and U.S. Provisional Patent Application No. 63/663,648, filed June 24, 2024, all of which applications are incorporated herein by reference in their entirety.
INCORPORATION BY REFERENCE OF SEQUENCE LISTING
[0002] This application contains an ST.26 compliant Sequence Listing, which is submitted concurrently in xml format and hereby incorporated by reference in its entirety. The .xml copy, created on December 9, 2024, is titled “146316_8017_WO01_SL.xml” and is 1 ,664 KB in size.
BACKGROUND
[0003] The ability to effectively increase weight and maintain healthy body mass in subjects suffering from various medical conditions and disorders is often challenging. These conditions, which can include muscle wasting, reduced appetite, and metabolic disorders such as cachexia, may significantly impact a subject's overall health, quality of life, and ability to respond to medical treatments. Treatment options are frequently limited by a subject's compromised physical state, affecting both the duration and dosing of therapeutic interventions. These limitations can reduce overall treatment efficacy and increase the risk that therapeutic interventions are not as effective as they could be.
[0004] Despite recent advances in therapeutic approaches for improving body mass and maintaining healthy weight levels, there remains a demand for novel approaches to address these challenges. Such approaches should be well-tolerated, with reduced adverse effects compared to conventional methods, while providing robust therapeutic activity for weight management and maintenance.
SUMMARY
[0005] The present technology comprises non-naturally occurring melanocortin analogs and uses thereof for increasing body weight in a subject.
[0006] In some embodiments, the present technology comprises a method of increasing body weight in a subject in need thereof, including administering to the subject a non-naturally occurring melanocortin analog including a sequence of Formula (I): X1 -X2-X3- R1 -R2-R3-R4-R5-R6-R7-R8-R9-Y1 -Y2-Y3-Y4-Y5-Y6-Y7 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cis-4-guanidinyl-proline (cisPro(guan)), trans-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dl_ys); R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-cis- CH=CH-CO, proline (Pro), and tryptophan (Trp); R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b- Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, cisPro(guan), transPro(guan), 4-amino-1 ,2,4,5- tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclopropane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5- a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 - amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip); R4 is selected from the group consisting of Pro, dPhe, 2'-D-naphthylalanine (dNal(2')), para- chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D- phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe), and para- fluoro-D-phenylalanine (p(F)dPhe); R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), cisPro(guan), and transPro(guan); R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2'- naphthylalanine (Nal(2')), 1 '-D-naphthylalanine (dNal(1 ')), and 1 '-naphthylalanine (Nal(1 ')); R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn); R8 is absent or is selected from the group consisting of Trp, Lys, and dPen; R9 is absent or Lys; Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp; Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn; Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys; Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp; Y5 is absent or dVal; Y6 is absent or dVal; Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-cis-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when R3 is dTrp or Phe, then R4 is not dNal(2') and R6 is not dPhe; when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2') or Nal(2'), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2') or Nal(2'); when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent; when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
[0007] In some embodiments, the present technology comprises use of a non- naturally occurring melanocortin analog for increasing body weight in a subject in need thereof, the non-naturally occurring melanocortin analog including a sequence of Formula (I): X1 -X2-X3-R1 -R2-R3-R4-R5-R6-R7-R8-R9-Y1 -Y2-Y3-Y4-Y5-Y6-Y7 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D- arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cis-4-guanidinyl-proline (cisPro(guan)), trans-4- guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D- asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys); R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D- aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-cis-CH=CH-CO, proline (Pro), and tryptophan (Trp); R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, cisPro(guan), transPro(guan), 4- amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo- [1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2H)- one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip); R4 is selected from the group consisting of Pro, dPhe, 2'-D-naphthylalanine (dNal(2')), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Bi dPhe), para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe); R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), cisPro(guan), and transPro(guan); R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2'), 2'-naphthylalanine (Nal(2')), 1 '-D-naphthylalanine (dNal(1 ')), and T- naphthylalanine (Nal(1 ’)); R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn); R8 is absent or is selected from the group consisting of Trp, Lys, and dPen; R9 is absent or Lys; Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp; Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn; Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys; Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp; Y5 is absent or dVal; Y6 is absent or dVal; Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO- cis-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when R3 is dTrp or Phe, then R4 is not dNal(2') and R6 is not dPhe; when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2') or Nal(2'), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2') or Nal(2'); when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent; when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
[0008] In some embodiments, the method further includes reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject.
[0009] In some embodiments, the lean mass is lean muscle mass.
[0010] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 0.5 mg/kg to about 10 mg/kg per body weight of the subject once daily.
[0011] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 1 mg/kg or 3 mg/kg per body weight of the subject once daily.
[0012] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily.
[0013] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily.
[0014] In some embodiments, the non-naturally occurring melanocortin analog is an antagonist of a melanocortin 4 receptor.
[0015] In some embodiments, the non-naturally occurring melanocortin analog is a full antagonist of the melanocortin 4 receptor.
[0016] In some embodiments, the non-naturally occurring melanocortin analog is a partial antagonist of the melanocortin 4 receptor.
[0017] In some embodiments, the non-naturally occurring melanocortin analog is an antagonist of a melanocortin 3 receptor.
[0018] In some embodiments, the non-naturally occurring melanocortin analog is a full antagonist of the melanocortin 3 receptor.
[0019] In some embodiments, the non-naturally occurring melanocortin analog is a partial antagonist of the melanocortin 3 receptor. [0020] In some embodiments, the non-naturally occurring melanocortin analog is an agonist of the melanocortin 3 receptor.
[0021] In some embodiments, the non-naturally occurring melanocortin analog is a full agonist of the melanocortin 3 receptor.
[0022] In some embodiments, the non-naturally occurring melanocortin analog is a partial agonist of the melanocortin 3 receptor.
[0023] In some embodiments, the non-naturally occurring melanocortin analog has no melanocortin 3 receptor activity.
[0024] In some embodiments, the method or the use further includes preventing or reducing one or more side effects associated with a metabolic disorder, relative to a control.
[0025] In some embodiments, the present technology comprises a method of preventing or reducing cachexia in a subject in need thereof relative to a control, including administering to the subject: a non-naturally occurring melanocortin analog including a sequence of Formula (I): X1 -X2-X3-R1 -R2-R3-R4-R5-R6-R7-R8-R9-Y1 -Y2-Y3-Y4-Y5-Y6- Y7 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Rhe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cis-4-guanidinyl-proline (cisPro(guan)), trans-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys); R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-cis-CH=CH-CO, proline (Pro), and tryptophan (Trp); R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, cisPro(guan), transPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2 ,3]triazolo-[ 1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip); R4 is selected from the group consisting of Pro, dPhe, 2'-D-naphthylalanine (dNal(2')), para-chloro-D-phenylalanine (p(CI)dPhe), para- iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para- trifluoromethyl-D-phenylalanine (p(CF3)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe); R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), cisPro(guan), and transPro(guan); R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2'), 2'-naphthylalanine (Nal(2')), T- D-naphthylalanine (dNal(1 ')), and 1 '-naphthylalanine (Nal(1 ')); R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D- ornithine (dOrn); R8 is absent or is selected from the group consisting of Trp, Lys, and dPen; R9 is absent or Lys; Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp; Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn; Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys; Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp; Y5 is absent or dVal; Y6 is absent or dVal; Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-cis-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when R3 is dTrp or Phe, then R4 is not dNal(2') and R6 is not dPhe; when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2') or Nal(2'), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2') or Nal(2'); when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent; when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu. .
[0026] In some embodiments, the present technology comprises use of a non- naturally occurring melanocortin analog for preventing or reducing cachexia in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog including a sequence of Formula (I): X1 -X2-X3-R1 -R2-R3-R4-R5-R6-R7-R8-R9-Y1 -Y2-Y3-Y4-Y5-Y6- Y7 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cis-4-guanidinyl-proline (cisPro(guan)), trans-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys); R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-cis-CH=CH-CO, proline (Pro), and tryptophan (Trp); R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, cisPro(guan), transPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip); R4 is selected from the group consisting of Pro, dPhe, 2'-D-naphthylalanine (dNal(2')), para-chloro-D-phenylalanine (p(CI)dPhe), para- iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para- trifluoromethyl-D-phenylalanine (p(CF3)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe); R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), cisPro(guan), and transPro(guan); R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2'), 2'-naphthylalanine (Nal(2')), 1'- D-naphthylalanine (dNal(1 ')), and T-naphthylalanine (Nal(1 ’)); R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D- ornithine (dOrn); R8 is absent or is selected from the group consisting of Trp, Lys, and dPen; R9 is absent or Lys; Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp; Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn; Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys; Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp; Y5 is absent or dVal; Y6 is absent or dVal; Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-cis-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when R3 is dTrp or Phe, then R4 is not dNal(2') and R6 is not dPhe; when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2') or Nal(2'), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2') or Nal(2'); when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent; when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
[0027] In some embodiments, the present technology comprises a method of preventing or reducing anorexia in a subject in need thereof relative to a control, including administering to the subject: a non-naturally occurring melanocortin analog including a sequence of Formula (I): X1 -X2-X3-R1 -R2-R3-R4-R5-R6-R7-R8-R9-Y1 -Y2-Y3-Y4-Y5-Y6- Y7 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cis-4-guanidinyl-proline (cisPro(guan)), trans-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys); R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-cis-CH=CH-CO, proline (Pro), and tryptophan (Trp); R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, cisPro(guan), transPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip); R4 is selected from the group consisting of Pro, dPhe, 2'-D-naphthylalanine (dNal(2')), para-chloro-D-phenylalanine (p(CI)dPhe), para- iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para- trifluoromethyl-D-phenylalanine (p(CF3)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe); R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), cisPro(guan), and transPro(guan); R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2'), 2'-naphthylalanine (Nal(2')), T- D-naphthylalanine (dNal(1 ')), and T-naphthylalanine (Nal(1 ')); R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D- ornithine (dOrn); R8 is absent or is selected from the group consisting of Trp, Lys, and dPen; R9 is absent or Lys; Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp; Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn; Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys; Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp; Y5 is absent or dVal; Y6 is absent or dVal; Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-cis-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when R3 is dTrp or Phe, then R4 is not dNal(2') and R6 is not dPhe; when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2') or Nal(2'), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2') or Nal(2'); when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent; when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
[0028] In some embodiments, the present technology comprises use of a non- naturally occurring melanocortin analog for preventing or reducing anorexia in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog including a sequence of Formula (I): X1 -X2-X3-R1 -R2-R3-R4-R5-R6-R7-R8-R9-Y1 -Y2-Y3-Y4-Y5-Y6- Y7 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cis-4-guanidinyl-proline (cisPro(guan)), trans-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys); R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-cis-CH=CH-CO, proline (Pro), and tryptophan (Trp); R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, cisPro(guan), transPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2 ,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip); R4 is selected from the group consisting of Pro, dPhe, 2'-D-naphthylalanine (dNal(2')), para-chloro-D-phenylalanine (p(CI)dPhe), para- iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para- trifluoromethyl-D-phenylalanine (p(CF3)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe); R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), cisPro(guan), and transPro(guan); R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2'), 2'-naphthylalanine (Nal(2')), T- D-naphthylalanine (dNal(1 ')), and T-naphthylalanine (Nal(1')); R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D- ornithine (dOrn); R8 is absent or is selected from the group consisting of Trp, Lys, and dPen; R9 is absent or Lys; Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp; Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn; Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys; Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp; Y5 is absent or dVal; Y6 is absent or dVal; Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-cis-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when R3 is dTrp or Phe, then R4 is not dNal(2') and R6 is not dPhe; when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2') or Nal(2'), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2') or Nal(2'); when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent; when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
[0029] In some embodiments, the present technology comprises a method of increasing, maintaining, or reducing a loss in a body mass index (BMI) level in a subject in need thereof relative to a control, including administering to the subject: a non-naturally occurring melanocortin analog including a sequence of Formula (I): X1 -X2-X3-R1 -R2-R3- R4-R5-R6-R7-R8-R9-Y1 -Y2-Y3-Y4-Y5-Y6-Y7 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cis- 4-guanidinyl-proline (cisPro(guan)), trans-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys); R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-cis-CH=CH-CO, proline (Pro), and tryptophan (Trp); R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, D- tryptophan (dTrp), Tyr, dTyr, cisPro(guan), transPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2- benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 - carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)- one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole- 2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro- isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 - cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip); R4 is selected from the group consisting of Pro, dPhe, 2'-D-naphthylalanine (dNal(2')), para- chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D- phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe), and para- fluoro-D-phenylalanine (p(F)dPhe); R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), cisPro(guan), and transPro(guan); R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2'), 2'- naphthylalanine (Nal(2')), 1 '-D-naphthylalanine (dNal(1')), and 1 '-naphthylalanine (Nal(1 ’)); R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn); R8 is absent or is selected from the group consisting of Trp, Lys, and dPen; R9 is absent or Lys; Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp; Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn; Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys; Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp; Y5 is absent or dVal; Y6 is absent or dVal; Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-cis-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when R3 is dTrp or Phe, then R4 is not dNal(2') and R6 is not dPhe; when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2') or Nal(2'), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2') or Nal(2') ; when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present orX1 and Y3 are both absent; when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and when R7 is
Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
[0030] In some embodiments, the present technology comprises use of a non- naturally occurring melanocortin analog for increasing, maintaining, or reducing a loss in a
BMI level in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog including a sequence of Formula (I): X1 -X2-X3-R1 -R2-R3-R4-R5-R6- R7-R8-R9-Y1 -Y2-Y3-Y4-Y5-Y6-Y7 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cis- 4-guanidinyl-proline (cisPro(guan)), trans-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys); R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-cis-CH=CH-CO, proline (Pro), and tryptophan (Trp); R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, D- tryptophan (dTrp), Tyr, dTyr, cisPro(guan), transPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2- benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 - carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)- one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole- 2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro- isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 - cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip); R4 is selected from the group consisting of Pro, dPhe, 2'-D-naphthylalanine (dNal(2')), para- chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D- phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe), and para- fluoro-D-phenylalanine (p(F)dPhe); R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), cisPro(guan), and transPro(guan); R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2'), 2'- naphthylalanine (Nal(2')), 1 '-D-naphthylalanine (dNal(1 ')), and 1 '-naphthylalanine (Nal(1 ’)); R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn); R8 is absent or is selected from the group consisting of Trp, Lys, and dPen; R9 is absent or Lys; Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp; Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn; Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys; Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp; Y5 is absent or dVal; Y6 is absent or dVal; Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-cis-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when R3 is dTrp or Phe, then R4 is not dNal(2') and R6 is not dPhe; when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2') or Nal(2'), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2') or Nal(2'); when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent; when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu. [0031] In some embodiments, the method or the use prevents fat mass gain after administration of the non-naturally occurring melanocortin analog, relative to a control.
[0032] In some embodiments, the method or the use reduces increases a fat mass level after administration of the non-naturally occurring melanocortin analog, relative to a control.
[0033] In some embodiments, the method or the use maintains or increases brain mass in the subject during or after administration of the non-naturally occurring melanocortin analog, relative to a control.
[0034] In some embodiments, the method or the use prevents or reduces brain mass loss in the subject during or after administration of the non-naturally occurring melanocortin analog, relative to a control.
[0035] In some embodiments, the non-naturally occurring melanocortin analog includes a sequence according to Formula (I): X1 -X2-X3-R1 -R2-R3-R4-R5-R6-R7-R8-R9- Y1 -Y2-Y3-Y4-Y5-Y6-Y7 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cis-4-guanidinyl- proline (cisPro(guan)), trans-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D- cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D- histidine (dHis), lysine (Lys), and D-lysine (dLys); R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D- penicillamine (dPen), glutamic acid (Glu), CO-cis-CH=CH-CO, proline (Pro), and tryptophan (Trp); R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, cisPro(guan), transPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip); R4 is selected from the group consisting of Pro, dPhe, 2'-D-naphthylalanine (dNal(2')), para-chloro-D-phenylalanine (p(CI)dPhe), para- iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para- trifluoromethyl-D-phenylalanine (p(CF3)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe); R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), cisPro(guan), and transPro(guan); R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2'), 2'-naphthylalanine (Nal(2')), 1'- D-naphthylalanine (dNal(1 ')), and 1 '-naphthylalanine (Nal(1 ’)); R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D- ornithine (dOrn); R8 is absent or is selected from the group consisting of Trp, Lys, and dPen; R9 is absent or Lys; Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp; Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn; Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys; Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp; Y5 is absent or dVal; Y6 is absent or dVal; Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-cis-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when R3 is dTrp or Phe, then R4 is not dNal(2') and R6 is not dPhe; when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2') or Nal(2'), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2') or Nal(2'); when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent; when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
[0036] In some embodiments, the non-naturally occurring melanocortin analog includes a sequence according to Formula (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cis- 4-guanidinyl-proline (cisPro(guan)), trans-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys) R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-cis-CH=CH-CO, proline (Pro), and tryptophan (Trp); R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, cisPro(guan), transPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[ 1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino- 1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip); R4 is selected from the group consisting of Pro, dPhe, 2'-D-naphthylalanine (dNal(2')), para-chloro-D-phenylalanine (p(CI)dPhe), para- iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para- trifluoromethyl-D-phenylalanine (p(CF3)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe); R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), cisPro(guan), and transPro(guan); R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2'), 2'-naphthylalanine (Nal(2')), T- D-naphthylalanine (dNal(1 ')), and 1 '-naphthylalanine (Nal(1 ’»; R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D- ornithine (dOrn); R8 is absent or is selected from the group consisting of Trp, Lys, and dPen; R9 is absent or Lys; Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp; Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn; Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys; Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp; Y5 is absent or dVal; Y6 is absent or dVal; Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-cis-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that the non-naturally occurring melanocortin analog does not include a sequence selected from the group consisting of: Ac-Nle-c[Asp-dTrp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 83); Ac-Nle-c[Asp-Phe-Phe-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 420); Ac- Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 223); Ac-Nle-c[dCys- His-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 460); Ac-Arg-c[Asp-His-p(F)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 464); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 465); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro- NH2 (SEQ ID NO: 466); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 467); Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 468); Ac- Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 469); Ac-Nle-c[Asp- His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 470); Ac-Nle-c[Asp-His-p(F)dPhe- Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 474); Ac-Nle-c[Asp-His-p(F)dPhe- Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 475); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp- Lys]-dTle-dPro-NH2 (SEQ ID NO: 476); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle- dPro-NH2 (SEQ ID NO: 477); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal- dPro-NH2 (SEQ ID NO: 478); Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 481 ); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 482); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 483); Ac-His- c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 484); Ac-dHis-c[Asp-His- p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 485); Ac-Nle-c[Cys-His-p(F)dPhe-Arg- Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 459); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Nal(2')-Lys]- dVal-dPro-NH2 (SEQ ID NO: 472); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal- dPro-NH2 (SEQ ID NO: 471 ); Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 463); Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 462); Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 479); Ac-Nle- c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 473); Ac-dArg-c[Asp- His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 480); Ac-Nle-c[Asp-dHis- p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 486); Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg- Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 491 ); Ac-Nle-c[dCys-His-p(F)dPhe-Arg-Trp-dCys]- dVal-dPro-NH2 (SEQ ID NO: 461 ); Ac-Nle-c[Asp-dGln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro- NH2 (SEQ ID NO: 492); Ac-Nle-c[Asp-dTyr-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 496); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 218); Ac- Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 442); Ac-Nle- c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 449); Ac-Lys-c[Asp-Pro- p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 455); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg- Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 447); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg- Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 438); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]- dTle-dPro-NH2 (SEQ ID NO: 450); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro- NH2 (SEQ ID NO: 435); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 439); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 441 ); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 436); Ac-Arg- c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 454); Ac-Ala-c[Asp-Pro- p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 452); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe- Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 451 ); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg- Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 456); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 437); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 440); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 448); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 457); Ac- dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 453); Ac-dHis-c[Asp- Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 458); Ac-Nle-c[Asp-Pro-p(F)dPhe- Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 446); Ac-Nle-c[dCys-Pro-p(F)dPhe-Arg-Trp- Cys]-dVal-dPro-NH2 (SEQ ID NO: 433); Ac-Nle-c[dCys-Pro-p(F)dPhe-Arg-Trp-dCys]-dVal- dPro-NH2 (SEQ ID NO: 434); Ac-Nle-c[Asp-dPhe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 488); Ac-Nle-c[Asp-dBip-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 490); Ac-Nle-c[Asp-dTrp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 494); Ac-Nle- c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 443); Ac-Arg-c[Asp-dAla- His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 268); Ac-Nle-c[Asp-His-dPhe-Arg-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 363); Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro- NH2 (SEQ ID NO: 365); Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 370); Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 378); Ac- dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 379); Ac-Nle-c[Asp- Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 380); Ac-Nle-c[Asp-His-dPhe-Arg- Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 418); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro- dVal-NH2 (SEQ ID NO: 621 ); Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 666); Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 297); Ac-Nle- c[Asp-His-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 228); Ac-Nle-c[Asp- His-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 229); Ac-Arg-c[Asp-dAla-His- dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 281); Ac-Nle-c[Asp-Leu-dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 355); Ac-Nle-c[Asp-Tic-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 362); Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 424); Ac- Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 366); Ac-Nle-c[Asp-Bip- dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 368); Ac-Nle-c[Asp-Phe-His-dPhe-Arg- Trp-l_ys]-dl_eu-dPro-NH2 (SEQ ID NO: 422); Ac-Nle-c[Asp-Trp-dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 372); Ac-Nle-c[Asp-Tyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 374); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 639); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dPro-dPro-Lys-Asp-NH2 (SEQ ID NO: 352); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 351 ); Ac-Nle-c[Asp- Pro-dPhe-Arg-Trp-Lys]-Trp-NH2 (SEQ ID NO: 600); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]- dVal-dPro-NH2 (SEQ ID NO: 322); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dAsn-NH2 (SEQ ID NO: 605); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Gly-Gly-NH2 (SEQ ID NO: 610); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Arg-NH2 (SEQ ID NO: 581 ); Ac-Nle-c[Asp-Pro-dPhe- Arg-Trp-Gly-Lys]-dPro-dPro-dLys-dAsp-NH2 (SEQ ID NO: 353); Ac-Nle-c[dCys-Pro-dPhe- Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 319); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asn- dPro-NH2 (SEQ ID NO: 607); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 638); Ac-Nle-c[Asp-Pro-His-Phe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 295); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 575); Ac-Nle- c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH2 (SEQ ID NO: 587); Ac-Nle-c[Asp-Pro- dPhe-Arg-Trp-Lys]-dArg-NH2 (SEQ ID NO: 582); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Arg- Pro-Val-NH2 (SEQ ID NO: 588); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAsn-dPro-NH2 (SEQ ID NO: 612); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-Pro-Val-NH2 (SEQ ID NO: 583); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Ala-Ala-NH2 (SEQ ID NO: 609); Ac-Nle-c[Asp- Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 594); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp- Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 631 ); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Arg- Val-Pro-NH2 (SEQ ID NO: 589); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal- dPro-NH2 (SEQ ID NO: 597); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 628); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 591 ); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 590); Ac-Arg- c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 311 ); Ac-Nle-Nle-Nle-c[Asp- Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 629); Ac-Nle-c[Asp-Pro-dPhe-Arg- Trp-Lys]-dVal-Hyp-NH2 (SEQ ID NO: 574); Ac-dPhe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 303); Ac-Nle-c[Asp-Oic-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 360); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 313); Ac- Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 291 ); Ac-dAla-c[Asp-Pro- dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 299); Phe-c[Asp-Pro-dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 305); His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 306); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 312); Ac- His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 314); Ac-dHis-c[Asp-Pro- dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 315); Ac-Nle-c[dCys-Pro-dPhe-Arg-Trp- dCys]-dVal-dPro-NH2 (SEQ ID NO: 321 ); Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dTle- dPro-NH2 (SEQ ID NO: 423); Ac-Nle-Phe-Phe-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 421 ); Ac-Nle-c[Cys-Trp-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 383); Ac-Nle-c[dCys-Trp-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 384); Ac-Lys-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 387); Ac-Arg- c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 389); Ac-Nle-c[Asp-Trp- Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 403); Ac-Nle-c[Asp-Trp-Pro- dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 407); Ac-Nle-c[Asp-Trp-Leu-dPhe-Arg- Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 395); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg- dPro-NH2 (SEQ ID NO: 633); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Val-Pro-NH2 (SEQ ID NO: 573); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 643); Ac-Nle- c[Asp-Pro-dPhe-Arg-Trp-Lys]-Val-NH2 (SEQ ID NO: 576); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp- Lys]-Pro-NH2 (SEQ ID NO: 577); dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 309); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 593); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH2 (SEQ ID NO: 632); Ac-Nle- c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asp-NH2 (SEQ ID NO: 603); Ac-Nle-c[Asp-Pro-dPhe-Arg- Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 617); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro- dVal-NH2 (SEQ ID NO: 620); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dPro-NH2 (SEQ ID NO: 634); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 635); Ac- dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 644); Ac-dTyr-c[Asp-Pro- dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 304); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp- Lys]-dTle-dPro-NH2 (SEQ ID NO: 642); dPhe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 308); Ac-Nle-c[Asp-Atc-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 212); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 226); Ac-Nle- c[dPen-Pro-dPhe-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 320); Ac-Nle-c[Cys-dPhe- Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 324); Ac-Nle-c[Asp-Cpe-dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 358); Ac-Nle-c[Asp-Che-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 359); Ac-Nle-c[Asp-dPhe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 367); Ac-Nle-c[Asp-dGln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 371 ); Ac-Nle- c[Asp-dTrp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 373); Ac-Nle-c[Asp-dTyr- dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 375); Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 381 ); Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 382); Ac-Nle-c[dCys-Trp-Pro-dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 385); Ac-Ala-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 386); Ac-dLys-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 388); Ac- dArg-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 390); Ac-dHis-c[Asp- Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 391 ); Ac-His-c[Asp-Trp-Pro-dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 392); Ac-Nle-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 393); Ac-Nle-c[Asp-Trp-Ala-dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 394); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro- NH2 (SEQ ID NO: 405); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH2 (SEQ ID NO: 406); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dLys-dPro-NH2 (SEQ ID NO: 408); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 409); Ac-Nle- c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 410); Ac-Nle-c[Asp-Trp- Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 411 ); Ac-Nle-c[Asp-Phe- Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 412); Ac-Nle-c[Asp-His-Pro-dPhe-Arg- Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 413); Ac-Nle-c[Asp-Tyr-Pro-dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 414); Ac-Nle-c[Asp-dPhe-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 415); Ac-Nle-c[Asp-dHis-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 416); Ac-Nle-c[Asp-dTyr-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 417); Ac-Nle- c[Asp-Hyp-dPhe-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 419); Ac-Nle-c[Asp-Pro- dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 596); Ac-Nle-c[dAsp-Pro-dPhe-Arg- Trp-dl_ys]-dPro-dVal-NH2 (SEQ ID NO: 622); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle- dPro-NH2 (SEQ ID NO: 645); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 646); Ac-dLeu-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 298); Ac- Nle-c[Asp-Ala-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 354); Ac-Nle-c[Asp-Hyp- dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 364); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp- Lys]-dVal-Arg-NH2 (SEQ ID NO: 578); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro- NH2 (SEQ ID NO: 300); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dArg-NH2 (SEQ ID NO: 579); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 580); Ac-Ala- c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 640); Ac-dArg-c[Asp-Pro-dPhe- Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 641 ); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]- dLys-dPro-NH2 (SEQ ID NO: 584); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-Val-Pro-NH2 (SEQ ID NO: 585); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-dVal-dPro-NH2 (SEQ ID NO: 586); Ac-dNle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 301 ); Ac-Nle- c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 595); Ac-Nle-c[Asp-Pro- dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 598); Ac-dArg-c[Asp-Pro-dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 302); Ac-Nle-Nle-Nle-Nle-c[Asp-Pro-dPhe-Arg- Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 630); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys- dPro-dVal-NH2 (SEQ ID NO: 601 ); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAla-dAla-NH2 (SEQ ID NO: 602); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dHyp-NH2 (SEQ ID NO: 604); Ac- Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-Asp-NH2 (SEQ ID NO: 606); Ac-Nle-c[Cys-Pro- dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 318); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp- Lys]-Hyp-NH2 (SEQ ID NO: 608); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asp-dPro-NH2 (SEQ ID NO: 61 1 ); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asn-NH2 (SEQ ID NO: 613); Ac- Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAsp-NH2 (SEQ ID NO: 614); Ac-Nle-c[Asp-Pro-dPhe- Arg-Trp-Lys]-dAsn-NH2 (SEQ ID NO: 615); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-dPro- NH2 (SEQ ID NO: 616); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dVal-dVal- dVal-dPro-NH2 (SEQ ID NO: 599); Ac-Nle-c[Asp-Pro-His-Phe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 296); Ac-Nle-c[Asp-Aba-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 198); Ac-Nle-c[Asp-Aia-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 207); Ac-Nle- c[Asp-Ata-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 208); Ac-Nle-c[Asp-Pro-Pro- dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 225); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp- Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 592); Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 425); Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(1 ’)-Lys]-dVal-dPro-NH2 (SEQ ID NO: 427); Ac-Nle-c[Asp-Pro-dPhe-Arg-Phe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 429); Ac-Nle-c[Pen-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 325); Ac-Nle-c[dPen- dPhe-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 326); Ac-Nle-c[Asp-dlle-dPhe-Arg-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 356); Ac-Nle-c[Asp-dVal-dPhe-Arg-Trp-Lys]-dVal-dPro- NH2 (SEQ ID NO: 357); Ac-Arg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 376); Ac-dArg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 377); Ac- Nle-c[Asp-Trp-dLeu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 396); Ac-Nle-c[Asp- Trp-dVal-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 397); Ac-Nle-c[Asp-Trp-Pro- dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 398); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg- dNal(1 ')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 400); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Phe-Lys]- dVal-dPro-NH2 (SEQ ID NO: 401 ); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-dPhe-Lys]-dVal-dPro- NH2 (SEQ ID NO: 402); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Nal(1 ')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 399); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 404); Ac-Nle-c[Asp-Pro-dPhe-Arg-dTrp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 187); Ac-Nle- c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 231 ); Ac-Nle-c[Asp- Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 232); Ac-Nle-c[Asp-Pro- dPhe-Arg-Aia-Lys]-dVal-dPro-NH2 (SEQ ID NO: 233); Ac-Nle-c[Asp-Pro-dPhe-Arg-Aba- Lys]-dVal-dPro-NH2 (SEQ ID NO: 234); Ac-Nle-c[Asp-Pro-dPhe-Arg-Ata-Lys]-dVal-dPro- NH2 (SEQ ID NO: 235); Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(1')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 428); Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 520); Ac- His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 522); Ac-dHis-c[Asp- His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 523); Ac-dArg-c[Asp-His- p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 518); Ac-Lys-c[Asp-His-p(CI)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 503); Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 505); Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro- NH2 (SEQ ID NO: 502); Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 519); Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 506); Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 501 ); Ac-dLys- c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 521 ); Ac-dLys-c[Asp-His- p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 504); Ac-Nle-c[Asp-dBip-p(CI)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 528); Ac-Nle-c[Asp-dGln-p(CI)dPhe-Arg-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 530); Ac-Nle-c[Asp-dTrp-p(CI)dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 532); Ac-Nle-c[Asp-Aba-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEO ID NO: 209); Ac-Nle-c[Asp-Aia-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 210); Ac-Nle-c[Asp-Ata-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 21 1 ); Ac-Nle- c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 512); Ac-Nle- c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 513); Ac-Nle-c[Asp- His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 511 ); Ac-Nle-Nle-c[Asp-His- p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 515); Ac-Nle-c[dPen-Ala-dNal(2’)- Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 338); Ac-Nle-c[dPen-Leu-dNal(2')-Arg-Trp- dPen]-dVal-dPro-NH2 (SEQ ID NO: 339); Ac-Nle-c[dPen-dLeu-dNal(2’)-Arg-Trp-dPen]- dVal-dPro-NH2 (SEQ ID NO: 340); Ac-Nle-c[dPen-dVal-dNal(2')-Arg-Trp-dPen]-dVal-dPro- NH2 (SEQ ID NO: 341 ); Ac-Nle-c[dPen-Gly-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 342); Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 536); Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 498); Ac- Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 499); Ac-Nle- c[dCys-His-p(Br)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 537); Ac-Nle-c[Cys- dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[dCys-dNal(2')-Arg-Trp- Cys]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Cys-dNal(2')-Arg-Trp-dCys]-dVal-dPro- NH2 (SEQ ID NO: 46); Ac-Nle-c[dCys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 47); Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-Nle-c[dCys- dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 57); Ac-Nle-c[Pen-dNal(2’)-Arg-Trp- Cys]-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 60); Ac-Nle-c[dPen-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 61 ); Ac-Nle-c[dPen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c[Pen- dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 63); Ac-Nle-c[Asp-His-dNal(2')-Arg- Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 8); and Ac-Nle-c[Asp-Pro-Glu-dNal(2’)-Arg-Trp- Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 258).
[0037] In some embodiments, the non-naturally occurring melanocortin analog includes a sequence according to Formula (IA): X1 -X2-X3-R1 -R2-R3-R4-R5-R6-R7-R8-Y1 - Y2-Y3-Y4-Y5-Y6-Y7 (IA), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert- leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cis-4-guanidinyl-proline (cisPro(guan)), trans-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys) R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-cis-CH=CH-CO, proline (Pro), and tryptophan (Trp); R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, Tyr, dTyr, cisPro(guan), transPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip); R4 is selected from the group consisting of 2'-D-naphthylalanine (dNal(2')), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D- phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para- trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), cisPro(guan), and transPro(guan); R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2'), 2'-naphthylalanine (Nal(2')), 1 '-D-naphthylalanine (dNal(1 ’)), and 1 '- naphthylalanine (Nal(T)); R7 is absent or is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn); R8 is Lys or dPen; Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp; Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn; Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys; Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp; Y5 is absent or dVal; Y6 is absent or dVal; Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-cis-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; a lactam bridge between R1 and R7 or R8 when R1 is Asp and R7 or R8 is Lys; provided that: when R4 is p(Br)dPhe, then R1 is Nle or Ala, Y4-Y7 are absent, and at least one of X1 and Y3 is absent; when R4 is p(CI)dPhe, then (i) R3 is selected from Phe, dPhe, Bip, Trp, Tyr, dTyr, and Pro or (ii) R3 is His and R6 is not Trp; when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R2 is not Pro.
[0038] In some embodiments, the non-naturally occurring melanocortin analog includes a sequence according to Formula (IA), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cis- 4-guanidinyl-proline (cisPro(guan)), trans-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys) R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-cis-CH=CH-CO, proline (Pro), and tryptophan (Trp); R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, Tyr, dTyr, cisPro(guan), transPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip); R4 is selected from the group consisting of 2'-D-naphthylalanine (dNal(2')), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D- phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para- trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), cisPro(guan), and transPro(guan); R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2'), 2'-naphthylalanine (Nal(2')), 1 '-D-naphthylalanine (dNal(1 ')), and 1 '- naphthylalanine (Nal(T)); R7 is absent or is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn); R8 is Lys or dPen; Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp; Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn; Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys; Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp; Y5 is absent or dVal; Y6 is absent or dVal; Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-cis-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that the non-naturally occurring melanocortin analog does not include a sequence selected from the group consisting of: Ac-dArg-c[Asp- His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 539); Ac-Arg-c[Asp-His- p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 540); Ac-Lys-c[Asp-His-p(BijdPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 541 ); Ac-dLys-c[Asp-His-p(Br)dPhe-Arg-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 542); Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 543); Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 544); Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 556); Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 557); Ac- Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 558); Ac-dLys-c[Asp- His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 559); Ac-His-c[Asp-His- p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 560); Ac-dHis-c[Asp-His-p(BijdPhe- Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 561 ); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]- dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 550); Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp- Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 554); Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 220); Ac-Nle-c[Cys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro- NH2 (SEQ ID NO: 497); Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 500); Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 507); Ac-Nle-c[Asp-His-p(CI)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 508); Ac-Nle-c[Asp- His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 514); Ac-Nle-Nle-c[Asp-His- p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 516); Ac-Ala-c[Asp-His- p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 517); Ac-Nle-c[Asp-dHis-p(CI)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 524); Ac-Nle-c[Asp-Gln-p(CI)dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 529); Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro- NH2 (SEQ ID NO: 520); Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 522); Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 523); Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 518); Ac-Lys- c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 503); Ac-His-c[Asp-His- p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 505); Ac-Arg-c[Asp-His-p(CI)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 502); Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]- dTle-dPro-NH2 (SEQ ID NO: 519); Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro- NH2 (SEQ ID NO: 506); Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 501 ); Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 521 ); Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 504); Ac-Nle- c[Asp-dBip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 528); Ac-Nle-c[Asp-dGln- p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 530); Ac-Nle-c[Asp-Aba-p(CI)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 209); Ac-Nle-c[Asp-Aia-p(CI)dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 210); Ac-Nle-c[Asp-Ata-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro- NH2 (SEQ ID NO: 211 ); Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro- NH2 (SEQ ID NO: 512); Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 513); Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 511 ); Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 515); Ac-Nle-c[dPen-Ala-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 338); Ac-Nle- c[dPen-Leu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 339); Ac-Nle-c[dPen- dLeu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 340); Ac-Nle-c[dPen-dVal- dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 341 ); Ac-Nle-c[dPen-Gly-dNal(2’)-Arg- Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 342); Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-Cys]- dVal-dPro-NH2 (SEQ ID NO: 536); Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro- NH2 (SEQ ID NO: 498); Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 499); Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 537); Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[dCys- dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Cys-dNal(2')-Arg-Trp- dCys]-dVal-dPro-NH2 (SEQ ID NO: 46); Ac-Nle-c[dCys-dNal(2’)-Arg-Trp-dCys]-dVal-dPro- NH2 (SEQ ID NO: 47); Ac-Nle-c[Cys-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 57); Ac-Nle-c[Pen- dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c[Pen-dNal(2’)-Arg-Trp- Pen]-dVal-dPro-NH2 (SEQ ID NO: 60); Ac-Nle-c[dPen-dNal(2')-Arg-Trp-Pen]-dVal-dPro- NH2 (SEQ ID NO: 61 ); Ac-Nle-c[dPen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c[Pen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 63); Ac-Nle-c[Asp- His-dNal(2')-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 8); and Ac-Nle-c[Asp-Pro-Glu- dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 258).
[0039] In some embodiments, the non-naturally occurring melanocortin analog includes a sequence according to Formula (IA), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent or Nle; X3 is absent or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert- leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), and glutamic acid (Glu); R2 is selected from the group consisting of dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-cis-CH=CH-CO, and tryptophan (Trp); R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, Tyr, dTyr, 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), and D-biphenylalanine (dBip); R4 is selected from the group consisting of 2'-D-naphthylalanine (dNal(2')), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para- trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, and ornithine (Orn); R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, dNal(2'), 2'-naphthylalanine (Nal(2')), 1 '-D- naphthylalanine (dNal(T)), and 1 '-naphthylalanine (Nal(T)); R7 is selected from the group consisting of Gly, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn); R8 is Lys or dPen; Y1 is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp; Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn; Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys; Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp; Y5 is absent or dVal; Y6 is absent or dVal; Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-cis-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when R4 is p(Br)dPhe, then R1 is Nle or Ala, R5 is Arg, Y4-Y7 are absent, and at least one of X1 and Y3 is absent; when R4 is p(CI)dPhe, then R3 is selected from Phe, dPhe, Bip, Trp, Tyr, dTyr, and Pro; and when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro and R1 is not dArg, Arg, dTyr, or Ala, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys.
[0040] In some embodiments, the non-naturally occurring melanocortin analog includes a sequence according to Formula (IA), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent or Nle; X3 is absent or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert- leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), and glutamic acid (Glu); R2 is selected from the group consisting of dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-cis-CH=CH-CO, and tryptophan (Trp); R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, Tyr, dTyr, 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), and D-biphenylalanine (dBip); R4 is selected from the group consisting of 2'-D-naphthylalanine (dNal(2'))> para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para- trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, and ornithine (Orn); R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, dNal(2'), 2'-naphthylalanine (Nal(2')), 1 '-D- naphthylalanine (dNal(1 ')), and 1 '-naphthylalanine (Nal(1 ')); R7 is selected from the group consisting of Gly, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn); R8 is Lys or dPen; Y1 is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp; Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn; Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys; Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp; Y5 is absent or dVal; Y6 is absent or dVal; Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-cis-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that the non-naturally occurring melanocortin analog does not include a sequence selected from the group consisting of: Ac-Nle-c[Asp- His-p(Br)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 546); Ac-dArg-c[Asp-His- p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 539); Ac-Arg-c[Asp-His-p(Br)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 540); Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp- Lys]-dTle-dPro-NH2 (SEQ ID NO: 556); Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle- dPro-NH2 (SEQ ID NO: 557); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal- dPro-NH2 (SEQ ID NO: 550); Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal- dPro-NH2 (SEQ ID NO: 554); Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-dNal(2')-Lys]-dVal-dPro- NH2 (SEQ ID NO: 509); Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 510); Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 220); Ac-Nle-c[Cys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 497); Ac-Ala- c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 500); Ac-Nle-Nle-c[Asp- His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 507); Ac-Nle-c[Asp-His- p(CI)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 508); Ac-Nle-c[Asp-His-p(CI)dPhe- Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 514); Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp- Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 516); Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]- dTle-dPro-NH2 (SEQ ID NO: 517); Ac-Nle-c[Asp-dHis-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro- NH2 (SEQ ID NO: 524); Ac-Nle-c[Asp-Gln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 529); Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 518); Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 502); Ac-Arg- c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 519); Ac-dArg-c[Asp-His- p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 501 ); Ac-Nle-c[Asp-dBip-p(CI)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 528); Ac-Nle-c[Asp-dGln-p(CI)dPhe-Arg-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 530); Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal- dVal-dVal-dPro-NH2 (SEQ ID NO: 512); Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro- dVal-dPro-NH2 (SEQ ID NO: 513); Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle- dVal-NH2 (SEQ ID NO: 51 1 ); Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 515); Ac-dArg-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 329); Ac-Arg-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 330); Ac-dTyr-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 332); Ac-Ala- c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 333); Ac-Nle-c[dPen-Ala- dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 338); Ac-Nle-c[dPen-Leu-dNal(2')- Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 339); Ac-Nle-c[dPen-dLeu-dNal(2')-Arg-Trp- dPen]-dVal-dPro-NH2 (SEQ ID NO: 340); Ac-Nle-c[dPen-dVal-dNal(2')-Arg-Trp-dPen]-dVal- dPro-NH2 (SEQ ID NO: 341 ); Ac-Nle-c[dPen-Gly-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 342); Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 536); Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 498); Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 499); Ac-Nle- c[dCys-His-p(Br)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 537); Ac-Nle-c[Cys- dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[dCys-dNal(2')-Arg-Trp- Cys]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Cys-dNal(2’)-Arg-Trp-dCys]-dVal-dPro- NH2 (SEQ ID NO: 46); Ac-Nle-c[dCys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 47); Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-Nle-c[dCys- dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 57); Ac-Nle-c[Pen-dNal(2’)-Arg-Trp- Cys]-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c[Pen-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2 (SEO ID NO: 60); Ac-Nle-c[dPen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 61 ); Ac-Nle-c[dPen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 62); and Ac-Nle-c[Pen- dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 63).
[0041] In some embodiments, the non-naturally occurring melanocortin analog includes a sequence according to Formula (IB): X1 -X2-X3-R1 -R2-R3-dNal(2')-R5-R6-R7- R8-Y1 -Y2-Y3-Y4-Y5-Y6-Y7 (IB), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cis- 4-guanidinyl-proline (cisPro(guan)), trans-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys) R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-cis-CH=CH-CO, proline (Pro), and tryptophan (Trp); R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, cisPro(guan), transPro(guan), 4- amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo- [1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2H)- one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), and 1 -amino-1 -cyclopentane carboxylic (Cpe); R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), cisPro(guan), and transPro(guan); R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2'), 1 '-D-naphthylalanine (dNal(T)), and 1 '-naphthylalanine (Nal(1 ')); R7 is absent or is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn); R8 is absent or is Lys or dPen; Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp; Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn; Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys; Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp; Y5 is absent or dVal; Y6 is absent or dVal; Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-cis-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is not Ala, Leu, dLeu, dVal, or Gly, and if R3 is absent, then R2 is Pen and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
[0042] In some embodiments, the non-naturally occurring melanocortin analog includes a sequence according to Formula (IB), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg); X2 is absent, phenylalanine (Phe), or Nle; X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cis- 4-guanidinyl-proline (cisPro(guan)), trans-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys) R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-cis-CH=CH-CO, proline (Pro), and tryptophan (Trp); R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, cisPro(guan), transPro(guan), 4- amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo- [1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2H)- one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), and 1 -amino-1 -cyclopentane carboxylic (Cpe); R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), cisPro(guan), and transPro(guan); R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2'), 1 '-D-naphthylalanine (dNal(T)), and 1 '-naphthylalanine (Nal(1 ')); R7 is absent or is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn); R8 is absent or is Lys or dPen; Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp; Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn; Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys; Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp; Y5 is absent or dVal; Y6 is absent or dVal; Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-cis-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that the non-naturally occurring melanocortin analog does not include a sequence selected from the group consisting of: Ac-Nle-c[dPen-Ala-dNal(2')-Arg-Trp-dPen]-dVal- dPro-NH2 (SEQ ID NO: 338); Ac-Nle-c[dPen-Leu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEO ID NO: 339); Ac-Nle-c[dPen-dLeu-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 340); Ac-Nle-c[dPen-dVal-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 341 ); Ac-Nle-c[dPen-Gly-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 342); Ac-Nle- c[Cys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[dCys-dNal(2')-Arg- Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Cys-dNal(2’)-Arg-Trp-dCys]-dVal- dPro-NH2 (SEQ ID NO: 46); Ac-Nle-c[dCys-dNal(2’)-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 47); Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-Nle- c[dCys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 57); Ac-Nle-c[Pen-dNal(2’)-Arg- Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Pen]-dVal-dPro- NH2 (SEQ ID NO: 60); Ac-Nle-c[dPen-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 61 ); Ac-Nle-c[dPen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c[Pen- dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 63); Ac-Nle-c[Asp-His-dNal(2')-Arg- Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 8); and Ac-Nle-c[Asp-Pro-Glu-dNal(2’)-Arg-Trp- Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 258).
[0043] In some embodiments, the non-naturally occurring melanocortin analog includes a sequence according to Formula (IC): X1 -R1 -R2-R3-R4-R5-R6-R7-Y1 -Y2-Y3-Y4 (IC), wherein: X1 is absent or norleucine (Nle) R1 is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys); R2 is aspartic acid (Asp) or cysteine (Cys); R3 is His or proline (Pro); R4 is selected from the group consisting of para-chloro-D-phenylalanine (p(CI)dPhe), para- iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para- trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R5 is Arg or His; R6 is selected from the group consisting of tryptophan (Trp), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3- 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino- 1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), 2'-D-naphthylalanine dNal(2'), and 2'-naphthylalanine (Nal(2')); R7 is Lys or Cys; Y1 is selected from the group consisting of D- valine (dVal), D-proline (dPro), and D-tert-leucine (dTle); Y2 is selected from the group consisting of dVal, dPro, and dTle; Y3 is absent or is dVal or dPro; Y4 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between Cys at R2 and Cys R7; and a lactam bridge between Asp at R2 and Lys at R7; provided that: when R4 is p(CI)dPhe, then R1 is Nle or Ala, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent. [0044] In some embodiments, the non-naturally occurring melanocortin analog includes a sequence according to Formula (IC), wherein: X1 -R1 -R2-R3-R4-R5-R6-R7-Y1 - Y2-Y3-Y4 (IC), wherein: X1 is absent or norleucine (Nle) R1 is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys); R2 is aspartic acid (Asp) or cysteine (Cys); R3 is His or proline (Pro); R4 is selected from the group consisting of para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R5 is Arg or His; R6 is selected from the group consisting of tryptophan (Trp), 4-amino-1 ,2,4,5-tetrahydro-2- benzazepin-3-one (Aba), 3- 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin- 6(5H)-one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), 2'-D- naphthylalanine dNal(2'), and 2'-naphthylalanine (Nal(2')); R7 is Lys or Cys; Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle); Y2 is selected from the group consisting of dVal, dPro, and dTle; Y3 is absent or is dVal or dPro; Y4 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between Cys at R2 and Cys R7; and a lactam bridge between Asp at R2 and Lys at R7; provided that the non- naturally occurring melanocortin analog does not include a sequence selected from the group consisting of: Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 520); Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 522); Ac- dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 523); Ac-dArg-c[Asp- His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 518); Ac-Lys-c[Asp-His- p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 503); Ac-His-c[Asp-His-p(CI)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 505); Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 502); Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro- NH2 (SEQ ID NO: 519); Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 506); Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 501 ); Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 521 ); Ac-dLys- c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 504); Ac-Nle-c[Asp-His- p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 512); Ac-Nle-c[Asp-His- p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 513); Ac-Nle-c[Asp-His- p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 51 1 ); and Ac-Nle-Nle-c[Asp-His- p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 515).
[0045] In some embodiments, the non-naturally occurring melanocortin analog includes a sequence according to Formula (ID): X1 -R1 -R2-R3-R4-R5-R6-R7-Y1 -Y2-Y3-Y4 (ID), wherein: X1 is absent or norleucine (Nle); R1 is absent or is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys) R2 is aspartic acid (Asp) or cysteine (Cys); R3 is selected from the group consisting of His, D-histidine (dHis), proline (Pro), phenylalanine (Phe), tryptophan (Trp), tyrosine (Tyr), glutamine (Gin), and biphenylalanine (Bip); R4 is selected from the group consisting of dPhe, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo- D-phenylalanine (p(Br)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe); R5 is selected from the group consisting of Arg, Lys, and His; R6 is selected from the group consisting of Trp, 2'-D-naphthylalanine (dNal(2')), and 2'-naphthylalanine (Nal(2')); R7 is Lys or Cys; Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle); Y2 is dVal or dPro; Y3 is absent, dVal, or dPro; Y4 is absent or dPro; and the non- naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between Cys at R2 and Cys at R7; and a lactam bridge between Asp at R2 and Lys at R7; provided that: when R4 is p(Br)dPhe and R1 is Nle or Ala, then the C-terminus is not dVal-dPro or dTle-dPro and if the C-terminus is dPro- dVal-dPro, then X1 is present, when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2') or Nal(2'), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; when R4 is dPhe, then R3 is Pro and either R5 is Lys or R6 is dNal(2') or Nal(2'); and when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, and Gin, R6 is Trp, and either X1 and Y3 are both present or X1 and Y3 are both absent.
[0046] In some embodiments, the non-naturally occurring melanocortin analog includes a sequence according to Formula (ID), wherein: R1 is absent or is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys) R2 is aspartic acid (Asp) or cysteine (Cys); R3 is selected from the group consisting of His, D-histidine (dHis), proline (Pro), phenylalanine (Phe), tryptophan (Trp), tyrosine (Tyr), glutamine (Gin), and biphenylalanine (Bip); R4 is selected from the group consisting of dPhe, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe); R5 is selected from the group consisting of Arg, Lys, and His; R6 is selected from the group consisting of Trp, 2'-D-naphthylalanine (dNal(2')), and 2'-naphthylalanine (Nal(2')); R7 is Lys or Cys; Y1 is selected from the group consisting of D-valine (dVal), D- proline (dPro), and D-tert-leucine (dTle); Y2 is dVal or dPro; Y3 is absent, dVal, or dPro; Y4 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between Cys at R2 and Cys at R7; and a lactam bridge between Asp at R2 and Lys at R7; provided that the non-naturally occurring melanocortin analog does not include a sequence selected from the group consisting of: Ac-Nle-c[Asp-Pro-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 217); Ac-Nle-c[Asp-dHis-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 562); Ac-Nle-c[Asp-Phe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 563); Ac-Nle- c[Asp-Bip-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 565); Ac-Nle-c[Asp-Gln- p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 567); Ac-Nle-c[Asp-Trp-p(Br)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 569); Ac-Nle-c[Asp-Tyr-p(Br)dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 571 ); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro- NH2 (SEQ ID NO: 222); Ac-Nle-c[Cys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 535); Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 538); Ac- Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 545); Ac-Nle- c[Asp-His-p(Br)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 546); Ac-Nle-c[Asp-His- p(Br)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 547); Ac-Nle-c[Asp-His- p(Br)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 548); Ac-Nle-c[Asp-His- p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 552); Ac-Nle-Nle-c[Asp-His- p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 553); Ac-Ala-c[Asp-His-p(Br)dPhe- Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 555); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]- dPro-dVal-dPro-NH2 (SEQ ID NO: 551 ); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 223); Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 464); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 465); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 466); Ac-His- c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 467); Ac-dHis-c[Asp-His- p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 468); Ac-Nle-Nle-c[Asp-His-p(F)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 469); Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 470); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal- dVal-dPro-NH2 (SEQ ID NO: 474); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal- dPro-NH2 (SEQ ID NO: 475); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 476); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 477); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 478); Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 481 ); Ac-Lys- c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 482); Ac-dLys-c[Asp-His- p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 483); Ac-His-c[Asp-His-p(F)dPhe-Arg- Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 484); Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]- dTle-dPro-NH2 (SEQ ID NO: 485); Ac-Nle-c[Cys-His-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro- NH2 (SEQ ID NO: 459); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 472); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 471 ); Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 463); Ac-Ala- c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 462); Ac-Ala-c[Asp-His- p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 479); Ac-Nle-c[Asp-His-p(F)dPhe-Arg- Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 473); Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp- Lys]-dTle-dPro-NH2 (SEQ ID NO: 480); Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 486); Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 491 ); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 218); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 442); Ac- Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 449); Ac-Lys-c[Asp- Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 455); Ac-Nle-c[Asp-Pro-p(F)dPhe- Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 447); Ac-Lys-c[Asp-Pro-p(F)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 438); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp- Lys]-dTle-dPro-NH2 (SEQ ID NO: 450); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 435); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 439); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 441 ); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 436); Ac- Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 454); Ac-Ala-c[Asp- Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 452); Ac-Nle-Nle-c[Asp-Pro- p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 451 ); Ac-dLys-c[Asp-Pro- p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 456); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg- Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 437); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 440); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro- NH2 (SEQ ID NO: 448); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 457); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 453); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 458); Ac-Nle- c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 443); Ac-Nle-c[Asp-His- dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 363); Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 365); Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro- NH2 (SEQ ID NO: 370); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 621 ); Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 297); Ac-Nle- c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 366); Ac-Nle-c[Asp-Bip-dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 368); Ac-Nle-c[Asp-Trp-dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 372); Ac-Nle-c[Asp-Tyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 374); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 639); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 638); Ac-Nle- c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 295); Ac-Nle-c[Asp-Pro-dPhe- Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 597); Ac-Nle-Nle-c[Asp-Pro-dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 628); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle- dPro-NH2 (SEQ ID NO: 591 ); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 311 ); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 313); Ac- Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 291 ); Ac-dAla-c[Asp-Pro- dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 299); His-c[Asp-Pro-dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 306); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 312); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 314); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 315); Ac-Lys-c[Asp- Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 643); dHis-c[Asp-Pro-dPhe-Arg-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 309); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal- OH (SEQ ID NO: 617); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 620); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 644); Ac-Arg- c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 642); Ac-Nle-c[Asp-Pro-dPhe- Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 596); Ac-His-c[Asp-Pro-dPhe-Arg-Trp- Lys]-dTle-dPro-NH2 (SEQ ID NO: 645); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro- NH2 (SEQ ID NO: 646); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 300); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 640); Ac-dArg- c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 641 ); Ac-Nle-c[Asp-Pro-dPhe- Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 595); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]- dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 598); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 302); Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 425); Ac-Nle-c[Cys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 318); Ac-Nle- c[Asp-Pro-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 215); Ac-Nle-c[Asp-His- p(CI)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 509); Ac-Nle-c[Asp-His- p(CI)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 510); Ac-Nle-c[Asp-Phe- p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 525); Ac-Nle-c[Asp-Bip-p(CI)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 527); Ac-Nle-c[Asp-Trp-p(CI)dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 531 ); Ac-Nle-c[Asp-Tyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro- NH2 (SEQ ID NO: 533); Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 520); Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 522); Ac- dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 523); Ac-dArg-c[Asp- His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 518); Ac-Lys-c[Asp-His- p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 503); Ac-His-c[Asp-His-p(CI)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 505); Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 502); Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro- NH2 (SEQ ID NO: 519); Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 506); Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 501 ); Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 521 ); Ac-dLys- c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 504); Ac-Nle-c[Asp-His- p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 512); Ac-Nle-c[Asp-His- p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 513); and Ac-Nle-Nle-c[Asp-His- p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 515).
[0047] In some embodiments, an N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an acyl group.
[0048] In some embodiments, the acyl group is an acetyl group.
[0049] In some embodiments, an N-terminus of the non-naturally occurring melanocortin analog, if present, is not modified.
[0050] In some embodiments, a C-terminus of the non-naturally occurring melanocortin analog is modified by an amide group.
[0051] In some embodiments, a C-terminus of the non-naturally occurring melanocortin analog is not modified.
[0052] In some embodiments, R4 is dNal(2').
[0053] In some embodiments, the non-naturally occurring melanocortin analog includes a sequence cyclized.
[0054] In some embodiments, R3 is Pro, Hyp, or His.
[0055] In some embodiments, the sequence of any one of Formulae (l)-( I D) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro (SEQ ID NO: 2); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 3); Ac-Nle- c[Asp-Hyp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 4); Ac-Nle-c[Asp-Pro-His- dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 5); Ac-Nle-c[Asp-Phe-His-dNal(2’)-Arg- Trp-l_ys]-dl_eu-dPro-NH2 (SEQ ID NO: 6); Ac-Nle-c[Asp-Phe-His-dNal(2')-Arg-Trp-Lys]- dTle-dPro-NH2 (SEQ ID NO: 7); Ac-Nle-c[Asp-Hyp-dNal(2')-Arg-Trp-Pro-Lys]-dVal-dPro- NH2 (SEQ ID NO: 9); and Ac-Nle-c[Asp-Pro-His-dNal(2’)-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 10), wherein c represents cyclization through R1 or R2 and R7 via a lactam bond.
[0056] In some embodiments, R9 is present. [0057] In some embodiments, wherein the sequence of any one of Formulae (l)-(ID) is: Ac-Nle-c[Asp-Phe-Phe-Pro-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 11 ), wherein c represents cyclization through R1 and R9 via a lactam bond.
[0058] In some embodiments, R9 is absent and X1 -X3 are present.
[0059] In some embodiments, the sequence of any one of Formulae (l)-(ID) is: Ac-Nle-
Phe-Phe-c[Asp-Phe-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 12), wherein c represents cyclization through R1 and R8 via a lactam bond.
[0060] In some embodiments, the non-naturally occurring melanocortin analog includes a sequence cyclized between R2 and R7 via a lactam bond or a disulfide bond.
[0061] In some embodiments, the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 38); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-dLys]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-Nle-c[Cys-Pro-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 40); Ac-Nle- c[dCys-Pro-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 41 ); Ac-Nle-c[Cys-Pro- dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 42); Ac-Nle-c[dCys-Pro-dNal(2’)-Arg- Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Cys-Pro-dNal(2’)-Arg-Trp-Pen]-dVal- dPro-NH2 (SEQ ID NO: 48); Ac-Nle-c[dCys-Pro-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 49); Ac-Nle-c[Pen-Pro-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 50); Ac-Nle-c[Pen-Pro-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 51 ); Ac-Nle- c[Pen-Pro-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 52); Ac-Nle-c[dPen-Pro- dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 53); Ac-Nle-c[dPen-Pro-dNal(2’)-Arg- Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 54); Ac-Nle-c[Pen-Pro-dNal(2')-Arg-Trp-dPen]- dVal-dPro-NH2 (SEQ ID NO: 55); Ac-Nle-c[Pen-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 59); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 64); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-dOrn]-dVal-dPro-NH2 (SEQ ID NO: 65); Ac-Nle-c[Glu- Pro-dNal(2')-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 66); Ac-Nle-c[Glu-Pro-dNal(2’)-Arg- Trp-dOrn]-dVal-dPro-NH2 (SEQ ID NO: 67); and c[CO-cis-CH = CH-CO-Pro-dNal(2')-Arg- Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 197), wherein c represents cyclization through R1 or R2 and R7 via a lactam bond or a disulfide bond. [0062] In some embodiments, the non-naturally occurring melanocortin analog includes a sequence cyclized through a lactam bond between Asp at R1 or R2 and Lys at R7.
[0063] In some embodiments, R1 is selected from the group consisting of dArg, dMet, dlle, dLeu, dVal, dAla, Ala, Tie, dTle, dNIe, Nva, Gly, dPro, dCys, dPhe, dGIn, dAsn, transPro(guan), cisPro(guan), dTyr, Tyr, and Dmt.
[0064] In some embodiments, the sequence of any one of Formulae (l)-( I D) is selected from the group consisting of: Ac-dArg-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 15); Ac-dMet-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 16); Ac-dlle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 17); Ac-dLeu- c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 18); Ac-dVal-c[Asp-Pro- dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 19); Ac-dAla-c[Asp-Pro-dNal(2’)-Arg- Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 20); Ac-Ala-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 21 ); Ac-Tle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 22); Ac-dTle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 23); Ac- dNle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 24); Ac-Nva-c[Asp-Pro- dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 25); Ac-Gly-c[Asp-Pro-dNal(2’)-Arg-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 26); Ac-dPro-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro- NH2 (SEQ ID NO: 27); Ac-dCys-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 28); Ac-dPhe-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 29); Ac- dTyr-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 30); Ac-dGln-c[Asp-Pro- dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 31 ); Ac-dAsn-c[Asp-Pro-dNal(2’)-Arg- Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 32); Ac-transPro(guan)-c[Asp-Pro-dNal(2')-Arg-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 33); Ac-cisPro(guan)-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 34); dTyr-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 35); Tyr-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 36); and Dmt-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 37), wherein c represents cyclization through R2 and R7 via a lactam bond. [0065] In some embodiments, R3 is absent or selected from the group consisting of Ala, dAla, dMet, Gly, Leu, He, Vai, dLeu, dlle, dVal, Trp, transPro(guan), cisPro(guan), b- Ala, Mamb, Acpc, Aba, Aia, Aic, Ope, Che, Oic, Tic, and Glu.
[0066] In some embodiments, the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 68); Ac-Nle-c[Asp-Ala-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 69); Ac-Nle- c[Asp-dAla-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 71 ); Ac-Nle-c[Asp-dMet- dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Nle-c[Asp-Pro-Gly-dNal(2’)-Arg- Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 73); Ac-Nle-c[Asp-Gly-Gly-dNal(2')-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 74); Ac-Nle-c[Asp-Gly-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 75); Ac-Nle-c[Asp-Leu-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 76); Ac-Nle-c[Asp-lle-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 77); Ac-Nle-c[Asp-Val- dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 78); Ac-Nle-c[Asp-dLeu-dNal(2’)-Arg- Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 79); Ac-Nle-c[Asp-dlle-dNal(2’)-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 80); Ac-Nle-c[Asp-dVal-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 81 ); Ac-Nle-c[Asp-Trp-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 82); Ac- Nle-c[Asp-transPro(guan)-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 84); Ac-Nle- c[Asp-cisPro(guan)-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 85), Ac-Nle-c[Asp- [3-Ala-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 199); Ac-Nle-c[Asp-Mamb- dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 200); Ac-Nle-c[Asp-Acpc-dNal(2') Arg- Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 201 ); Ac-Nle-c[Asp-Aba-dNal(2’)-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 204); Ac-Nle-c[Asp-Aia-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 205); Ac-Nle-c[Asp-Aic-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 239); Ac- Nle-c[Asp-Cpe-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 240); Ac-Nle-c[Asp-Che- dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 241 ); Ac-Nle-c[Asp-Oic-dNal(2')-Arg- Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 242); Ac-Nle-c[Asp-Tic-dNal(2')-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 244); and Ac-Nle-c[Asp-Glu-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 255), wherein c represents cyclization through R1 or R2 and R7 via a lactam bond. [0067] In some embodiments, R5 is absent or selected from the group consisting of Lys, Orn, His, Ala, transPro(guan), cisPro(guan), and Glu.
[0068] In some embodiments, the sequence of any one of Formulae ( l)-( I D) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-dNal(2')-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 86); Ac-Nle-c[Asp-Pro-dNal(2’)-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 87); Ac-Nle- c[Asp-Pro-dNal(2')-Orn-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 90); Ac-Nle-c[Asp-Pro- dNal(2')-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 92); Ac-Nle-c[Asp-Pro-dNal(2')-Ala-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 93); Ac-Nle-c[Asp-Pro-dNal(2')-Glu-Trp-Lys]-dVal-dPro- NH2 (SEQ ID NO: 96); Ac-Nle-c[Asp-His-dNal(2')-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 247); Ac-Nle-c[Asp-His-dNal(2')-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 248); Ac-Nle-c[Asp-Pro-dNal(2’)-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 250); and Ac-Nle-c[Asp-Pro-dNal(2')-cisPro(guan)Pro-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 251 ), wherein c represents cyclization through R2 and R7 via a lactam bond.
[0069] In some embodiments, R6 is selected from the group consisting of Nal(1 '), dNal(1 '), Aia, Phe, dPhe, Tyr, dTyr, dNal(2'), dTrp, Aba, and Ata.
[0070] In some embodiments, the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Nal(1 ')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 102); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Aia-Lys]-dVal-dPro-NH2 (SEQ ID NO: 103); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Phe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 104); Ac-Nle- c[Asp-Pro-dNal(2')-Arg-Tyr-Lys]-dVal-dPro-NH2 (SEQ ID NO: 105); Ac-Nle-c[Asp-Pro- dNal(2')-Arg-dNal(1 ')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 108); Ac-Nle-c[Asp-Pro-dNal(2')- Arg-dPhe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 109); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-dNal(2']- Lys]-dVal-dPro-NH2 (SEQ ID NO: 1 10); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dTyr-Lys]-dVal- dPro-NH2 (SEQ ID NO: 111 ); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-dTrp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 196); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Aba-Lys]-dVal-dPro-NH2 (SEQ ID NO: 253); and Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Ata-Lys]-dVal-dPro-NH2 (SEQ ID NO: 254), wherein c represents cyclization through R2 and R7 via a lactam bond.
[0071] In some embodiments, (i) Y1 is selected from dPro, Vai, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, Lys, dLys, Trp, and dTle and Y2 is absent or selected from dVal, Vai, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, and dTle; or (ii) Y1 is dVal, Y2 is dPro, and the C-terminus of the non-naturally occurring melanocortin analog is not modified.
[0072] In some embodiments, the sequence of any one of Formulae ( l)-( I D) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-Val-Pro-NH2 (SEQ ID NO: 1 15); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 116); Ac- Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 117); Ac-Nle-c[Asp-Pro- dNal(2')-Arg-Trp-Lys]-dVal-Hyp-NH2 (SEQ ID NO: 118); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg- Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 119); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Val- Hyp-NH2 (SEQ ID NO: 120); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-Val-dHyp-NH2 (SEQ ID NO: 121 ); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-Hyp-dVal-NH2 (SEQ ID NO: 122); Ac- Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dHyp-dVal-NH2 (SEQ ID NO: 123); Ac-Nle-c[Asp-Pro- dNal(2')-Arg-Trp-Lys]-Hyp-Val-NH2 (SEQ ID NO: 124); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp- Lys]-dHyp-Val-NH2 (SEQ ID NO: 125); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dVal- NH2 (SEQ ID NO: 126); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-dPro-NH2 (SEQ ID NO: 127); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-NH2 (SEQ ID NO: 128); Ac-Nle- c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-NH2 (SEQ ID NO: 129); Ac-Nle-c[Asp-Pro-dNal(2’)- Arg-Trp-Lys]-Val-NH2 (SEQ ID NO: 130); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Pro-NH2 (SEQ ID NO: 131 ); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Ala-NH2 (SEQ ID NO: 132); Ac- Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dAla-NH2 (SEQ ID NO: 133); Ac-Nle-c[Asp-Pro- dNal(2')-Arg-Trp-Lys]-dHyp-NH2 (SEQ ID NO: 134); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp- Lys]-Hyp-NH2 (SEQ ID NO: 135); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAla-dAla-NH2 (SEQ ID NO: 136); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Ala-Ala-NH2 (SEQ ID NO: 137); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-Gly-Gly-NH2 (SEQ ID NO: 138); Ac-Nle-c[Asp-Pro- dNal(2')-Arg-Trp-Lys]-dVal-Asp-NH2 (SEQ ID NO: 139); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg- Trp-Lys]-dVal-Arg-NH2 (SEQ ID NO: 140); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal- Asn-NH2 (SEQ ID NO: 141 ); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dAsp-NH2 (SEQ ID NO: 142); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dArg-NH2 (SEQ ID NO: 143); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dAsn-NH2 (SEQ ID NO: 144); Ac-Nle-c[Asp- Pro-dNal(2')-Arg-Trp-Lys]-Asp-dPro-NH2 (SEQ ID NO: 145); Ac-Nle-c[Asp-Pro-dNal(2’)- Arg-Trp-Lys]-Arg-dPro-NH2 (SEQ ID NO: 146); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]- Asn-dPro-NH2 (SEQ ID NO: 147); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dAsp-dPro-NH2 (SEQ ID NO: 148); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 149); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dAsn-dPro-NH2 (SEQ ID NO: 150); Ac-Nle- c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-Asp-NH2 (SEQ ID NO: 151 ); Ac-Nle-c[Asp-Pro-dNal(2')- Arg-Trp-Lys]-Arg-NH2 (SEQ ID NO: 152); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Asn-NH2 (SEQ ID NO: 153); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dAsp-NH2 (SEQ ID NO: 154); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-NH2 (SEQ ID NO: 155); Ac-Nle-c[Asp-Pro- dNal(2')-Arg-Trp-Lys]-dAsn-NH2 (SEQ ID NO: 156); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp- Lys]-Lys-Pro-Val-NH2 (SEQ ID NO: 157); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-Lys- dPro-dVal-NH2 (SEQ ID NO: 158); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dLys-dPro- dVal-NH2 (SEQ ID NO: 159); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-dPro-NH2 (SEQ ID NO: 160); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dLys-dPro-NH2 (SEQ ID NO: 161 ); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-Lys-Val-Pro-NH2 (SEQ ID NO: 162); Ac-Nle-c[Asp- Pro-dNal(2')-Arg-Trp-Lys]-Lys-dVal-dPro-NH2 (SEQ ID NO: 163); Ac-Nle-c[Asp-Pro- dNal(2')-Arg-Trp-Lys]-dLys-dVal-dPro-NH2 (SEQ ID NO: 164); Ac-Nle-c[Asp-Pro-dNal(2')- Arg-Trp-Lys]-Arg-Pro-Val-NH2 (SEQ ID NO: 165); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]- Arg-dPro-dVal-NH2 (SEQ ID NO: 166); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-dPro- dVal-NH2 (SEQ ID NO: 167); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-Arg-Val-Pro-NH2 (SEQ ID NO: 168); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-Arg-dVal-dPro-NH2 (SEQ ID NO: 169); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 170); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dVal-dPro-NH2 (SEQ ID NO: 171 ); Ac-Nle- c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 172); Ac-Nle-c[Asp-Pro- dNal(2')-Arg-Trp-Lys]-dTle-dVal-NH2 (SEQ ID NO: 173); Ac-Nle-c[Asp-Pro-dNal(2')-Arg- Trp-Lys]-dTle-dTle-NH2 (SEQ ID NO: 174); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle- dTle-dPro-NH2 (SEQ ID NO: 175); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dTle-dVal- NH2 (SEQ ID NO: 176); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dTle-NH2 (SEQ ID NO: 177); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 178); Ac- Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-Trp-NH2 (SEQ ID NO: 203); and Ac-Nle-c[Asp-Pro- dNal(2')-Arg-Trp-Lys]-dPro-dPro-dLys-dAsp-NH2 (SEQ ID NO: 263), wherein c represents cyclization through R2 and R7 via a lactam bond.
[0073] In some embodiments, one or more of Y3-Y7 are present and are each independently dVal or dPro. [0074] In some embodiments, the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 179); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 180); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 181 ); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 182); and Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dVal-dVal-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 183), wherein c represents cyclization through R2 and R7 via a lactam bond.
[0075] In some embodiments, one or more of X1 -X3 are present and are Nle.
[0076] In some embodiments, the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 184); Ac-Nle-Nle-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 185); and Ac-Nle-Nle-Nle-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 186), wherein c represents cyclization through R2 and R7 via a lactam bond.
[0077] In some embodiments, the non-naturally occurring melanocortin analog includes a sequence cyclized through a lactam bond between (i) Asp at R1 and Lys at R7, (ii) Asp at R2 and Lys at R8, or (ii) Asp at R1 and Lys at R8.
[0078] In some embodiments, R2 is selected from Asp, Trp, Pro, and Glu, R3 is selected from Pro, Glu, and His, and R7 is selected from Lys, Pro, and Gly.
[0079] In some embodiments, the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 194); Ac-Nle-c[Asp-Trp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 195); Ac-Nle-c[Asp-Pro-Glu-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 257); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 245); Ac-Nle- c[Asp-Glu-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 256); Ac-Nle-c[Asp-Pro- dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 259); Ac-Nle-c[Asp-Pro-dNal(2')- Arg-Trp-Gly-Lys]-dPro-dPro-Lys-Asp-NH2 (SEQ ID NO: 260); Ac-Nle-c[Asp-Pro-dNal(2')- Arg-Trp-Gly-Lys]-dPro-dPro-dLys-dAsp-NH2 (SEQ ID NO: 261 ); Ac-Glu-c[Asp-Pro-dNal(2')- Arg-Trp-Gly-Lys]-dPro-dPro-Lys-Asp-NH2 (SEQ ID NO: 262); Ac-Nle-c[Asp-Glu-His- dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 264); and Ac-Nle-c[Asp-Glu-His- dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 265), wherein c represents cyclization through R1 or R2 and R7 or R8 via a lactam bond.
[0080] In some embodiments, one of R2 and R3 is Ala or dAla.
[0081] In some embodiments, the sequence of any one of Formulae (l)-( I D) is selected from the group consisting of: Ac-Nle-c[Asp-dAla-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 266); Ac-Arg-c[Asp-dAla-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 267); Ac-Arg-c[Cys-dAla-His-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 269); Ac-dArg-c[Asp-dAla-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 270); Ac-Arg- c[Asp-dAla-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 271 ); Ac-dArg-c[Asp-dAla- dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 272); Ac-Nle-c[Asp-Ala-His-dNal(2')- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 273); Ac-Arg-c[Asp-Ala-His-dNal(2’)-Arg-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 274); Ac-dArg-c[Asp-Ala-His-dNal(2’)-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 275); Ac-Arg-c[Cys-dAla-His-dNal(2')-Arg-Trp-Cys]-NH2 (SEQ ID NO: 282); and Ac-Arg-c[Asp-dAla-His-dNal(2’)-Arg-Trp-Lys]-NH2 (SEQ ID NO: 283), wherein c represents cyclization through R1 or R2 and R7 via a lactam bond or a disulfide bond.
[0082] In some embodiments, the non-naturally occurring melanocortin analog includes a sequence cyclized through a disulfide bond between dPen at R2 and dPen at R7 or R8.
[0083] In some embodiments, R1 is selected from the group consisting of Nle, dLeu, dNIe, dArg, Arg, dPhe, dTyr, Ala, dHis, His, dLys, and Lys.
[0084] In some embodiments, the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-dl_eu-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 327); Ac-dNle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 328); Ac-dArg-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 329); Ac-Arg-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 330); Ac-dPhe- c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 331 ); Ac-dTyr-c[dPen- Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 332); Ac-Ala-c[dPen-Pro-dNal(2')- Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 333); Ac-dHis-c[dPen-Pro-dNal(2')-Arg-Trp- dPen]-dVal-dPro-NH2 (SEQ ID NO: 334); Ac-His-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal- dPro-NH2 (SEQ ID NO: 335); Ac-dLys-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 336); Ac-Lys-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 337); Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dArg-dVal-dPro-NH2 (SEQ ID NO: 344); Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dLys-dVal-dPro-NH2 (SEQ ID NO: 345); Ac- Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dArg-dPro-NH2 (SEQ ID NO: 346); Ac-Nle-c[dPen- Pro-dNal(2')-Arg-Trp-dPen]-dLys-dPro-NH2 (SEQ ID NO: 347); Ac-Nle-c[dPen-Pro- dNal(2')-Arg-Trp-dPen]-dVal-dHyp-NH2 (SEQ ID NO: 348); Ac-Nle-c[dPen-Pro-dNal(2')- Arg-Trp-dPen]-dTle-dPro-NH2 (SEQ ID NO: 349); and Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp- Gly-dPen]-dVal-dPro-NH2 (SEQ ID NO: 350), wherein c represents cyclization through R1 or R2 and R7 or R8 via a disulfide bond.
[0085] In some embodiments, the non-naturally occurring melanocortin analog is linear.
[0086] In some embodiments, the sequence of any one of Formulae (l)-(ID) is: Ac-Nle- Asp-Pro-dNal(2')-Arg-Trp-Lys-dVal-dPro-NH2 (SEQ ID NO: 13); or Ac-Nle-Pro-dNal(2')-Arg- Trp-dVal-dPro-NH2 (SEQ ID NO: 14).
[0087] In some embodiments, R4 is selected from the group consisting of dPhe, p(CI)dPhe p(l)dPhe, p(Br)dPhe, p(F)dPhe, or p(CF3)dPhe.
[0088] In some embodiments, the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 215); Ac-Nle-c[Asp-Pro-p(l)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 216); Ac-Nle-c[Asp-Pro-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 217); Ac-Nle- c[Asp-Pro-p(CF3)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 219); Ac-Nle-c[Asp-His- p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 220); Ac-Nle-c[Asp-His-p(l)dPhe-Arg- Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 221 ); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 222); Ac-Nle-c[Asp-His-p(CF3)dPhe-Arg-Trp-Lys]-dVal-dPro- NH2 (SEQ ID NO: 224); Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Aia-Lys]-dVal-dPro-NH2 (SEQ ID NO: 236); Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Aba-Lys]-dVal-dPro-NH2 (SEQ ID NO: 237); Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Ata-Lys]-dVal-dPro-NH2 (SEQ ID NO: 238); Ac- Nle-c[Asp-dBip-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 369); Ac-Nle-c[Asp-Pro- dPhe-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 426); Ac-Nle-c[Asp-Pro-dPhe-Arg- dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 430); Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(2')-Lys]- dVal-dPro-NH2 (SEQ ID NO: 431 ); Ac-Nle-c[Cys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro- NH2 (SEQ ID NO: 432); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2’)-Lys]-dVal-dPro-NH2 (SEQ ID NO: 444); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 445); Ac-Nle-c[Asp-Phe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 487); Ac- Nle-c[Asp-Bip-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 489); Ac-Nle-c[Asp-Trp- p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 493); Ac-Nle-c[Asp-Tyr-p(F)dPhe-Arg- Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 495); Ac-Nle-c[Cys-His-p(CI)dPhe-Arg-Trp-Cys]- dVal-dPro-NH2 (SEQ ID NO: 497); Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro- NH2 (SEQ ID NO: 500); Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 507); Ac-Nle-c[Asp-His-p(CI)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 508); Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 509); Ac- Nle-c[Asp-His-p(CI)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 510); Ac-Nle-c[Asp- His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 514); Ac-Nle-Nle-c[Asp-His- p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 516); Ac-Ala-c[Asp-His- p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 517); Ac-Nle-c[Asp-dHis-p(CI)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 524); Ac-Nle-c[Asp-Phe-p(CI)dPhe-Arg-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 525); Ac-Nle-c[Asp-dPhe-p(CI)dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 526); Ac-Nle-c[Asp-Bip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 527); Ac-Nle-c[Asp-Gln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 529); Ac-Nle-c[Asp-Trp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 531 ); Ac-Nle- c[Asp-Tyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 533); Ac-Nle-c[Asp-dTyr- p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 534); Ac-Nle-c[Cys-His-p(Br)dPhe- Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 535); Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 538); Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro- NH2 (SEQ ID NO: 539); Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 540); Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 541 ); Ac- dLys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 542); Ac-His-c[Asp- His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 543); Ac-dHis-c[Asp-His- p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 544); Ac-Nle-Nle-c[Asp-His- p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 545); Ac-Nle-c[Asp-His-p(Br)dPhe- His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 546); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-dNal(2')- Lys]-dVal-dPro-NH2 (SEQ ID NO: 547); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Nal(2’)-Lys]-dVal- dPro-NH2 (SEQ ID NO: 548); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal- NH2 (SEQ ID NO: 549); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro- NH2 (SEQ ID NO: 550); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 551 ); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 552); Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 553); Ac- Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 554); Ac-Ala- c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 555); Ac-dArg-c[Asp-His- p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 556); Ac-Arg-c[Asp-His-p(Br)dPhe- Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 557); Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]- dTle-dPro-NH2 (SEQ ID NO: 558); Ac-dLys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro- NH2 (SEQ ID NO: 559); Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 560); Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 561 ); Ac-Nle-c[Asp-dHis-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 562); Ac-Nle- c[Asp-Phe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 563); Ac-Nle-c[Asp-dPhe- p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 564); Ac-Nle-c[Asp-Bip-p(Br)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 565); Ac-Nle-c[Asp-dBip-p(Br)dPhe-Arg-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 566); Ac-Nle-c[Asp-Gln-p(Br)dPhe-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 567); Ac-Nle-c[Asp-dGln-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 568); Ac-Nle-c[Asp-Trp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 569); Ac-Nle-c[Asp-dTrp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 570); Ac- Nle-c[Asp-Tyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 571 ); and Ac-Nle- c[Asp-dTyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 572), wherein c represents cyclization through R2 and R7 via a lactam bond or a disulfide bond.
[0089] In some embodiments, the non-naturally occurring melanocortin analog includes any one of the sequences of SEQ ID NOs: 2-7, 9-12, 13-23, 24-27, 28-30, 31 -43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-1 11 , 1 15-122, 123-138, 139-157, 158-164, 165-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219- 222, 224, 236-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327- 337, 344-350, 369, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-510, 514, 516-517, 524-527, 529, 531 , 533-535, and 538-572.
[0090] In some embodiments, the non-naturally occurring melanocortin analog includes any one of the sequences of SEQ ID NOs: 2-7, 9-10, 12-23, 24-27, 28-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-11 1 , 115-138, 139-157, 158- 162, 164-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219, 221 -222, 224, 236-242, 244-245, 247-248, 250-257, 259-267, 269-275, 282-283, 327-337, 344-350, 509- 510, 525-527, 531 , 533-535, 538, 545-549, 551 -553, 555, 562-569, 571 -572.
[0091] In some embodiments, the non-naturally occurring melanocortin analog includes any one of the sequences of SEQ ID NOs: 2-4, 13, 15-23, 24-32, 35-43, 48-55, 59, 64-69, 71 -76, 77-82, 86-87, 90, 92-93, 96, 102, 104-105, 108-111 , 1 15-138, 139-162, 164, 165-186, 195-197, 199-201 , 203, 215-217, 219, 221 -222, 224, 240-242, 244, 255-256, 259- 267, 269-275, 327-328, 331 , 344-350, 525-527, 531 , 533-535, 538, 545, 547-549, 551 -553, 555, 562-569, 571 -572.
[0092] In some embodiments, the non-naturally occurring melanocortin analog includes any one of the sequences of SEQ ID NOs: 2-7, 9-10, 12-43, 48-55, 59, 64-69, 71 - 76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-111 , 115-138, 139-162, 164, 165-186, 194- 197, 199-201 , 203-206, 239-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, 344-350.
[0093] In some embodiments, the non-naturally occurring melanocortin analog includes any one of the sequences of SEQ ID NOs: 215-217, 219-222, 224, 236-238, 497, 500, 507-510, 514, 516-517, 535, 538-561 .
[0094] In some embodiments, the non-naturally occurring melanocortin analog includes any one of the sequences of SEQ ID NOs: 220, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-508, 514, 516-517, 524, 529, 539-544, 550, 554, 556-561.
[0095] In some embodiments, the non-naturally occurring melanocortin analog includes a sequence of SEQ ID NO: 3.
[0096] In some embodiments, the non-naturally occurring melanocortin analog is present in a pharmaceutical composition. [0097] In some embodiments, the pharmaceutical composition includes one or more pharmaceutically acceptable excipients and/or carriers.
[0098] In some embodiments, the one or more pharmaceutically acceptable excipients and/or carriers of the pharmaceutical composition include water.
[0099] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg/kg to about 20 mg/kg administered once a day for about 5 days to about 10 days; (ii) at a second dose of about 10 mg/kg to about 40 mg/kg administered once a day after administration of the first dose for about 5 days to about 10 days; (iii) at a third dose of about 5 mg/kg to about 30 mg/kg administered twice a day after administration of the second dose for at least about 5 days to about 10 days.
[0100] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg/kg administered once a day for about 7 days; (ii) at a second dose of about 15 mg/kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 10 mg/kg administered twice a day after administration of the second dose for at least about 7 days.
[0101] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 10 mg/kg administered once a day for about 7 days; (ii) at a second dose of about 20 mg/kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 15 mg/kg administered twice a day after administration of the second dose for at least about 7 days.
[0102] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 15 mg/kg administered once a day for about 7 days; (ii) at a second dose of about 25 mg/kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 20 mg/kg administered twice a day after administration of the second dose for at least about 7 days.
[0103] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 0.5 mg/kg to about 10 mg/kg per body weight of the subject once daily. [0104] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 1 mg/kg or 3 mg/kg per body weight of the subject once daily.
[0105] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily.
[0106] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily.
[0107] In some embodiments, the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.
[0108] In some embodiments, the non-naturally occurring melanocortin analog crosses a blood-brain-barrier of a subject.
[0109] In some embodiments, the non-naturally occurring melanocortin analog includes a sequence of SEQ ID NO: 3 and is administered at least once daily in an amount ranging from 0.001 mg/kg to 25 mg/kg per body weight of the subject.
[0110] In some embodiments, the non-naturally occurring melanocortin analog includes a sequence of SEQ ID NOs: 3 and is administered at least once daily in an amount ranging from 0.5 mg/kg to 10 mg/kg per body weight of the subject.
[0111] In some embodiments, the non-naturally occurring melanocortin analog is administered to a subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.
[0112] In some embodiments, the non-naturally occurring melanocortin analog is administered to a subject for 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 1 10 days, or 120 days.
[0113] In some embodiments, the method or the use further includes maintaining muscle mass or promoting muscle mass gain in the subject. DETAILED DESCRIPTION
[0114] The present technology comprises non-naturally occurring melanocortin analogs, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, collectively referred to herein as melanocortin analogs, for modulating weight in subjects in need thereof. In some embodiments, the non-naturally occurring melanocortin analog is a non-naturally occurring melanocortin analog. The non-naturally occurring melanocortin analogs may be useful in treating, preventing, or reducing one or more symptoms or conditions associated with weight loss. For example, the non-naturally occurring melanocortin analogs may be used to treat, prevent, or otherwise ameliorate one or more of anorexia, cachexia, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite. Cachexia may include cancer-induced cachexia or drug-induced cachexia.
[0115] In some embodiments, the present technology comprises methods of treating, preventing, reducing, or otherwise ameliorating one or more symptoms or conditions associated with metabolic dysfunction in a subject in need thereof. The methods comprise administering a non-naturally occurring melanocortin analog of the present technology to the subject. In some embodiments, the method comprises increasing a level of, reducing a loss of, or maintaining an appetite, a weight, a body mass index (BMI) measurement, a fat mass, or a cardiac mass in the subject.
[0116] The present technology comprises methods of treating, preventing, or reducing one or more symptoms or conditions associated with weight loss in a subject in need thereof using a non-naturally occurring melanocortin receptor antagonist. In some embodiments, the method comprises preventing or reducing loss of lean mass (e.g., muscle, organ, and bone mass) in a subject using a non-naturally occurring melanocortin analog. In some embodiments, the method comprises preventing or reducing loss of lean mass in a subject using a non-naturally occurring melanocortin analog. In some embodiments, the method comprises promoting weight loss in a subject, comprising administering a weight loss agent and a non-naturally occurring melanocortin analog to the subject, wherein the subject’s weight is decreased by loss of fat mass while maintaining or increasing muscle mass. In some embodiments, the non-naturally occurring melanocortin analogs may prevent or reduce the loss of lean mass, e.g., muscle and bone mass, associated with weight loss. [0117] The following description is merely exemplary in nature and is not intended to limit the present technology, its applications, or its uses. It should be understood that throughout the drawings, corresponding reference numerals indicate like or corresponding parts and features. The description of specific examples indicated in various embodiments of the present technology are intended for purposes of illustration only and are not intended to limit the scope of the present technology disclosed herein. Moreover, recitation of multiple embodiments having stated features is not intended to exclude other embodiments having additional features or other embodiments incorporating different combinations of the stated features.
[0118] Furthermore, the detailed description herein is presented for purposes of illustration only and not of limitation. For example, steps recited in any method or process may be executed in any order and are not limited to the order presented. Moreover, any of the steps thereof may be outsourced to or performed by one or more third parties.
Definitions
[0119] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present technology belongs. For the purposes of the present technology, the following terms are defined below.
[0120] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Likewise, any reference to singular includes plural embodiments, and any reference to more than one component may include a singular embodiment.
[0121] The term “about” means a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by acceptable levels in the art. Typically, such variation may be as much 10% above and below a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length and such variation may be influenced by standard applicable measurement practices. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth.
[0122] The terms “administering” or “administer” include delivery of therapies (e.g., non-naturally occurring melanocortin analogs (also referred to herein as peptides)) of the present technology to a subject either by local or systemic administration. Administration may be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer), intratracheal, intranasal, epidermal and transdermal, oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
[0123] The terms “active ingredient” and “active compound” refer to a biologically active substance, whether naturally or non-naturally occurring, that is the main component of the pharmaceutical composition which elicits the intended effect of an administered therapeutic. This may be any component that drives the pharmacological activity or direct effect in the diagnosis, cure, mitigation, treatment, or prevention of the conditions associated with the present technology, such as but not limited to, reduced appetite and weight loss.
[0124] As used herein, a “composition” or a “pharmaceutical composition” refers to a mixture of the active ingredient with other chemical components, such as pharmaceutically acceptable carriers and/or excipients.
[0125] As used herein, a “pharmaceutically acceptable carrier” of the first or the second pharmaceutical composition refers to a carrier or diluent that does not cause significant irritation to an organism, does not abrogate the biological activity and properties of the administered active ingredient, and/or does not interact in a deleterious manner with the other components of the composition in which it is contained. The term “carrier” encompasses any excipient, binder, diluent, filler, salt, buffer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations. The choice of a carrier for use in a composition will depend upon the intended route of administration for the composition. The preparation of pharmaceutically acceptable carriers and formulations containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 21 st Edition, ed. University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia Pa., 2005, which is incorporated herein by reference in its entirety). Some examples of physiologically acceptable carriers include antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEN® (ICI, Inc.; Bridgewater, N.J.), polyethylene glycol (PEG), and PLURONICS™ (BASF; Florham Park, N.J.). An “excipient” of the first or the second pharmaceutical composition refers to an inert substance added to a composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
[0126] The terms “treat,” “treatment,” and “treating” refer to a manner of providing a pharmaceutical composition and/or melanocortin analog to alleviate disease outcomes. This includes utilizing administration techniques as described in the context of the present technology. Efficacy of treatment may be determined by various assessment methods as described in the context of the present technology (e.g., assessment of appetite, food consumption, body weight, muscle mass, fat mass, and measurement of biomarkers). The term “biomarker” refers to a biological output that is used as a measure of cellular response, whether that be to assess response to therapeutics, disease status, such as cachexia, or as a predictor of clinical outcomes. Biomarkers evaluated in the context of cells, tissue, or whole organisms. The term “disease” herein refers to any disorder adversely affecting biological status. This includes weight-related disorders, such as cachexia. Disease also may be in the context of human and animal health.
[0127] The terms “treat,” “treatment,” and “treating” may also refer to the reduction or inhibition of the progression and/or duration of a disease or disorder (e.g., metabolic disease, including, but not limited to, cachexia), the reduction or amelioration of the severity of the disease or disorder, and/or the amelioration of one or more symptoms thereof resulting from the administration of one or more therapies. Specifically, these terms may refer to: (1 ) a stabilization, reduction, or elimination of the disease or disorder, (2) inhibiting exacerbation of the disease or disorder, (3) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with a pathology related to or caused in part by unregulated or aberrant metabolism, (4) an increase in disease-free, relapse-free, progression-free, and/or overall survival, duration, or rate, (5) a decrease in hospitalization rate, and (6) a decrease in hospitalization length. The terms “treat,” “treatment,” and “treating” include prophylactic and/or therapeutic treatments. If it is administered prior to clinical manifestation of a condition, the treatment is considered prophylactic. Therapeutic treatment includes, e.g., ameliorating or reducing the severity of a disease or disorder, or shortening the length or frequency of the disease or disorder.
[0128] As used herein, the terms “effective amount” or “therapeutically effective amount,” refer to that amount of the active ingredient being administered which will relieve to some extent one or more of the symptoms of the disease or disorder being treated. The result may be a reduction and/or alleviation of the signs, symptoms, or causes of a disease or disorder, or any other desired alteration of a biological system. An appropriate “effective amount” may differ from one individual to another. An appropriate “effective amount” in any individual case may be determined using techniques, such as a dose escalation study.
[0129] The term “after administration” refers to any duration of time after the non- naturally occurring melanocortin analog or pharmaceutical composition thereof has been administered to a subject. “After administration” may also refer to the duration of time after one dose has been completed or after more than one dose has been completed, such as two doses, three doses, four doses, and the like. In some embodiments, “after administration” refers to completion of dosing regimen that includes one or more doses. Likewise, the term “prior to” refers to any duration of time before the non-naturally occurring melanocortin analog or pharmaceutical composition thereof has been administered to a subject. Unless otherwise specified, durations of time encompassed by “after administration” or “prior to administration” may include seconds, minutes, hours, days, weeks, months, and years.
[0130] "Appetite" in a subject and/or patient is typically assessed by their desire to eat and/or the amount of food they consume. As used herein, appetite may be assessed through a daily questionnaire given at specified or random times of the day. In the questionnaire, subjects or patients rate their hunger and/or desire to eat greater varieties of food using scales ranging from 0 (not at all) to 100 (extremely).
[0131] “Cachexia” refers to a state of general ill health and malnutrition characterized by loss of body mass including loss of weight, loss of muscle mass (skeletal, smooth, and/or cardiac muscle), loss of fat mass, or a combination thereof, and wasting. It is often associated with and induced by certain diseases or conditions such as, but not limited to, cancer, cystic fibrosis, or AIDS. The term “cancer cachexia” refers to cachexia induced by cancer. Diagnostic criterion for cachexia may include (i) weight loss of greater than 5% over past 6 months; (ii) weight loss of greater than 2% in patients with a body mass index (BMI) less than 20 kg/m2; or (iii) weight loss of greater than 2% in patients with sarcopenia (or appendicular skeletal muscle index consistent with sarcopenia). See Fearon K, et al., Lancet Oncol. 12(5):489-95 (2011 ). Cachexia may be used interchangeably with the term “Protein- Energy Wasting” (i.e., PEW).
[0132] “Anorexia” refers to a loss of appetite, whether brought on by medical, physiological, or psychological factors. Anorexia is often closely associated with, and generally contributes to, cachexia seen in patients with advanced cancers and other conditions.
[0133] The term “Body Mass Index” or “BMI” refers to a value derived from an individual’s body weight and height. Specifically, BMI is determined by body weight (kilograms) divided by the square of height (m2) and is expressed in units of “kg/m2.” "Normal" BMI ranges are known to a person of ordinary skill in the art and consider factors such as patient sex, age, height, race, and body type. Typically, a normal BMI range is about 18.5 kg/m2 to about 25 kg/m2.
[0134] The terms “subject” and “patient” refer to anyone being evaluated for disease, disorder, or condition or being administered a therapeutic or pharmaceutical composition. This includes people without diagnosed or confirmed disease or condition. This also includes people with diagnosed or confirmed disease or condition, such as cancer, loss of appetite, nausea, emesis, anorexia, or cachexia. [0135] The term “control subject,” as used herein, refers to any subject used as a basis for comparison to the subject (e.g., test subject). A control subject includes, but is not limited to, any subject who has not been administered the therapeutic or pharmaceutical composition (e.g., the non-naturally occurring melanocortin analog, a therapeutically effective amount of the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof) or administered a placebo.
[0136] “Melanocortin analogs,” “non-naturally occurring melanocortin analogs,” “melanocortin peptides,” “melanocortin receptor peptides,” or “melanocortins,” are used interchangeably and refer to melanocortin-receptor ligands, which are macromolecules containing at least one melanocortin pharmacophore. Melanocortin analogs are typically peptides that bind melanocortin receptors under physiological conditions. Melanocortin analogs include naturally occurring non-naturally occurring melanocortin analogs (i.e., “synthetic peptides” or “synthetic analogs”) and truncated and/or modified versions of melanocortin full-length protein or peptides. For example, the full-length proopiomelanocortin protein (POMC), prior to proteolytic cleavage of “sub-peptides,” consists of 241 amino acids. Tissue-specific proteolytic cleavage of POMC yields peptides ranging in size from 13 amino acids to 76 amino acids. See Bicknell and Lawry, Encyclopedia of Stress, vol. 3, 257-265, Academic Press (2000). Synthesized, non-naturally occurring melanocortin analogs having increased melanocortin receptor activity as discussed herein are approximately 7-12 amino acids in size. Melanocortin analogs exhibit binding functionality with melanocortin receptors. The binding to the melanocortin receptor is inhibitory (antagonist). In addition to peptides, the non-naturally occurring melanocortin analogs include small molecule analogs of melanocortin or portions thereof comprised of organic compounds, inorganic compounds, or combinations of peptide and small molecule — i.e., peptide mimetics, or various combinations thereof. “Non-naturally occurring melanocortin analogs” may be structurally similar and/or functionally similar to biological melanocortin proteins in their ability to bind melanocortin receptors. Further, the melanocortin analogs generally contain the pharmacophore: His-Phe-Arg-Trp (SEQ ID NO: 1 ) or a modified version thereof, or a structural or functional peptide mimetic thereof. [0137] A “pharmacophore” is the minimum set of amino acid residues necessary to achieve a physiological effect; or a small molecule that is (with respect to a receptor) a structural mimic of the amino acid residues required for binding to and activation of a receptor. His-Phe-Arg-Trp (SEQ ID NO: 1 ) and their analogs are the pharmacophore of melanocortin for the regulated physiological effect. Therefore, non-naturally occurring melanocortin pharmacophore analogs may be small peptides or organic molecules designed to mimic the appearance or function (including activation or deactivation of receptor activity) of the melanocortin pharmacophore core sequence peptide.
[0138] A melanocortin receptor “agonist” is a naturally occurring substance or manufactured drug substance or composition that may interact with a melanocortin receptor and initiate a pharmacological response characteristic of the melanocortin receptor.
[0139] A melanocortin receptor “antagonist” is a naturally occurring substance or manufactured drug substance or composition that opposes the melanocortin receptor- associated responses normally induced by a melanocortin receptor agonist agent.
[0140] “Potentiated therapeutic activity” refers to an increase in melanocortin activity in a non-naturally occurring melanocortin analog that has undergone derivatization at the N- and/or C-terminus. Such derivatizations do not necessarily involve the pharmacophore, but do imply a relative increase in in vivo biological half-life.
[0141] The terms “bind,” “binding,” “complex,” and “complexing,” refer to all types of physical and chemical binding, reactions, complexing, attraction, chelating and the like.
[0142] The “peptides” of the present technology may be (a) naturally-occurring, (b) produced by chemical synthesis, (c) produced by recombinant DNA technology, (d) produced by biochemical or enzymatic fragmentation of larger molecules, (e) produced by methods resulting from a combination of methods (a) through (d) listed above, or (f) produced by any other means for producing peptides.
[0143] The term “peptide” as used herein includes any structure comprised of two or more amino acids, including chemical modifications and derivatives of amino acids. The amino acids forming all or a part of a peptide may be naturally occurring amino acids, stereoisomers and modifications of such amino acids, non-protein amino acids, post- translationally modified amino acids, enzymatically modified amino acids, constructs or structures designed to mimic amino acids, and the like, so that the term “peptide” includes pseudopeptides and peptidomimetics, including structures which have a non-peptidic backbone. The term “peptide” also includes dimers or multimers of peptides. A “manufactured” peptide includes a peptide produced by chemical synthesis, recombinant DNA technology, biochemical, or enzymatic fragmentation of larger molecules, combinations of the foregoing or, in general, made by any other method. The term “peptide” includes peptides containing a variable number of amino acid residues, optionally with nonamino acid residue groups at the N- and C-termini, such groups including acyl, acetyl, alkenyl, alkyl, N-alkyl, amine, or amide groups, among others.
[0144] By employing chemical synthesis, a useful means of production, it is possible to introduce various amino acids which do not naturally occur along the chain, modify the N- or C-terminus, and the like, thereby providing for improved stability and formulation, resistance to protease degradation, and the like.
[0145] “Amino acids” are molecules containing an amine group, a carboxylic acid group, and a side-chain that is specific to each amino acid. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen and have the generic formula H2N — CHR — COOH, wherein R represents a side chain group. The various a-amino acids differ in the side-chain moiety that is attached to the a-carbon. The “amino acids” of the present technology include the known naturally occurring protein amino acids, which are referred to by both their common three letter abbreviation and single letter abbreviation. See generally Synthetic Peptides: A User’s Guide, G. A. Grant, editor, W.H. Freeman & Co., New York (1992), the teachings of which are incorporated herein by reference, including the text and table set forth at pages 11 through 24. As set forth above, the term “amino acid” also includes stereoisomers and modifications of naturally occurring protein amino acids, nonprotein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs or structures designed to mimic amino acids, and the like. Modified and unusual amino acids are described generally in Synthetic Peptides: A User’s Guide, supra; Hruby et al., Biochem. J. 268:249-262 (1990); and Toniolo, Int. J. Peptide Protein Res. 35:287-300 (1990); the teachings of all of which are incorporated herein by reference.
[0146] The phrase “amino acid side chain moiety” used herein, including as used in the specification and claims, includes any side chain of any amino acid, as the term “amino acid” is defined herein. This thus includes the side chain moiety present in naturally occurring amino acids. It further includes side chain moieties in modified naturally occurring amino acids, such as glycosylated amino acids. It further includes side chain moieties in stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs, or structures designed to mimic amino acids, and the like. For example, the side chain moiety of any amino acid of the present technology is included within the definition. A “derivative” of an amino acid side chain moiety is included within the definition of an amino acid side chain moiety.
[0147] The “derivative” of an amino acid side chain moiety includes any modification to or variation in any amino acid side chain moieties, including a modification of naturally occurring amino acid side chain moieties. By way of example, derivatives of amino acid side chain moieties include straight chain or branched, cyclic or noncyclic, substituted or unsubstituted, saturated or unsaturated, alkyl, aryl or aralkyl moieties.
[0148] In the peptides of the present technology, conventional amino acid residues have their conventional meaning as given in Chapter 2400, of the Manual of Patent Examining Procedure, 8th Ed. Thus, “Ala” is alanine; “Arg” is arginine; “Asn” is asparagine; “Asp” is aspartic acid; “Cys” is cysteine; “Gin” is glutamine; “Glu” is glutamic acid; “His” is histidine; “He” is isoleucine; “Leu” is leucine; “Lys” is lysine; “Met” is methionine; “Phe” is phenylalanine; “Pro” is proline; “Ser” is serine; “Thr” is threonine; “Trp” is tryptophan; “Tyr” is tryosine; and “Vai” is valine. Unless otherwise indicated, all amino acids abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or combinations thereof may be used. Thus, for example, “L-Phe” is L-phenylalanine; “D-Phe” is D-phenylalanine; “D-/L-Phe” is D-phenylalanine, L-phenylalanine, or combinations thereof; “Phe” is also D-phenylalanine, L-phenylalanine, or combinations thereof, and so on. [0149] An alpha (a)-amino acid has the generic formula H2N — CaHR — COOH, where R is a side chain moiety and the amino group is attached to the carbon atom immediately adjacent to the carboxylate group (i.e. , the a-carbon). Other types of amino acids exist when the amino group is attached to a different carbon atom. For example, beta (P)-amino acids, the carbon atom to which the amino group is attached is separated from the carboxylate group by one carbon atom, Cp.
[0150] When p-amino acids are incorporated into peptides, two main types of p- peptides exist: those with the side chain residue, R, on the carbon next to the amine are called 3 peptides and those with the side chain residue on the carbon next to the carbonyl group are called p2 amino acids.
[0151] Gamma (y)-amino acids are amino acids with the carbon atom to which the amino group attaches is separated from the carboxylate moiety by two carbon atoms.
[0152] For additional modified and unusual amino acids, see §2422 of the MPEP, particularly Table 4 at 2400-24. Additionally, “Ac” indicates N-acetyl and “cyclo” refers to a cyclic structure, which is also shown as “c.” “NH2” indicates an amine group, typically added on the C-terminus of a polypeptide. Accordingly, as used herein, an — NH2 moiety on the C- terminus of a peptide indicates an amide, i.e., —CO — NH2.
[0153] Additional abbreviations are used as follows: Nle is norleucine; Nal(2’) is 2'- naphthylalanine; Nal(1 ') is 1 '-naphthylalanine; Tie is tert-leucine; Nva is norvaline; Orn is ornithine; Bip is biphenylalanine; Hyp is hydroxyproline; Mamb is 3-aminomethyl-benzoic acid; Pen is Penicillamine; Tic is 1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid; Aba is 4- amino-1 ,2,4,5-tetra-hydro-2-benzazepin-3-one; Oic is octohydroindole-2-carboxylic acid; Ate is 2-aminotetraline-2-carboxylic acid; APC is 1 -amino-4-phenylcyclohexane-carboxylic acid; APPC is 4-aminophenylpiperidine-4-carboxylic acid; Acpc is 1 -aminocyclo-propane-1 - carboxylic acid; Aic is 2-aminoindone-2-carboxylic acid; Ata is 7-amino-7,8-dihydro-4H- [1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one; Aia is 4-amino-1 ,4,5,6-tetrahydroazepino[4,3- b]indol-3(2H)-one; Che is 1 -amino-1 -cyclohexanecarboxylic acid loc is indoline-2-carboxylic acid, Aic is 2-aminoindone-2-carboxylic acid; Cpe is 1 -amino-1 -cyclopentane carboxylic; and p(CI)dPhe is para-chloro-phenylalanine (I - iodo, F - fluoro, Br - bromo, CF3 - trifluoromethyl). [0154] The term “acyl” includes a group RCO — , where R is an organic group. An example is the acetyl group CH3CO — , referred to herein as “Ac.”
[0155] A peptide or aliphatic moiety is “acylated” when an alkyl or substituted alkyl group as defined above is bonded through one or more carbonyl { — (C=O) — } groups. A peptide is most usually acylated at the N-terminus.
[0156] An “amine” includes compounds that contain an amine group ( — NH2).
[0157] An “amide” includes compounds that have a trivalent nitrogen attached to a carbonyl group (i.e., — CO — NH2), such as for example methylamide, ethylamide, propylamide, and the like. A peptide is most usually amidated at the C-terminus by the addition of an amine ( — NH2) moiety to the C-terminal carboxyl group.
[0158] Amino acids, including stereoisomers and modifications of naturally occurring amino acids, protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs, or structures designed to mimic amino acids (peptide mimetics), and the like, including all of the foregoing, are sometimes referred to herein as “residues.”
[0159] “Substantial degradation” refers to the degradation of the N-terminal extension, the C-terminal extension, both N- and C-terminal degradation or degradation to other regions of the non-naturally occurring melanocortin analog by physiological enzymes and other factors, in such a manner or to a degree that side effects appear. According to one aspect, a non-naturally occurring melanocortin analog having a C-terminal extension that resists substantial degradation is one where no more than 50% of the administered peptide causes side effects and/or displays a low half-life. In some aspects, no more than 25% of the administered peptide causes side effects and/or displays a low half-life. More preferably, in some aspects, less than 10% of the administered peptide causes side effects and/or displays a low half-life, as compared to a non-naturally occurring melanocortin analog that lacks a C-terminal extension.
[0160] The term “weight loss agent” refers to a therapeutic agent useful for the treatment or prevention of metabolic dysfunction or one or more symptoms associated with metabolic dysfunction in a subject. In some embodiments, such weight loss agents may be effective to treat, reduce, prevent, or otherwise be useful for a subject having a disease or condition that is not metabolic dysfunction, or besides metabolic dysfunction. The present technology is expected to be useful for subjects that may receive, have received, or are receiving one or more doses of a weight loss agent regardless of the underlying disease or condition that the subject has or develops.
[0161] The disclosure of all publications, patents, and published patent applications listed herein are hereby incorporated by reference in their entireties, including but not limited to U.S. Patent Nos. 8,541 ,545 and 9,534,018.
Non-naturally Occurring Melanocortin Analogs
[0162] The non-naturally occurring melanocortin analogs of the present technology may comprise a non-naturally occurring melanocortin analog or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Non-naturally occurring melanocortin analogs of the present technology may be selective for the melanocortin 4 receptor (MC4R) and/or melanocortin 3 receptor (MC3R) over other melanocortin receptors, i.e., the melanocortin 1 receptor (MC1 R), the melanocortin 2 receptor (MC2R), and the melanocortin 5 receptor (MC5R). Some of the non-naturally occurring melanocortin analogs may bind only the MC3R or the MC4R. Alternatively, some of the non-naturally occurring melanocortin analogs may bind the MC3R with greater affinity than the MC4R, whereas other melanocortin analogs may bind the MC4R with greater affinity than the MC3R. Certain melanocortin analogs may bind the MC3R with the same or generally similar affinity as the MC4R.
[0163] The non-naturally occurring melanocortin analogs of the present technology may be full agonists or full antagonists for one or more melanocortin receptors. A full agonist may comprise a non-naturally occurring melanocortin analog having a maximum effect (Emax) agonist value of greater than or equal to 85%. Similarly, a full antagonist may comprise a non-naturally occurring melanocortin analog having an Emax antagonist value of greater than or equal to 85%.
[0164] The non-naturally occurring melanocortin analogs of the present technology may be partial agonists or partial antagonists A partial agonist may comprise a non-naturally occurring melanocortin analog having a maximum effect Emax agonist value of less than 85%. Similarly, a partial antagonist may comprise a non-naturally occurring melanocortin analog having an Emax antagonist value of less than 85%.
[0165] If a non-naturally occurring melanocortin analog’s Emax agonist value is greater than it’s Emax antagonist value, then the non-naturally occurring melanocortin analog may be classified as an agonist (e.g., a full agonist or a partial agonist).
[0166] If a non-naturally occurring melanocortin analog’s Emax antagonist value is greater than it’s Emax agonist value, then the non-naturally occurring melanocortin analog may be classified as an antagonist (e.g., a full antagonist or a partial antagonist).
[0167] The non-naturally occurring melanocortin analogs of the present technology may be one or more of (i) a full MC4R antagonist and a full MC3R antagonist; (ii) a full MC4R antagonist and a partial MC3R antagonist; (iii) a full MC4R antagonist and a full MC4R agonist; (iv) a full MC4R antagonist and a partial MC3R agonist; (v) a full MC4R antagonist having no MC3R activity; (vi) a partial MC4R antagonist and a full MC3R antagonist; (vii) a partial MC4R antagonist and a partial MC3R antagonist; a partial MC4R antagonist and a full MC4R agonist; (viii) a partial MC4R antagonist and a partial MC3R agonist; (ix) a partial MC4R antagonist having no MC3R activity; (x) a partial MC4R agonist and a full MC3R antagonist; (xi) a partial MC4R agonist and a partial MC3R antagonist; (xii) a partial MC4R agonist and a partial MC3R agonist; (xiii) a partial MC4R agonist and a full MC3R agonist; and (ixx) a partial MC4R agonist having no MC3R activity.
[0168] The non-naturally occurring melanocortin analogs in accordance with the present technology may have certain structural features that impart specific properties on the analogs, such as, for example, degradation resistance, enhanced epithelial, gastrointestinal, and/or blood brain barrier transport, and binding affinity for the melanocortin 4 receptor and/or melanocortin 3 receptor. Accordingly, in some embodiments, the non- naturally occurring melanocortin analogs have one or more beta hairpin (p-hairpin) and/or beta turn (p-turn) structures. The presence of amino acids that are structurally rigid, such as, for example, Aia, Aba, Ata, Hyp, dHyp, Pro, dPro, transPro(guar\), and c/'sPro(guan), may lead to formation of p-hairpin and/or p-turn structures in the non-naturally occurring melanocortin analog. Additionally, D-Met and disulfide bridges (e.g., cyclization via disulfide bond), as well as Pro-Gly and Gly-Gly linkers may induce and/or stabilize beta-turn structures of the non-naturally occurring melanocortin analogs. In general, cyclization may stabilize beta-turns, and D-amino acids may induce and/or stabilize beta-turns. Further, in some embodiments, melanocortin analogs include D-valine-D-proline (dVal-dPro) chain as their C-terminus, which may provide enhanced transport and resistance to degradation.
[0169] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I),
X1 -X2-X3- R1 - R2- R3- R4- R5- R6- R7- R8- R9-Y1 - Y2- Y3-Y4- Y5-Y6- Y7 (I),
[0170] wherein:
[0171] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[0172] X2 is absent, phenylalanine (Phe), or Nle;
[0173] X3 is absent, Phe, or Nle;
[0174] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), trans-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys);
[0175] R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s-CH=CH-CO, proline (Pro), and tryptophan (Trp);
[0176] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), tra/?sPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[ 1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino- 1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
[0177] R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
[0178] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fransPro(guan);
[0179] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
[0180] R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[0181] R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
[0182] R9 is absent or Lys;
[0183] Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro,
Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[0184] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[0185] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[0186] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp; [0187] Y5 is absent or dVal;
[0188] Y6 is absent or dVal;
[0189] Y7 is absent or dPro; and
[0190] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[0191] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[0192] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and
[0193] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[0194] provided that:
[0195] when R3 is dTrp or Phe, then R4 is not dNal(2’) and R6 is not dPhe;
[0196] when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii)
R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7;
[0197] when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2’) or Nal(2’);
[0198] when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent;
[0199] when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and
[0200] when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu. [0201] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein:
X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[0202] X2 is absent, phenylalanine (Phe), or Nle;
[0203] X3 is absent, Phe, or Nle;
[0204] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), tra/?s-4-guanidinyl-proline (f/'ansPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys)
[0205] R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s-CH=CH-CO, proline (Pro), and tryptophan (Trp);
[0206] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), tra/?sPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[ 1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino- 1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
[0207] R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Bi dPhe), para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
[0208] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), czsPro(guan), and transP ro (guan);
[0209] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
[0210] R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[0211] R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
[0212] R9 is absent or Lys;
[0213] Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro,
Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[0214] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[0215] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[0216] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[0217] Y5 is absent or dVal;
[0218] Y6 is absent or dVal;
[0219] Y7 is absent or dPro; and
[0220] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: [0221] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[0222] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn;
[0223] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[0224] provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:
[0225] Ac-Nle-c[Asp-dTrp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 83);
[0226] Ac-Nle-c[Asp-Phe-Phe-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID
NO: 420);
[0227] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 223);
[0228] Ac-Nle-c[dCys-His-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 460);
[0229] Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 464);
[0230] Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 465);
[0231] Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 466);
[0232] Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 467);
[0233] Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 468);
[0234] Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
469);
[0235] Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 470);
[0236] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 474); [0237] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
475);
[0238] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 476);
[0239] Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
477);
[0240] Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 478);
[0241] Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 481 );
[0242] Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 482);
[0243] Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 483);
[0244] Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 484);
[0245] Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 485);
[0246] Ac-Nle-c[Cys-His-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 459);
[0247] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 472);
[0248] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
471 );
[0249] Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 463);
[0250] Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 462);
[0251] Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 479);
[0252] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO:
473);
[0253] Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 480);
[0254] Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 486);
[0255] Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 491 );
[0256] Ac-Nle-c[dCys-His-p(F)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 461 ); [0257] Ac-Nle-c[Asp-dGln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 492);
[0258] Ac-Nle-c[Asp-dTyr-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 496);
[0259] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 218);
[0260] Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
442);
[0261] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 449);
[0262] Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 455);
[0263] Ac-Nle-c[Asp-Pro-p(F)dP e-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 447);
[0264] Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 438);
[0265] Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
450);
[0266] Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 435);
[0267] Ac-dl_ys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 439);
[0268] Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 441 );
[0269] Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 436);
[0270] Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 454);
[0271] Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 452);
[0272] Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 451 );
[0273] Ac-dl_ys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 456);
[0274] Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 437);
[0275] Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 440);
[0276] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
448); [0277] Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 457);
[0278] Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 453);
[0279] Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 458);
[0280] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO:
446);
[0281] Ac-Nle-c[dCys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 433);
[0282] Ac-Nle-c[dCys-Pro-p(F)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 434);
[0283] Ac-Nle-c[Asp-dPhe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 488);
[0284] Ac-Nle-c[Asp-dBip-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 490);
[0285] Ac-Nle-c[Asp-dTrp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 494);
[0286] Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 443); Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 268);
[0287] Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 363);
[0288] Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 365);
[0289] Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 370);
[0290] Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 378);
[0291] Ac-dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 379);
[0292] Ac-Nle-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 380);
[0293] Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 418);
[0294] Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 621 );
[0295] Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 666);
[0296] Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 297);
[0297] Ac-Nle-c[Asp-His-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
228); [0298] Ac-Nle-c[Asp-His-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 229);
[0299] Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 281 );
[0300] Ac-Nle-c[Asp-Leu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 355);
[0301] Ac-Nle-c[Asp-Tic-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 362);
[0302] Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 424);
[0303] Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 366);
[0304] Ac-Nle-c[Asp-Bip-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 368);
[0305] Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dLeu-dPro-NH2 (SEQ ID NO: 422);
[0306] Ac-Nle-c[Asp-Trp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 372);
[0307] Ac-Nle-c[Asp-Tyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 374);
[0308] Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
639);
[0309] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dPro-dPro-Lys-Asp-NH2 (SEQ ID
NO: 352);
[0310] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 351 );
[0311] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Trp-NH2 (SEQ ID NO: 600);
[0312] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 322);
[0313] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dAsn-NH2 (SEQ ID NO: 605);
[0314] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Gly-Gly-NH2 (SEQ ID NO: 610);
[0315] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Arg-NH2 (SEQ ID NO: 581 );
[0316] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dPro-dPro-dl_ys-dAsp-NH2 (SEQ ID
NO: 353);
[0317] Ac-Nle-c[dCys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 319);
[0318] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asn-dPro-NH2 (SEQ ID NO: 607); [0319] Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 638);
[0320] Ac-Nle-c[Asp-Pro-His-Phe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 295);
[0321] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 575);
[0322] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH2 (SEQ ID NO: 587);
[0323] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-NH2 (SEQ ID NO: 582);
[0324] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Arg-Pro-Val-NH2 (SEQ ID NO: 588);
[0325] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAsn-dPro-NH2 (SEQ ID NO: 612);
[0326] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-Pro-Val-NH2 (SEQ ID NO: 583);
[0327] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Ala-Ala-NH2 (SEQ ID NO: 609);
[0328] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 594);
[0329] Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 631 );
[0330] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Arg-Val-Pro-NH2 (SEQ ID NO: 589);
[0331] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO:
597);
[0332] Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 628);
[0333] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-l_ys]-dTle-dPro-NH2 (SEQ ID NO: 591 );
[0334] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 590);
[0335] Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 311 );
[0336] Ac-Nle-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
629);
[0337] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-Hyp-NH2 (SEQ ID NO: 574);
[0338] Ac-dPhe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 303);
[0339] Ac-Nle-c[Asp-Oic-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 360);
[0340] Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 313); [0341] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 291 );
[0342] Ac-dAla-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 299);
[0343] Phe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 305);
[0344] His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 306);
[0345] Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 312);
[0346] Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 314);
[0347] Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 315);
[0348] Ac-Nle-c[dCys-Pro-dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 321 );
[0349] Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 423);
[0350] Ac-Nle-Phe-Phe-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID
NO: 421 );
[0351] Ac-Nle-c[Cys-Trp-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 383);
[0352] Ac-Nle-c[dCys-Trp-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 384);
[0353] Ac-Lys-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 387);
[0354] Ac-Arg-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 389);
[0355] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
403);
[0356] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 407);
[0357] Ac-Nle-c[Asp-Trp-Leu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 395);
[0358] Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 633);
[0359] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Val-Pro-NH2 (SEQ ID NO: 573);
[0360] Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 643);
[0361] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Val-NH2 (SEQ ID NO: 576);
[0362] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Pro-NH2 (SEQ ID NO: 577); [0363] dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 309);
[0364] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 593);
[0365] Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH2 (SEQ ID NO: 632);
[0366] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asp-NH2 (SEQ ID NO: 603);
[0367] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 617);
[0368] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 620);
[0369] Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dPro-NH2 (SEQ ID NO: 634);
[0370] Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 635);
[0371] Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 644);
[0372] Ac-dTyr-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 304);
[0373] Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 642);
[0374] dPhe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 308);
[0375] Ac-Nle-c[Asp-Atc-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 212);
[0376] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 226);
[0377] Ac-Nle-c[dPen-Pro-dPhe-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 320);
[0378] Ac-Nle-c[Cys-dPhe-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 324);
[0379] Ac-Nle-c[Asp-Cpe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 358);
[0380] Ac-Nle-c[Asp-Che-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 359);
[0381] Ac-Nle-c[Asp-dPhe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 367);
[0382] Ac-Nle-c[Asp-dGln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 371 );
[0383] Ac-Nle-c[Asp-dTrp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 373);
[0384] Ac-Nle-c[Asp-dTyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 375);
[0385] Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 381 );
[0386] Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 382); [0387] Ac-Nle-c[dCys-Trp-Pro-dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 385);
[0388] Ac-Ala-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 386);
[0389] Ac-dLys-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 388);
[0390] Ac-dArg-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 390);
[0391] Ac-dHis-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 391 );
[0392] Ac-His-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 392);
[0393] Ac-Nle-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
393);
[0394] Ac-Nle-c[Asp-Trp-Ala-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 394);
[0395] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO:
405);
[0396] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dl_ys-dVal-dPro-NH2 (SEQ ID NO:
406);
[0397] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dl_ys-dPro-NH2 (SEQ ID NO: 408);
[0398] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 409);
[0399] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 410);
[0400] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 411 );
[0401] Ac-Nle-c[Asp-Phe-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 412);
[0402] Ac-Nle-c[Asp-His-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 413);
[0403] Ac-Nle-c[Asp-Tyr-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 414);
[0404] Ac-Nle-c[Asp-dPhe-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 415);
[0405] Ac-Nle-c[Asp-dHis-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 416);
[0406] Ac-Nle-c[Asp-dTyr-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 417);
[0407] Ac-Nle-c[Asp-Hyp-dPhe-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 419); [0408] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 596);
[0409] Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-dPro-dVal-NH2 (SEQ ID NO: 622);
[0410] Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 645);
[0411] Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 646);
[0412] Ac-dLeu-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 298);
[0413] Ac-Nle-c[Asp-Ala-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 354);
[0414] Ac-Nle-c[Asp-Hyp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 364);
[0415] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-Arg-NH2 (SEQ ID NO: 578);
[0416] Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 300);
[0417] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dArg-NH2 (SEQ ID NO: 579);
[0418] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 580);
[0419] Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 640);
[0420] Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 641 );
[0421] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dPro-NH2 (SEQ ID NO: 584);
[0422] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-Val-Pro-NH2 (SEQ ID NO: 585);
[0423] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-dVal-dPro-NH2 (SEQ ID NO: 586);
[0424] Ac-dNle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 301 );
[0425] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 595);
[0426] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-d al-dPro-NH2 (SEQ ID NO:
598);
[0427] Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 302);
[0428] Ac-Nle-Nle-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
630);
[0429] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-dPro-dVal-NH2 (SEQ ID NO: 601 ); [0430] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAla-dAla-NH2 (SEQ ID NO: 602);
[0431] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dHyp-NH2 (SEQ ID NO: 604);
[0432] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-Asp-NH2 (SEQ ID NO: 606);
[0433] Ac-Nle-c[Cys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 318);
[0434] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Hyp-NH2 (SEQ ID NO: 608);
[0435] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asp-dPro-NH2 (SEQ ID NO: 61 1 );
[0436] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asn-NH2 (SEQ ID NO: 613);
[0437] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAsp-NH2 (SEQ ID NO: 614);
[0438] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAsn-NH2 (SEQ ID NO: 615);
[0439] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-dPro-NH2 (SEQ ID NO: 616);
[0440] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dVal-dVal-dVal-dPro-
NH2 (SEQ ID NO: 599);
[0441] Ac-Nle-c[Asp-Pro-His-Phe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 296);
[0442] Ac-Nle-c[Asp-Aba-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 198);
[0443] Ac-Nle-c[Asp-Aia-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 207);
[0444] Ac-Nle-c[Asp-Ata-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 208);
[0445] Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 225);
[0446] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 592);
[0447] Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 425);
[0448] Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(1 ’)-Lys]-dVal-dPro-NH2 (SEQ ID NO: 427);
[0449] Ac-Nle-c[Asp-Pro-dPhe-Arg-Phe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 429);
[0450] Ac-Nle-c[Pen-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 325);
[0451] Ac-Nle-c[dPen-dPhe-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 326);
[0452] Ac-Nle-c[Asp-dlle-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 356); [0453] Ac-Nle-c[Asp-dVal-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 357);
[0454] Ac-Arg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 376);
[0455] Ac-dArg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-d al-dPro-NH2 (SEQ ID NO: 377);
[0456] Ac-Nle-c[Asp-Trp-dLeu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 396);
[0457] Ac-Nle-c[Asp-Trp-dVal-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 397);
[0458] Ac-Nle-c[Asp-Trp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 398);
[0459] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-dNal(1')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
400);
[0460] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Phe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 401 );
[0461] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-dPhe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 402);
[0462] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Nal(1 ')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 399);
[0463] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 404);
[0464] Ac-Nle-c[Asp-Pro-dPhe-Arg-dTrp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 187);
[0465] Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
231 );
[0466] Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
232);
[0467] Ac-Nle-c[Asp-Pro-dPhe-Arg-Aia-Lys]-dVal-dPro-NH2 (SEQ ID NO: 233);
[0468] Ac-Nle-c[Asp-Pro-dPhe-Arg-Aba-Lys]-dVal-dPro-NH2 (SEQ ID NO: 234);
[0469] Ac-Nle-c[Asp-Pro-dPhe-Arg-Ata-Lys]-dVal-dPro-NH2 (SEQ ID NO: 235);
[0470] Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(1 ’)-Lys]-dVal-dPro-NH2 (SEQ ID NO: 428);
[0471] Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 520);
[0472] Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 522);
[0473] Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 523);
[0474] Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 518); [0475] Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 503);
[0476] Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 505);
[0477] Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 502);
[0478] Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 519);
[0479] Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 506);
[0480] Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 501 );
[0481] Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 521 );
[0482] Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 504);
[0483] Ac-Nle-c[Asp-dBip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 528);
[0484] Ac-Nle-c[Asp-dGln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 530);
[0485] Ac-Nle-c[Asp-dTrp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 532);
[0486] Ac-Nle-c[Asp-Aba-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 209);
[0487] Ac-Nle-c[Asp-Aia-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 210);
[0488] Ac-Nle-c[Asp-Ata-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 211 );
[0489] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 512);
[0490] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
513);
[0491] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO:
511 );
[0492] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
515);
[0493] Ac-Nle-c[dPen-Ala-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 338);
[0494] Ac-Nle-c[dPen-Leu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 339);
[0495] Ac-Nle-c[dPen-dl_eu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 340); [0496] Ac-Nle-c[dPen-dVal-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 341 );
[0497] Ac-Nle-c[dPen-Gly-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 342);
[0498] Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 536);
[0499] Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 498);
[0500] Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO:
499);
[0501] Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO:
537);
[0502] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 44);
[0503] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 45);
[0504] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 46);
[0505] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 47);
[0506] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 56);
[0507] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 57);
[0508] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 58);
[0509] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 60);
[0510] Ac-Nle-c[dPen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 61 );
[0511] Ac-Nle-c[dPen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 62);
[0512] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 63);
[0513] Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 8); and
[0514] Ac-Nle-c[Asp-Pro-Glu-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO:
258).
[0515] In some embodiments, R9 is absent. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA): X1 -X2-X3- R1 - R2- R3- R4- R5- R6- R7- R8- Y1 - Y2-Y3- Y4- Y5-Y6- Y7 ( I A) ,
[0516] wherein:
[0517] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[0518] X2 is absent, phenylalanine (Phe), or Nle;
[0519] X3 is absent, Phe, or Nle;
[0520] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), frans-4-guanidinyl-proline (fransPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys)
[0521] R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s-CH=CH-CO, proline (Pro), and tryptophan (Trp);
[0522] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, Tyr, dTyr, c/sPro(guan), fransPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip); [0523] R4 is selected from the group consisting of 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);
[0524] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fransPro(guan);
[0525] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
[0526] R7 is absent or is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[0527] R8 is Lys or dPen;
[0528] Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[0529] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[0530] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[0531] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[0532] Y5 is absent or dVal;
[0533] Y6 is absent or dVal;
[0534] Y7 is absent or dPro; and
[0535] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: [0536] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[0537] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn;
[0538] a lactam bridge between R1 and R7 or R8 when R1 is Asp and R7 or R8 is Lys;
[0539] provided that:
[0540] when R4 is p(Br)dPhe, then R1 is Nle or Ala, Y4-Y7 are absent, and at least one of X1 and Y3 is absent;
[0541] when R4 is p(CI)dPhe, then (i) R3 is selected from Phe, dPhe, Bip, Trp, Tyr, dTyr, and Pro or (ii) R3 is His and R6 is not Trp;
[0542] when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and
[0543] when R7 is Pro or Gly, then (i) R3 is not His or (ii) R2 is not Pro.
[0544] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA), wherein:
X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[0545] X2 is absent, phenylalanine (Phe), or Nle;
[0546] X3 is absent, Phe, or Nle;
[0547] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), frans-4-guanidinyl-proline (fransPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys)
[0548] R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s-CH=CH-CO, proline (Pro), and tryptophan (Trp);
[0549] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, Tyr, dTyr, c/sPro(guan), fransPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
[0550] R4 is selected from the group consisting of 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);
[0551] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and transPro(guan);
[0552] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and T- naphthylalanine (Nal(1 ’));
[0553] R7 is absent or is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[0554] R8 is Lys or d Pen; [0555] Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[0556] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[0557] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[0558] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[0559] Y5 is absent or dVal;
[0560] Y6 is absent or dVal;
[0561] Y7 is absent or dPro; and
[0562] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[0563] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[0564] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn;
[0565] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[0566] provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:
[0567] Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 539);
[0568] Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 540);
[0569] Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 541 ); [0570] Ac-dLys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 542);
[0571] Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 543);
[0572] Ac-dHis-c[Asp-His-p(Br)dP e-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 544);
[0573] Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 556);
[0574] Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 557);
[0575] Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 558);
[0576] Ac-dl_ys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 559);
[0577] Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 560);
[0578] Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 561 );
[0579] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 550);
[0580] Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 554);
[0581] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 220);
[0582] Ac-Nle-c[Cys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 497);
[0583] Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 500);
[0584] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
507);
[0585] Ac-Nle-c[Asp-His-p(CI)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 508);
[0586] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 514);
[0587] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 516);
[0588] Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 517);
[0589] Ac-Nle-c[Asp-dHis-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 524);
[0590] Ac-Nle-c[Asp-Gln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 529); [0591] Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 520);
[0592] Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 522);
[0593] Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 523);
[0594] Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 518);
[0595] Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 503);
[0596] Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 505);
[0597] Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 502);
[0598] Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 519);
[0599] Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 506);
[0600] Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 501 );
[0601] Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 521 );
[0602] Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 504);
[0603] Ac-Nle-c[Asp-dBip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 528);
[0604] Ac-Nle-c[Asp-dGln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 530);
[0605] Ac-Nle-c[Asp-Aba-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 209);
[0606] Ac-Nle-c[Asp-Aia-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 210);
[0607] Ac-Nle-c[Asp-Ata-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 211 );
[0608] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 512);
[0609] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
513);
[0610] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO:
511 );
[0611] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
515); [0612] Ac-Nle-c[dPen-Ala-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 338);
[0613] Ac-Nle-c[dPen-Leu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 339);
[0614] Ac-Nle-c[dPen-dLeu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 340);
[0615] Ac-Nle-c[dPen-dVal-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 341 );
[0616] Ac-Nle-c[dPen-Gly-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 342);
[0617] Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 536);
[0618] Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 498);
[0619] Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO:
499);
[0620] Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO:
537);
[0621] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 44);
[0622] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 45);
[0623] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 46);
[0624] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 47);
[0625] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 56);
[0626] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 57);
[0627] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 58);
[0628] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 60);
[0629] Ac-Nle-c[dPen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 61 );
[0630] Ac-Nle-c[dPen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 62);
[0631] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 63);
[0632] Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 8); and [0633] Ac-Nle-c[Asp-Pro-Glu-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 258).
[0634] In some embodiments, the non-naturally occurring melanocortin analog is a full antagonist on the melanocortin 4 receptor and the melanocortin 3 receptor. In some embodiments, when the non-naturally occurring melanocortin analog is a full antagonist on the melanocortin 4 receptor and the melanocortin 3 receptor, then R4 is not dPhe. In further embodiments, R4 is selected from dNal(2’), p(CI)dPhe, p(l)dPhe, p(Br)dPhe, and p(CF3)dPhe. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA), wherein:
[0635] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[0636] X2 is absent or Nle;
[0637] X3 is absent or Nle;
[0638] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), and glutamic acid (Glu);
[0639] R2 is selected from the group consisting of dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s- CH=CH-CO, and tryptophan (Trp);
[0640] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, fFalanine (P-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, Tyr, dTyr, 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), and D-biphenylalanine (dBip); [0641] R4 is selected from the group consisting of 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);
[0642] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, and ornithine (Orn);
[0643] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
[0644] R7 is selected from the group consisting of Gly, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[0645] R8 is Lys or dPen;
[0646] Y1 is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[0647] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[0648] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[0649] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[0650] Y5 is absent or dVal;
[0651] Y6 is absent or dVal;
[0652] Y7 is absent or dPro; and
[0653] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: [0654] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[0655] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn;
[0656] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[0657] provided that:
[0658] when R4 is p(Br)dPhe, then R1 is Nle or Ala, R5 is Arg, Y4-Y7 are absent, and at least one of X1 and Y3 is absent;
[0659] when R4 is p(CI)dPhe, then R3 is selected from Phe, dPhe, Bip, Trp, Tyr, dTyr, and Pro; and
[0660] when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro and R1 is not dArg, Arg, dTyr, or Ala, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys.
[0661] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA), wherein:
[0662] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[0663] X2 is absent or Nle;
[0664] X3 is absent or Nle;
[0665] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), and glutamic acid (Glu); [0666] R2 is selected from the group consisting of dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/'s- CH=CH-CO, and tryptophan (Trp);
[0667] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, Tyr, dTyr, 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), and D-biphenylalanine (dBip);
[0668] R4 is selected from the group consisting of 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);
[0669] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, and ornithine (Orn);
[0670] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, dNal(2’), 2’-naphthylalanine (Nal(2’)), T-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
[0671] R7 is selected from the group consisting of Gly, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[0672] R8 is Lys or dPen;
[0673] Y1 is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[0674] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn; 10675] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[0676] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[0677] Y5 is absent or dVal;
[0678] Y6 is absent or dVal;
[0679] Y7 is absent or dPro; and
[0680] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[0681] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[0682] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn;
[0683] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[0684] provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:
[0685] Ac-Nle-c[Asp-His-p(Br)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 546);
[0686] Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 539);
[0687] Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 540);
[0688] Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 556);
[0689] Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 557);
[0690] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 550);
-H O- [0691] Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 554);
[0692] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
509);
[0693] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
510);
[0694] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 220);
[0695] Ac-Nle-c[Cys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 497);
[0696] Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 500);
[0697] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
507);
[0698] Ac-Nle-c[Asp-His-p(CI)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 508);
[0699] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 514);
[0700] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 516);
[0701] Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 517);
[0702] Ac-Nle-c[Asp-dHis-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 524);
[0703] Ac-Nle-c[Asp-Gln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 529);
[0704] Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 518);
[0705] Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 502);
[0706] Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 519);
[0707] Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 501 );
[0708] Ac-Nle-c[Asp-dBip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 528);
[0709] Ac-Nle-c[Asp-dGln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 530); [0710] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 512);
[0711] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
513);
[0712] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO:
511 );
[0713] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
515);
[0714] Ac-dArg-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 329);
[0715] Ac-Arg-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 330);
[0716] Ac-dTyr-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 332);
[0717] Ac-Ala-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 333);
[0718] Ac-Nle-c[dPen-Ala-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 338);
[0719] Ac-Nle-c[dPen-Leu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 339);
[0720] Ac-Nle-c[dPen-dl_eu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 340);
[0721] Ac-Nle-c[dPen-dVal-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 341 );
[0722] Ac-Nle-c[dPen-Gly-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 342);
[0723] Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 536);
[0724] Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 498);
[0725] Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO:
499);
[0726] Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO:
537);
[0727] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 44);
[0728] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 45); [0729] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 46);
[0730] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 47);
[0731] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 56);
[0732] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 57);
[0733] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 58);
[0734] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 60);
[0735] Ac-Nle-c[dPen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 61 );
[0736] Ac-Nle-c[dPen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 62); and
[0737] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 63).
[0738] In some embodiments, R4 is dNal(2’). In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB):
X1 -X2-X3- R1 - R2- R3-d Nal (2’)- R5- R6- R7- R8-Y1 - Y2- Y3-Y4- Y5-Y6- Y7 (IB),
[0739] wherein:
[0740] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[0741] X2 is absent, phenylalanine (Phe), or Nle;
[0742] X3 is absent, Phe, or Nle;
[0743] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), frans-4-guanidinyl-proline (fransPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys) [0744] R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s-CH=CH-CO, proline (Pro), and tryptophan (Trp);
[0745] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, c/'sPro(guan), transPro(guan), 4-amino- 1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 - aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5- a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), and 1 -amino-1 -cyclopentane carboxylic (Cpe);
[0746] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and transP ro (guan);
[0747] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’-naphthylalanine (Nal(1 ’));
[0748] R7 is absent or is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[0749] R8 is absent or is Lys or dPen;
[0750] Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[0751] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[0752] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[0753] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp; [0754] Y5 is absent or dVal;
[0755] Y6 is absent or dVal;
[0756] Y7 is absent or dPro; and
[0757] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[0758] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[0759] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn;
[0760] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[0761] provided that:
[0762] when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is not Ala, Leu, dLeu, dVal, or Gly, and if R3 is absent, then R2 is Pen and R7 is dCys; and
[0763] when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
[0764] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB), wherein:
[0765] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[0766] X2 is absent, phenylalanine (Phe), or Nle;
[0767] X3 is absent, Phe, or Nle;
[0768] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), frans-4-guanidinyl-proline (fransPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys)
[0769] R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s-CH=CH-CO, proline (Pro), and tryptophan (Trp);
[0770] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, c/sPro(guan), fransPro(guan), 4-amino- 1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 - aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5- a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), and 1 -amino-1 -cyclopentane carboxylic (Cpe);
[0771] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fra/?sPro(guan);
[0772] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’-naphthylalanine (Nal(T));
[0773] R7 is absent or is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[0774] R8 is absent or is Lys or dPen;
[0775] Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp; [0776] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[0777] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[0778] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[0779] Y5 is absent or dVal;
[0780] Y6 is absent or dVal;
[0781] Y7 is absent or dPro; and
[0782] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[0783] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[0784] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn;
[0785] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[0786] provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:
[0787] Ac-Nle-c[dPen-Ala-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 338);
[0788] Ac-Nle-c[dPen-Leu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 339);
[0789] Ac-Nle-c[dPen-dLeu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 340);
[0790] Ac-Nle-c[dPen-dVal-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 341 );
[0791] Ac-Nle-c[dPen-Gly-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 342); [0792] Ac-Nle-c[Cys-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 44);
[0793] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 45);
[0794] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 46);
[0795] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 47);
[0796] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 56);
[0797] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 57);
[0798] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 58);
[0799] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 60);
[0800] Ac-Nle-c[dPen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 61 );
[0801] Ac-Nle-c[dPen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 62);
[0802] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 63);
[0803] Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 8); and
[0804] Ac-Nle-c[Asp-Pro-Glu-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO:
258).
[0805] Alternatively, in some embodiments, R4 is not dNal(2’). In some embodiments, R4 is selected from p(CI)dPhe, p(l)dPhe, p(Br)dPhe, and p(CF3)dPhe. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC):
X1 - R1 - R2- R3- R4- R5- R6- R7- Y1 - Y2- Y3- Y4 ( I C) ,
[0806] wherein:
[0807] X1 is absent or norleucine (Nle)
[0808] R1 is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys);
[0809] R2 is aspartic acid (Asp) or cysteine (Cys);
[0810] R3 is His or proline (Pro); [0811] R4 is selected from the group consisting of para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);
[0812] R5 is Arg or His;
[0813] R6 is selected from the group consisting of tryptophan (Trp), 4-amino-1 ,2,4,5- tetrahydro-2-benzazepin-3-one (Aba), 3- 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5- a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), 2’-D-naphthylalanine dNal(2’), and 2’-naphthylalanine (Nal(2’));
[0814] R7 is Lys or Cys;
[0815] Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle);
[0816] Y2 is selected from the group consisting of dVal, dPro, and dTle;
[0817] Y3 is absent or is dVal or dPro;
[0818] Y4 is absent or dPro; and
[0819] the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of:
[0820] a disulfide bond between Cys at R2 and Cys R7; and
[0821] a lactam bridge between Asp at R2 and Lys at R7;
[0822] provided that:
[0823] when R4 is p(CI)dPhe, then R1 is Nle or Ala, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent.
[0824] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC), wherein:
X1 is absent or norleucine (Nle)
[0825] R1 is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys); [0826] R2 is aspartic acid (Asp) or cysteine (Cys);
[0827] R3 is His or proline (Pro);
[0828] R4 is selected from the group consisting of para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);
[0829] R5 is Arg or His;
[0830] R6 is selected from the group consisting of tryptophan (Trp), 4-amino-1 ,2,4,5- tetrahydro-2-benzazepin-3-one (Aba), 3- 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5- a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), 2’-D-naphthylalanine dNal(2’), and 2’-naphthylalanine (Nal(2’));
[0831] R7 is Lys or Cys;
[0832] Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle);
[0833] Y2 is selected from the group consisting of dVal, dPro, and dTle;
[0834] Y3 is absent or is dVal or dPro;
[0835] Y4 is absent or dPro; and
[0836] the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of:
[0837] a disulfide bond between Cys at R2 and Cys R7; and
[0838] a lactam bridge between Asp at R2 and Lys at R7;
[0839] provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:
[0840] Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 520);
[0841] Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 522);
[0842] Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 523);
[0843] Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 518); [0844] Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 503);
[0845] Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 505);
[0846] Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 502);
[0847] Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 519);
[0848] Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 506);
[0849] Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 501 );
[0850] Ac-dl_ys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 521 );
[0851] Ac-dl_ys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 504);
[0852] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 512);
[0853] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
513);
[0854] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO:
511 ); and
[0855] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
515).
[0856] Alternatively, in some embodiments, when R4 is not dNal(2’), then R4 is selected from dPhe, p(CI)dPhe, p(Br)dPhe, and p(F)dPhe. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (ID):
[0857] X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4 (ID),
[0858] wherein:
[0859] X1 is absent or norleucine (Nle);
[0860] R1 is absent or is selected from the group consisting of Nle, arginine (Arg), D- arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys)
[0861] R2 is aspartic acid (Asp) or cysteine (Cys); [0862] R3 is selected from the group consisting of His, D-histidine (dHis), proline (Pro), phenylalanine (Phe), tryptophan (Trp), tyrosine (Tyr), glutamine (Gin), and biphenylalanine (Bip);
[0863] R4 is selected from the group consisting of dPhe, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
[0864] R5 is selected from the group consisting of Arg, Lys, and His;
[0865] R6 is selected from the group consisting of Trp, 2’-D-naphthylalanine (dNal(2’)), and 2’-naphthylalanine (Nal(2’));
[0866] R7 is Lys or Cys;
[0867] Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle);
[0868] Y2 is dVal or dPro;
[0869] Y3 is absent, dVal, or dPro;
[0870] Y4 is absent or dPro; and
[0871] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[0872] a disulfide bond between Cys at R2 and Cys at R7; and
[0873] a lactam bridge between Asp at R2 and Lys at R7;
[0874] provided that:
[0875] when R4 is p(Br)dPhe and R1 is Nle or Ala, then the C-terminus is not dVal-dPro or dTle-dPro and if the C-terminus is dPro-dVal-dPro, then X1 is present.
[0876] when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; [0877] when R4 is dPhe, then R3 is Pro and either R5 is Lys or R6 is dNal(2’) or Nal(2’); and
[0878] when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, and Gin, R6 is Trp, and either X1 and Y3 are both present or X1 and Y3 are both absent.
[0879] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (ID), wherein:
[0880] X1 is absent or norleucine (Nle);
[0881] R1 is absent or is selected from the group consisting of Nle, arginine (Arg), D- arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys) [0882] R2 is aspartic acid (Asp) or cysteine (Cys);
[0883] R3 is selected from the group consisting of His, D-histidine (dHis), proline (Pro), phenylalanine (Phe), tryptophan (Trp), tyrosine (Tyr), glutamine (Gin), and biphenylalanine (Bip);
[0884] R4 is selected from the group consisting of dPhe, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
[0885] R5 is selected from the group consisting of Arg, Lys, and His;
[0886] R6 is selected from the group consisting of Trp, 2’-D-naphthylalanine (dNal(2’)), and 2’-naphthylalanine (Nal(2’));
[0887] R7 is Lys or Cys;
[0888] Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle);
[0889] Y2 is dVal or dPro;
[0890] Y3 is absent, dVal, or dPro;
[0891] Y4 is absent or dPro; and [0892] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[0893] a disulfide bond between Cys at R2 and Cys at R7; and
[0894] a lactam bridge between Asp at R2 and Lys at R7;
[0895] provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:
[0896] Ac-Nle-c[Asp-Pro-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 217);
[0897] Ac-Nle-c[Asp-dHis-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 562);
[0898] Ac-Nle-c[Asp-Phe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 563);
[0899] Ac-Nle-c[Asp-Bip-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 565);
[0900] Ac-Nle-c[Asp-Gln-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 567);
[0901] Ac-Nle-c[Asp-Trp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 569);
[0902] Ac-Nle-c[Asp-Tyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 571 );
[0903] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 222);
[0904] Ac-Nle-c[Cys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 535);
[0905] Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 538);
[0906] Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
545);
[0907] Ac-Nle-c[Asp-His-p(Br)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 546);
[0908] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
547);
[0909] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
548);
[0910] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 552); [0911] Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
553);
[0912] Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 555);
[0913] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
551 );
[0914] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 223);
[0915] Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 464);
[0916] Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 465);
[0917] Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 466);
[0918] Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 467);
[0919] Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 468);
[0920] Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
469);
[0921] Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 470);
[0922] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 474);
[0923] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
475);
[0924] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 476);
[0925] Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
477);
[0926] Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 478);
[0927] Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 481 );
[0928] Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 482);
[0929] Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 483); [0930] Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 484);
[0931] Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 485);
[0932] Ac-Nle-c[Cys-His-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 459);
[0933] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 472);
[0934] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
471 );
[0935] Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 463);
[0936] Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 462);
[0937] Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 479);
[0938] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO:
473);
[0939] Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 480);
[0940] Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 486);
[0941] Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 491 );
[0942] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 218);
[0943] Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
442);
[0944] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 449);
[0945] Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 455);
[0946] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 447);
[0947] Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 438);
[0948] Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
450);
[0949] Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 435); [0950] Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 439);
[0951] Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 441 );
[0952] Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 436);
[0953] Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 454);
[0954] Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 452);
[0955] Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 451 );
[0956] Ac-dl_ys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 456);
[0957] Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 437);
[0958] Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 440);
[0959] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
448);
[0960] Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 457);
[0961] Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 453);
[0962] Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 458);
[0963] Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 443);
[0964] Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 363);
[0965] Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 365);
[0966] Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 370);
[0967] Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 621 );
[0968] Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 297);
[0969] Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 366);
[0970] Ac-Nle-c[Asp-Bip-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 368);
[0971] Ac-Nle-c[Asp-Trp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 372); [0972] Ac-Nle-c[Asp-Tyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 374);
[0973] Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
639);
[0974] Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 638);
[0975] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 295);
[0976] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO:
597);
[0977] Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 628);
[0978] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 591 );
[0979] Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 311 );
[0980] Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 313);
[0981] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 291 );
[0982] Ac-dAla-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 299);
[0983] His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 306);
[0984] Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 312);
[0985] Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 314);
[0986] Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 315);
[0987] Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 643);
[0988] dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 309);
[0989] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 617);
[0990] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 620);
[0991] Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 644);
[0992] Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 642);
[0993] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 596); [0994] Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 645);
[0995] Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 646);
[0996] Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 300);
[0997] Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 640);
[0998] Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 641 );
[0999] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 595);
[1000] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO:
598);
[1001] Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 302);
[1002] Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 425);
[1003] Ac-Nle-c[Cys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 318);
[1004] Ac-Nle-c[Asp-Pro-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 215);
[1005] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
509);
[1006] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
510);
[1007] Ac-Nle-c[Asp-Phe-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 525);
[1008] Ac-Nle-c[Asp-Bip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 527);
[1009] Ac-Nle-c[Asp-Trp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 531 );
[1010] Ac-Nle-c[Asp-Tyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 533);
[1011] Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 520);
[1012] Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 522);
[1013] Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 523);
[1014] Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 518);
[1015] Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 503); [1016] Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 505);
[1017] Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 502);
[1018] Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 519);
[1019] Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-d al-dPro-NH2 (SEQ ID NO: 506);
[1020] Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 501 );
[1021] Ac-dl_ys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 521 );
[1022] Ac-dl_ys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 504);
[1023] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 512);
[1024] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
513); and
[1025] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
515).
[1026] In some embodiments, the non-naturally occurring melanocortin analog of any one of Formulae (l)-(ID) has one or more beta hairpin (p-hairpin) and/or beta turn (p-turn) structures. In some embodiments, the presence of Pro, dPro, Hyp, dHyp, dAla, dMet, Pro- Gly, Gly-Gly, transPro(guan), and/or czsPro(guan), provides the p-hairpin and/or p-turn structures of the non-naturally occurring melanocortin analog. In some embodiments, the disulfide bond of the sequence according to Formula (I), if present, provides the p-hairpin and/or p-turn structures of the non-naturally occurring melanocortin analog.
[1027] As will be appreciated by the skilled artisan, non-naturally occurring melanocortin analogs comprising a sequence of any one of Formulae (l)-(ID), have an N- terminus and a C-terminus. The melanocortin analogs of the present technology are written beginning with the N-terminus at the left-most amino acid residue and ending with the C- terminus at the right most residue. Accordingly, the N-terminus of a non-naturally melanocortin analog comprising a sequence of any one of Formulae (l)-(ID) may be at any of X1, X2, X3, R1 and R2. Analogously, the C-terminus of a non-naturally occurring melanocortin analog comprising a sequence of any one of Formulae (l)-(ID) may be at any of R7, R8, R9, Y1, Y2, Y3, Y4, Y5, Y6, and Y7.
[1028] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog is modified by an acyl group. In some embodiments, the acyl group is acetyl group
Figure imgf000132_0001
some embodiments, the N-terminus of the non-naturally occurring melanocortin analog is not modified.
[1029] As discussed above, Y1Y2Y3Y4Y5Y6Y7 represents a C-terminus of the non- naturally occurring melanocortin analog. In some embodiments, Y1-Y7 are absent.
[1030] In some embodiments, Y1 is present and Y2-Y7 are absent. In some embodiments, Y2-Y7 are absent and Y1 is selected from the group consisting of Vai, Pro, Arg, dArg, Trp, Asp, dAsp, Asn, dAsn, dHyp, and Hyp.
[1031] In some embodiments, Y1 and Y2 are present and Y3-Y7 are absent. In some embodiments, Y3-Y7 are absent, and Y1 is dVal and Y2 is dPro. In some embodiments, Y3- Y7 are absent, and Y1 is an amino acid other than dVal and Y2 is an amino acid other than dPro.
[1032] In some embodiments, Y1-Y3 is present and Y4-Y7 are absent. In some embodiments, Y1-Y3 are each independently selected from dVal and dPro. In some embodiments, one or more of Y1-Y3 is an amino acid other than dVal and dPro.
[1033] In some embodiments, Y1-Y4 are present, and Y5-Y7 are absent. In some embodiments, Y1-Y4 are each independently selected from dVal and dPro. In some embodiments, one or more of Y1-Y4 is an amino acid other than dVal and dPro.
[1034] In some embodiments, Y1-Y5 are present, and Y6 and Y7 are absent. In some embodiments, Y1-Y5 are each independently selected from dVal and dPro.
[1035] In some embodiments, Y1-Y6 are present, and Y7 is absent. In some embodiments, Y1-Y6 are each independently selected from dVal and dPro. [1036] In some embodiments, Y1-Y7 are present. In some embodiments, Y1-Y7 are each independently selected from dVal and dPro.
[1037] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified by a functional group selected from the group consisting of an amide group, an ester group, and an aldehyde group.
[1038] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified by an amide group
Figure imgf000133_0001
the sequence of Formula (I), a non-naturally occurring melanocortin analog with a C-terminus modified by an amide may be represented by a terminal -NH2.
[1039] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is not modified. In the sequence of any one of Formulae (l)-( I D), a non- naturally occurring melanocortin analog with an unmodified C-terminus may be represented by -OH or by the absence of a C-terminal group.
[1040] Melanocortin analogs in accordance with the present technology may reduce lean mass loss, maintain lean mass, or promote lean mass gain in a subject in need thereof. Additionally, the melanocortin analogs of the present technology may not induce change in plasma insulin levels in the subject, as is seen for other melanocortin analog peptides and small molecules that exhibit antagonist activity on one or more melanocortin receptors. For example, a subject may maintain stable plasma insulin levels, while maintaining or gaining lean mass, following administration of a melanocortin antagonist of the present technology.
[1041] In some embodiments, the non-naturally occurring melanocortin analog of any one of Formulae (l)-(ID) is cyclized. For example, the non-naturally occurring melanocortin analog may be cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO- c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys.
[1042] In some embodiments, the sequence of any one of Formulae (l)-(ID) is cyclized through a lactam bond. In some embodiments, when the melanocortin analog is cyclized via a lactam bond, R4 is dNal(2'). In further embodiments, R1 is Nle or Asp, R2 is Asp, Pro, or Phe, R3 is Pro, Hyp, or His, R5 arginine, R6 is Trp, R7 is Pro or Lys, and R8 is Lys or absent. In some embodiments, the sequence of Formula (IA) is selected from the group consisting of:
[1043] Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro (SEQ ID NO: 2);
[1044] Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 3);
[1045] Ac-Nle-c[Asp-Hyp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 4);
[1046] Ac-Nle-c[Asp-Pro-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 5);
[1047] Ac-Nle-c[Asp-Phe-His-dNal(2')-Arg-Trp-Lys]-dLeu-dPro-NH2 (SEQ ID NO: 6);
[1048] Ac-Nle-c[Asp-Phe-His-dNal(2')-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 7);
[1049] Ac-Nle-c[Asp-Hyp-dNal(2')-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 9); and
[1050] Ac-Nle-c[Asp-Pro-His-dNal(2’)-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 10),
[1051] wherein c represents cyclization through R1 or R2 and R7 via a lactam bond.
[1052] In some embodiments, R9 is present. In some embodiments, the sequence of any one of Formulae (l)-(ID) is: Ac-Nle-c[Asp-Phe-Phe-Pro-His-dNal(2')-Arg-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 1 1 ), wherein c represents cyclization through R1 and R9 via a lactam bond.
[1053] In some embodiments, R9 is absent. In some embodiments, X1-X3 are present. In further embodiments, X1 is Nle, X2 is Phe and X3 is Phe. In some embodiments, the sequence of any one of Formulae (l)-(ID) is: Ac-Nle-Phe-Phe-c[Asp-Phe-His-dNal(2')-Arg- Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 12), wherein c represents cyclization through R1 and R8 via a lactam bond. [1054] In some embodiments, the sequence of any one of Formulae (l)-(ID) is linear. In some embodiments, the sequence of any one of Formulae (l)-(ID) is: Ac-Nle-Asp-Pro- dNal(2')-Arg-Trp-Lys-dVal-dPro-NH2 (SEQ ID NO: 13). In some embodiments, the sequence of Formula (IA) is: Ac-Nle-Pro-dNal(2’)-Arg-Trp-dVal-dPro-NH2 (SEQ ID NO: 14).
[1055] In some embodiments of the sequence of any one of Formulae (l)-(ID), R1 is Nle. Alternatively, in some embodiments, R1 is an amino acid other than Nle. In some embodiments, R1 is selected from dArg, dMet, dlle, dLeu, dVal, dAla, Ala, Tie, dTle, dNIe, Nva, Gly, dPro, dCys, dPhe, dGIn, dAsn, f/ia/?sPro(guan), c/sPro(guan), dTyr, Tyr, and Dmt. In further embodiments, R3 is Pro, R4 is dNal(2’), R5 is Arg, R6 is Trp, Y1 is dVal, and Y2 is dPro. In some embodiments, the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[1056] Ac-dArg-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 15);
[1057] Ac-dMet-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 16);
[1058] Ac-dlle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 17);
[1059] Ac-dl_eu-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 18);
[1060] Ac-dVal-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 19);
[1061] Ac-dAla-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 20);
[1062] Ac-Ala-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 21 );
[1063] Ac-Tle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 22);
[1064] Ac-dTle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 23);
[1065] Ac-dNle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 24);
[1066] Ac-Nva-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 25);
[1067] Ac-Gly-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 26);
[1068] Ac-dPro-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 27);
[1069] Ac-dCys-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 28);
[1070] Ac-dPhe-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 29); [1071] Ac-dTyr-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 30);
[1072] Ac-dGln-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 31 );
[1073] Ac-dAsn-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 32);
[1074] Ac-fransPro(guan)-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID
NO: 33);
[1075] Ac-c/sPro(guan)-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
34);
[1076] dTyr-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 35);
[1077] Tyr-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 36); and
[1078] Dmt-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 37),
[1079] wherein c represents cyclization through R2 and R7 via a lactam bond.
[1080] In some embodiments, when the sequence of any one of Formulae (l)-(ID) is cyclized through R2 and R7, then R2 is Asp and R7 is Lys. Alternatively, in some embodiments, when the sequence of any one of Formulae (l)-(ID) is cyclized through R2 and R7, then R2 is an amino acid capable of forming a linkage to the residue at R7 other than Asp and R7 is an amino acid capable of forming a linkage to the residue at R2 other than Lys. For example, when R2 is an amino acid other than Arg and R7 is an amino acid other than Lys, the residue at R2 may be capable of forming a linkage such as a lactam bond or a disulfide bond with the residue at R7. In some embodiments, the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[1081] Ac-Nle-c[dAsp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 38);
[1082] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-dLys]-dVal-dPro-NH2 (SEQ ID NO: 39);
[1083] Ac-Nle-c[Cys-Pro-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 40);
[1084] Ac-Nle-c[dCys-Pro-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 41 );
[1085] Ac-Nle-c[Cys-Pro-dNal(2’)-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 42);
[1086] Ac-Nle-c[dCys-Pro-dNal(2’)-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 43); [1087] Ac-Nle-c[Cys-Pro-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 48);
[1088] Ac-Nle-c[dCys-Pro-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 49);
[1089] Ac-Nle-c[Pen-Pro-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 50);
[1090] Ac-Nle-c[Pen-Pro-dNal(2’)-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 51 );
[1091] Ac-Nle-c[Pen-Pro-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 52);
[1092] Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 53);
[1093] Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 54);
[1094] Ac-Nle-c[Pen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 55);
[1095] Ac-Nle-c[Pen-dNal(2’)-Arg-Trp-dOys]-dVal-dPro-NH2 (SEQ ID NO: 59);
[1096] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 64);
[1097] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-dOrn]-dVal-dPro-NH2 (SEQ ID NO: 65);
[1098] Ac-Nle-c[Glu-Pro-dNal(2’)-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 66);
[1099] Ac-Nle-c[Glu-Pro-dNal(2’)-Arg-Trp-dOrn]-dVal-dPro-NH2 (SEQ ID NO: 67); and
[1100] c[CO-cis-CH = CH-CO-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 197),
[1101] wherein c represents cyclization through R1 or R2 and R7 via a lactam bond or a disulfide bond.
[1102] In some embodiments, when the sequence of any one of Formulae (l)-(ID) is cyclized through a lactam bond between Asp at R1 or R2 and Lys at R7.
[1103] In some embodiments of the sequence of any one of Formulae (l)-(ID), R3 is Pro. Alternatively, in some embodiments, R3 is absent or an amino acid other than Pro. In some embodiments, R3 is absent or selected from the group consisting of Ala, dAla, dMet, Gly, Leu, lie, Vai, dLeu, dlle, dVal, Trp, f/'ansPro(guan), c/sPro(guan), {3-Ala, Mamb, Acpc, Aba, Aia, Aic, Cpe, Che, Oic, Tic, and Glu. In further embodiments, R1 is Nle, R4 is dNal(2’), R5 is Arg, R6 is Trp, Y1 is dVal, and Y2 is dPro. In some embodiments, the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: [1104] Ac-Nle-c[Asp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 68);
[1105] Ac-Nle-c[Asp-Ala-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 69);
[1106] Ac-Nle-c[Asp-dAla-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 71 );
[1107] Ac-Nle-c[Asp-dMet-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 72);
[1108] Ac-Nle-c[Asp-Pro-Gly-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 73);
[1109] Ac-Nle-c[Asp-Gly-Gly-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 74);
[1110] Ac-Nle-c[Asp-Gly-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 75);
[1111] Ac-Nle-c[Asp-Leu-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 76);
[1112] Ac-Nle-c[Asp-lle-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 77);
[1113] Ac-Nle-c[Asp-Val-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 78);
[1114] Ac-Nle-c[Asp-dLeu-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 79);
[1115] Ac-Nle-c[Asp-dlle-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 80);
[1116] Ac-Nle-c[Asp-dVal-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 81 );
[1117] Ac-Nle-c[Asp-Trp-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 82);
[1118] Ac-Nle-c[Asp-?ransPro(guan)-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID
NO: 84);
[1119] Ac-Nle-c[Asp-c/sPro(guan)-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
85),
[1120] Ac-Nle-c[Asp-p-Ala-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 199);
[1121] Ac-Nle-c[Asp-Mamb-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 200);
[1122] Ac-Nle-c[Asp-Acpc-dNal(2') Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 201 );
[1123] Ac-Nle-c[Asp-Aba-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 204);
[1124] Ac-Nle-c[Asp-Aia-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 205);
[1125] Ac-Nle-c[Asp-Aic-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 239); [1126] Ac-Nle-c[Asp-Cpe-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 240);
[1127] Ac-Nle-c[Asp-Che-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 241 );
[1128] Ac-Nle-c[Asp-Oic-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 242);
[1129] Ac-Nle-c[Asp-Tic-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 244); and
[1130] Ac-Nle-c[Asp-Glu-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 255),
[1131] wherein c represents cyclization through R1 or R2 and R7 via a lactam bond.
[1132] In some embodiments of the sequence of any one of Formulae (l)-(ID), R5 is Arg. Alternatively, in some embodiments, R5 is absent or an amino acid other than Arg. In some embodiments, R5 is absent or selected from Lys, Orn, His, Ala, fransPro(guan), c/sPro(guan), and Glu. In further embodiments, R1 is Nle, R3 is His or Pro, R4 is dNal(2’), R6 is Trp, Y1 is dVal, and Y2 is dPro. In some embodiments, the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[1133] Ac-Nle-c[Asp-Pro-dNal(2’)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 86);
[1134] Ac-Nle-c[Asp-Pro-dNal(2’)-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 87);
[1135] Ac-Nle-c[Asp-Pro-dNal(2’)-Orn-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 90);
[1136] Ac-Nle-c[Asp-Pro-dNal(2’)-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 92);
[1137] Ac-Nle-c[Asp-Pro-dNal(2’)-Ala-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 93);
[1138] Ac-Nle-c[Asp-Pro-dNal(2’)-Glu-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 96);
[1139] Ac-Nle-c[Asp-His-dNal(2’)-fransPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID
NO: 247);
[1140] Ac-Nle-c[Asp-His-dNal(2’)-c/sPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 248);
[1141] Ac-Nle-c[Asp-Pro-dNal(2’)-fransPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID
NO: 250); and
[1142] Ac-Nle-c[Asp-Pro-dNal(2’)-c/sPro(guan)Pro-Trp-Lys]-dVal-dPro-NH2 (SEQ ID
NO: 251 ), [1143] wherein c represents cyclization through R2 and R7 via a lactam bond.
[1144] In some embodiments of the sequence of any one of Formulae (l)-(ID), R6 is
Trp. Alternatively, in some embodiments, R6 is absent or an amino acid other than Trp. In some embodiments, R6 is selected from Nal ( 1 ’) , dNal(1 ’), Aia, Phe, dPhe, Tyr, dTyr, dNal(2’), dTrp, Aba, and Ata. In further embodiments, R1 is Nle, R3 is Pro, R4 is dNal(2’), R5 is Arg, Y1 is dVal, and Y2 is dPro. In some embodiments, the sequence of any one of Formulae (I)- (ID) is selected from the group consisting of:
[1145] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Nal(1 ’)-Lys]-dVal-dPro-NH2 (SEQ ID NO: 102);
[1146] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Aia-Lys]-dVal-dPro-NH2 (SEQ ID NO: 103);
[1147] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Phe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 104);
[1148] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Tyr-Lys]-dVal-dPro-NH2 (SEQ ID NO: 105);
[1149] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dNal(1 ’)-Lys]-dVal-dPro-NH2 (SEQ ID NO:
108);
[1150] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dPhe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 109);
[1151] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dNal(2’]-Lys]-dVal-dPro-NH2 (SEQ ID NO:
1 10);
[1152] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dTyr-Lys]-dVal-dPro-NH2 (SEQ ID NO: 111 );
[1153] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dTrp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 196);
[1154] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Aba-Lys]-dVal-dPro-NH2 (SEQ ID NO: 253); and
[1155] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Ata-Lys]-dVal-dPro-NH2 (SEQ ID NO: 254),
[1156] wherein c represents cyclization through R2 and R7 via a lactam bond.
[1157] In some embodiments of the sequence of any one of Formulae (l)-(ID), Y1 is dVal and Y2 is dPro. Alternatively, in some embodiments, Y1 is an amino acid other than dVal and Y2 is absent or an amino acid other than dPro. In some embodiments, Y1 is dVal and Y2 is an amino acid other than dPro. In some embodiments, Y1 is an amino acid other than dVal and Y2 is dPro. [1158] In some embodiments, Y1 is dVal, Y2 is dPro, and the C-terminus is modified by NH2. In some embodiments, Y1 is an amino acid other than dVal, Y2 is an amino acid other than dPro, and the C-terminus is modified by NH2. In some embodiments, Y1 is dVal, Y2 is an amino acid other than dPro, and the C-terminus is modified by NH2. In some embodiments, Y1 is an amino acid other than dVal, Y2 is dPro, and the C-terminus is modified by NH2. In some embodiments, Y1 is dVal, Y2 is dPro, and the C-terminus is unmodified.
[1159] In some embodiments of any one of Formulae (l)-(ID), when Y1 is an amino acid other than dVal, then Y1 is selected from dPro, Vai, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, Lys, dLys, Trp, and dTle. In some embodiments of any one of Formulae (l)-(ID) when Y2 is absent or an amino acid other than dPro, then Y2 is absent or selected from dVal, Vai, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, and dTle. In further embodiments, R1 is Nle, R3 is Pro, R4 is dNal(2’), R5 is Arg, and R6 is Trp. In some embodiments, the sequence of any one of Formulae (l)-(ID), is selected from the group consisting of:
[1160] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Val-Pro-NH2 (SEQ ID NO: 115);
[1161] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 1 16);
[1162] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 1 17);
[1163] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-Hyp-NH2 (SEQ ID NO: 1 18);
[1164] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 1 19);
[1165] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Val-Hyp-NH2 (SEQ ID NO: 120);
[1166] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Val-dHyp-NH2 (SEQ ID NO: 121 );
[1167] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Hyp-dVal-NH2 (SEQ ID NO: 122);
[1168] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dHyp-dVal-NH2 (SEQ ID NO: 123);
[1169] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Hyp-Val-NH2 (SEQ ID NO: 124);
[1170] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dHyp-Val-NH2 (SEQ ID NO: 125);
[1171] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dVal-NH2 (SEQ ID NO: 126);
[1172] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-dPro-NH2 (SEQ ID NO: 127); [1173] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-NH2 (SEQ ID NO: 128);
[1174] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-NH2 (SEQ ID NO: 129);
[1175] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Val-NH2 (SEQ ID NO: 130);
[1176] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Pro-NH2 (SEQ ID NO: 131 );
[1177] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Ala-NH2 (SEQ ID NO: 132);
[1178] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAla-NH2 (SEQ ID NO: 133);
[1179] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dHyp-NH2 (SEQ ID NO: 134);
[1180] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Hyp-NH2 (SEQ ID NO: 135);
[1181] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAla-dAla-NH2 (SEQ ID NO: 136);
[1182] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Ala-Ala-NH2 (SEQ ID NO: 137);
[1183] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Gly-Gly-NH2 (SEQ ID NO: 138);
[1184] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-Asp-NH2 (SEQ ID NO: 139);
[1185] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-Arg-NH2 (SEQ ID NO: 140);
[1186] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-Asn-NH2 (SEQ ID NO: 141 );
[1187] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dAsp-NH2 (SEQ ID NO: 142);
[1188] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dArg-NH2 (SEQ ID NO: 143);
[1189] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dAsn-NH2 (SEQ ID NO: 144);
[1190] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Asp-dPro-NH2 (SEQ ID NO: 145);
[1191] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-dPro-NH2 (SEQ ID NO: 146);
[1192] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Asn-dPro-NH2 (SEQ ID NO: 147);
[1193] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAsp-dPro-NH2 (SEQ ID NO: 148);
[1194] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 149);
[1195] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAsn-dPro-NH2 (SEQ ID NO: 150);
[1196] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Asp-NH2 (SEQ ID NO: 151 ); [1197] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-NH2 (SEQ ID NO: 152);
[1198] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Asn-NH2 (SEQ ID NO: 153);
[1199] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAsp-NH2 (SEQ ID NO: 154);
[1200] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dArg-NH2 (SEQ ID NO: 155);
[1201] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAsn-NH2 (SEQ ID NO: 156);
[1202] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-Pro-Val-NH2 (SEQ ID NO: 157);
[1203] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-dPro-dVal-NH2 (SEQ ID NO: 158);
[1204] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dLys-dPro-dVal-NH2 (SEQ ID NO: 159);
[1205] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-dPro-NH2 (SEQ ID NO: 160);
[1206] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dLys-dPro-NH2 (SEQ ID NO: 161 );
[1207] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-Val-Pro-NH2 (SEQ ID NO: 162);
[1208] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-dVal-dPro-NH2 (SEQ ID NO: 163);
[1209] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dLys-dVal-dPro-NH2 (SEQ ID NO:
164);
[1210] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-Pro-Val-NH2 (SEQ ID NO: 165);
[1211] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-dPro-dVal-NH2 (SEQ ID NO: 166);
[1212] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dArg-dPro-dVal-NH2 (SEQ ID NO:
167);
[1213] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-Val-Pro-NH2 (SEQ ID NO: 168);
[1214] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-dVal-dPro-NH2 (SEQ ID NO: 169);
[1215] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO:
170);
[1216] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dVal-dPro-NH2 (SEQ ID NO:
171 ); [1217] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 172);
[1218] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dVal-NH2 (SEQ ID NO: 173);
[1219] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dTle-NH2 (SEQ ID NO: 174);
[1220] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO:
175);
[1221] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO:
176);
[1222] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-dTle-NH2 (SEQ ID NO: 177);
[1223] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 178);
[1224] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Trp-NH2 (SEQ ID NO: 203); and
[1225] Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dPro-dl_ys-dAsp-NH2 (SEQ ID
NO: 263),
[1226] wherein c represents cyclization through R2 and R7 via a lactam bond.
[1227] In some embodiments of the sequence of any one of Formulae (l)-(ID), when
Y3 is present and Y4-8 are absent, then each of Y1, Y2, and Y3 are independently selected form dVal and dPro. In some embodiments of the sequence of any one of Formulae (l)-(ID) , when Y3 and Y4 are present and Y5-8 are absent, then each of Y1, Y2, Y3, and Y4 are independently selected form dVal and dPro. In some embodiments of the sequence of any one of Formulae (l)-(ID), when Y3-Y5 are present and Y6-8 are absent, then each of Y1-Y5 are independently selected form dVal and dPro. In some embodiments of the sequence of any one of Formulae (l)-(ID), when Y3-Y6 are present and Y7-8 are absent, then each of Y1-Y6 are independently selected form dVal and dPro. In some embodiments of the sequence of any one of Formulae (l)-(ID), when Y3-Y7 are present and Y8 is absent, then each of Y1-Y7 are independently selected form dVal and dPro. In some embodiments of the sequence of any one of Formulae (l)-(ID), when Y3-Y8 are present, then each of Y1-Y8 are independently selected form dVal and dPro. In some embodiments, the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: [1228] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-d\/al-dVal-dPro-NH2 (SEQ ID NO:
179);
[1229] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
180);
[1230] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 181 );
[1231] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID
NO: 182); and
[1232] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dVal-dVal-dVal-dVal-dVal-dPro-
NH2 (SEQ ID NO: 183),
[1233] wherein c represents cyclization through R2 and R7 via a lactam bond.
[1234] In some embodiments of the sequence of any one of Formulae (l)-(ID), X1 is present and is Nle, and R1 is present and is Nle. In some embodiments, X2 is present and is Nle. In some embodiments, X3 is present and is Nle. In some embodiments, the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[1235] Ac-Nle-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 184);
[1236] Ac-Nle-Nle-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
185); and
[1237] Ac-Nle-Nle-Nle-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID
NO: 186),
[1238] wherein c represents cyclization through R2 and R7 via a lactam bond.
[1239] In some embodiments, the sequence of any one of Formulae (l)-(ID) is cyclized through R1 and R7. In further embodiments, at least one of R2 and R3 is Pro. In some embodiments, R2 is Pro or Trp and R3 is selected from Pro, or Glu. In some embodiments, the sequence of any one of Formulae (l)-(ID) is cyclized through R2 and R8. In further embodiments, R7 is Pro or Gly. In some embodiments, the sequence of any one of Formulae (l)-(ID) is cyclized through R1 and R8. In further embodiments, R2 is Glu, R3 is His, and R7 is Gly. In some embodiments, the sequence of any one of Formulae (l)-(l D) is selected from the group consisting of:
[1240] Ac-Nle-c[Asp-Pro-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 194);
[1241] Ac-Nle-c[Asp-Trp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 195);
[1242] Ac-Nle-c[Asp-Pro-Glu-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 257);
[1243] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 245);
[1244] Ac-Nle-c[Asp-Glu-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 256);
[1245] Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 259);
[1246] Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys]-dPro-dPro-Lys-Asp-NH2 (SEQ ID
NO: 260);
[1247] Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys]-dPro-dPro-dLys-dAsp-NH2 (SEQ
ID NO: 261 );
[1248] Ac-Glu-c[Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys]-dPro-dPro-Lys-Asp-NH2 (SEQ ID
NO: 262);
[1249] Ac-Nle-c[Asp-Glu-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 264); and
[1250] Ac-Nle-c[Asp-Glu-His-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO:
265),
[1251] wherein c represents cyclization through R1 or R2 and R7 or R8 via a lactam bond
[1252] In some embodiments in sequence of any one of Formulae (l)-(ID) at least one of R2 and R3 is Ala or dAla. In some embodiments, R2 is Ala or dAla and R3 is His. In some embodiments, R3 is Ala or dAla. In some embodiments, the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[1253] Ac-Nle-c[Asp-dAla-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
266); [1254] Ac-Arg-c[Asp-dAla-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
267);
[1255] Ac-Arg-c[Cys-dAla-His-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO:
269);
[1256] Ac-dArg-c[Asp-dAla-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
270);
[1257] Ac-Arg-c[Asp-dAla-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 271 );
[1258] Ac-dArg-c[Asp-dAla-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 272);
[1259] Ac-Nle-c[Asp-Ala-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 273);
[1260] Ac-Arg-c[Asp-Ala-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 274);
[1261] Ac-dArg-c[Asp-Ala-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
275);
[1262] Ac-Arg-c[Cys-dAla-His-dNal(2’)-Arg-Trp-Cys]-NH2 (SEQ ID NO: 282); and
[1263] Ac-Arg-c[Asp-dAla-His-dNal(2’)-Arg-Trp-Lys]-NH2 (SEQ ID NO: 283),
[1264] wherein c represents cyclization through R1 or R2 and R7 via a lactam bond or a disulfide bond.
[1265] In some embodiments, the sequence of any one of Formulae (l)-(ID) is cyclized through R2 and R7 or R8 via a disulfide bond. In further embodiments, R2 and R7 or R8 are both dPen. In some embodiments, R1 is selected from Nle, dLeu, dNIe, dArg, Arg, dPhe, dTyr, Ala, dHis, His, dLys, and Lys, R2 is dPen, R3 is Pro, R4 is dNal(2’), R5 is Arg, R6 is Trp, R7 is Gly or Lys, and R8 is absent or Lys. In some embodiments, the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[1266] Ac-dLeu-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO:
327);
[1267] Ac-dNle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 328);
[1268] Ac-dArg-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 329); [1269] Ac-Arg-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 330);
[1270] Ac-dPhe-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO:
331 );
[1271] Ac-dTyr-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 332);
[1272] Ac-Ala-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 333);
[1273] Ac-dHis-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 334);
[1274] Ac-His-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 335);
[1275] Ac-dl_ys-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 336);
[1276] Ac-Lys-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 337);
[1277] Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dArg-dVal-dPro-NH2 (SEQ ID NO:
344);
[1278] Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dl_ys-dVal-dPro-NH2 (SEQ ID NO:
345);
[1279] Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dArg-dPro-NH2 (SEQ ID NO: 346);
[1280] Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dl_ys-dPro-NH2 (SEQ ID NO: 347);
[1281] Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dHyp-NH2 (SEQ ID NO: 348);
[1282] Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dTle-dPro-NH2 (SEQ ID NO: 349); and
[1283] Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-Gly-dPen]-dVal-dPro-NH2 (SEQ ID NO:
350),
[1284] wherein c represents cyclization through R2 and R7 or R8 via a disulfide bond.
[1285] In some embodiments of the sequence of any one of Formulae (l)-(ID), R4 is dNal(2’). Alternatively, in some embodiments, R4 is an amino acid other than dNal(2’). In some embodiments, when R4 is an amino acid other than dNal(2’), then R4 is dPhe, p(CI)dPhe p(l)dPhe, p(Br)dPhe, p(F)dPhe, or p(CF3)dPhe. In some embodiments, the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: [1286] Ac-Nle-c[Asp-Pro-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 215);
[1287] Ac-Nle-c[Asp-Pro-p(l)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 216);
[1288] Ac-Nle-c[Asp-Pro-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 217);
[1289] Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 219);
[1290] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 220);
[1291] Ac-Nle-c[Asp-His-p(l)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 221 );
[1292] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 222);
[1293] Ac-Nle-c[Asp-His-p(CF3)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 224);
[1294] Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Aia-Lys]-dVal-dPro-NH2 (SEQ ID NO: 236);
[1295] Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Aba-Lys]-dVal-dPro-NH2 (SEQ ID NO: 237);
[1296] Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Ata-Lys]-dVal-dPro-NH2 (SEQ ID NO: 238);
[1297] Ac-Nle-c[Asp-dBip-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 369);
Ac-Nle-c[Asp-Pro-dPhe-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 426);
Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2’)-Lys]-dVal-dPro-NH2 (SEQ ID NO: 430);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 431 );
[1298] Ac-Nle-c[Cys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 432);
[1299] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
444);
[1300] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Nal(2’)-Lys]-dVal-dPro-NH2 (SEQ ID NO:
445);
[1301] Ac-Nle-c[Asp-Phe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 487);
[1302] Ac-Nle-c[Asp-Bip-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 489);
[1303] Ac-Nle-c[Asp-Trp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 493);
[1304] Ac-Nle-c[Asp-Tyr-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 495); [1305] Ac-Nle-c[Cys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 497);
[1306] Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 500);
[1307] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
507);
[1308] Ac-Nle-c[Asp-His-p(CI)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 508);
[1309] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
509);
[1310] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Nal(2’)-Lys]-dVal-dPro-NH2 (SEQ ID NO:
510);
[1311] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 514);
[1312] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 516);
[1313] Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 517);
[1314] Ac-Nle-c[Asp-dHis-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 524);
[1315] Ac-Nle-c[Asp-Phe-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 525);
[1316] Ac-Nle-c[Asp-dPhe-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 526);
[1317] Ac-Nle-c[Asp-Bip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 527);
[1318] Ac-Nle-c[Asp-Gln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 529);
[1319] Ac-Nle-c[Asp-Trp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 531 );
[1320] Ac-Nle-c[Asp-Tyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 533);
[1321] Ac-Nle-c[Asp-dTyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 534);
[1322] Ac-Nle-c[Cys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 535);
[1323] Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 538);
[1324] Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 539);
[1325] Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 540); [1326] Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 541 );
[1327] Ac-dl_ys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 542);
[1328] Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 543);
[1329] Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 544);
[1330] Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
545);
[1331] Ac-Nle-c[Asp-His-p(Br)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 546);
[1332] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
547);
[1333] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Nal(2’)-Lys]-dVal-dPro-NH2 (SEQ ID NO:
548);
[1334] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO:
549);
[1335] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 550);
[1336] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
551 );
[1337] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 552);
[1338] Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
553);
[1339] Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 554);
[1340] Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 555);
[1341] Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 556);
[1342] Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 557);
[1343] Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 558); [1344] Ac-dLys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 559);
[1345] Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 560);
[1346] Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 561 );
[1347] Ac-Nle-c[Asp-dHis-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 562);
[1348] Ac-Nle-c[Asp-Phe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 563);
[1349] Ac-Nle-c[Asp-dPhe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 564);
[1350] Ac-Nle-c[Asp-Bip-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 565);
[1351] Ac-Nle-c[Asp-dBip-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 566);
[1352] Ac-Nle-c[Asp-Gln-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 567);
[1353] Ac-Nle-c[Asp-dGln-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 568);
[1354] Ac-Nle-c[Asp-Trp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 569);
[1355] Ac-Nle-c[Asp-dTrp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 570);
[1356] Ac-Nle-c[Asp-Tyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 571 ); and
[1357] Ac-Nle-c[Asp-dTyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 572),
[1358] wherein c represents cyclization through R2 and R7 via a lactam bond or a disulfide bond.
[1359] In some embodiments, the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[1360] Ac-Nle-c[Asp-Pro-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 215);
[1361] Ac-Nle-c[Asp-Pro-p(l)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 216);
[1362] Ac-Nle-c[Asp-Pro-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 217);
[1363] Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 219);
[1364] Ac-Nle-c[Asp-His-p(l)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 221 );
[1365] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 222); [1366] Ac-Nle-c[Asp-His-p(CF3)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 224);
[1367] Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Aia-Lys]-dVal-dPro-NH2 (SEQ ID NO: 236);
[1368] Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Aba-Lys]-dVal-dPro-NH2 (SEQ ID NO: 237);
[1369] Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Ata-Lys]-dVal-dPro-NH2 (SEQ ID NO: 238);
[1370] Ac-Nle-c[Asp-dBip-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 369);
[1371] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
509);
[1372] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Nal(2’)-Lys]-dVal-dPro-NH2 (SEQ ID NO:
510);
[1373] Ac-Nle-c[Asp-Phe-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 525);
[1374] Ac-Nle-c[Asp-dPhe-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 526);
[1375] Ac-Nle-c[Asp-Bip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 527);
[1376] Ac-Nle-c[Asp-Trp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 531 );
[1377] Ac-Nle-c[Asp-Tyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 533);
[1378] Ac-Nle-c[Asp-dTyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 534);
[1379] Ac-Nle-c[Cys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 535);
[1380] Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 538);
[1381] Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
545);
[1382] Ac-Nle-c[Asp-His-p(Br)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 546);
[1383] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
547);
[1384] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Nal(2’)-Lys]-dVal-dPro-NH2 (SEQ ID NO:
548); [1385] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 549);
[1386] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
551 );
[1387] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 552);
[1388] Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
553);
[1389] Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 555);
[1390] Ac-Nle-c[Asp-dHis-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 562);
[1391] Ac-Nle-c[Asp-Phe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 563);
[1392] Ac-Nle-c[Asp-dPhe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 564);
[1393] Ac-Nle-c[Asp-Bip-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 565);
[1394] Ac-Nle-c[Asp-dBip-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 566);
[1395] Ac-Nle-c[Asp-Gln-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 567);
[1396] Ac-Nle-c[Asp-dGln-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 568);
[1397] Ac-Nle-c[Asp-Trp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 569);
[1398] Ac-Nle-c[Asp-dTrp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 570);
[1399] Ac-Nle-c[Asp-Tyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 571 ); and
[1400] Ac-Nle-c[Asp-dTyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 572),
[1401] wherein c represents cyclization through R2 and R7 via a lactam bond or a disulfide bond.
[1402] In some embodiments, the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[1403] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 220); [1404] Ac-Nle-c[Asp-Pro-dPhe-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 426);
[1405] Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2’)-Lys]-dVal-dPro-NH2 (SEQ ID NO: 430);
[1406] Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(2')-l_ys]-dVal-dPro-NH2 (SEQ ID NO: 431 );
[1407] Ac-Nle-c[Cys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 432);
[1408] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
444);
[1409] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Nal(2’)-Lys]-dVal-dPro-NH2 (SEQ ID NO:
445);
[1410] Ac-Nle-c[Asp-Phe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 487);
[1411] Ac-Nle-c[Asp-Bip-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 489);
[1412] Ac-Nle-c[Asp-Trp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 493);
[1413] Ac-Nle-c[Asp-Tyr-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 495);
[1414] Ac-Nle-c[Cys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 497);
[1415] Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 500);
[1416] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
507);
[1417] Ac-Nle-c[Asp-His-p(CI)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 508);
[1418] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 514);
[1419] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 516);
[1420] Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 517);
[1421] Ac-Nle-c[Asp-dHis-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 524);
[1422] Ac-Nle-c[Asp-Gln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 529);
[1423] Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 539);
[1424] Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 540); [1425] Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 541 );
[1426] Ac-dl_ys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 542);
[1427] Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 543);
[1428] Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 544);
[1429] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 550);
[1430] Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 554);
[1431] Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 556);
[1432] Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 557);
[1433] Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 558);
[1434] Ac-dLys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 559);
[1435] Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 560);
[1436] Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 561 ),
[1437] wherein c represents cyclization through R2 and R7 via a lactam bond or a disulfide bond.
[1438] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-7, 9-12, 13-23, 24-27, 28-30, 31 -43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 10S- 111 , 115-122, 123-138, 139-157, 158-164, 165-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219-222, 224, 236-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, 344-350, 369, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-510, 514, 516-517, 524-527, 529, 531 , 533-535, and 538-572. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-7, 9-10, 12-23, 24-27, 28-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-11 1 , 115-138, 139-157, 158- 162, 164-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219, 221 -222, 224, 236-242, 244-245, 247-248, 250-257, 259-267, 269-275, 282-283, 327-337, 344-350, 509- 510, 525-527, 531 , 533-535, 538, 545-549, 551 -553, 555, 562-569, and 571 -572. In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-4, 13, 15-23, 24-32, 35-43, 48-55, 59, 64-69, 71 -76, 77-82, 86-87, 90, 92-93, 96, 102, 104-105, 108-11 1 , 115-138, 139-162, 164, 165-186, 195-197, 199-201 , 203, 215-217, 219, 221 -222, 224, 240-242, 244, 255-256, 259-267, 269-275, 327- 328, 331 , 344-350, 525-527, 531 , 533-535, 538, 545, 547-549, 551 -553, 555, 562-569, and 571 -572. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-7, 9-10, 12-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-111 , 115-138, 139-162, 164, 165- 186, 194-197, 199-201 , 203-206, 239-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, and 344-350. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 215-217, 219-222, 224, 236-238, 497, 500, 507-510, 514, 516- 517, 535, and 538-561. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 220, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-508, 514, 516-517, 524, 529, 539-544, 550, 554, and 556-561 .
Non-Naturally Occurring Melanocortin Analog Synthesis
[1439] The non-naturally occurring melanocortin analogs of the present technology may be readily synthesized by any known conventional procedure for the formation of a peptide linkage between amino acids. Such conventional procedures include, for example, any solution phase procedure permitting a condensation between the free alpha amino group of an amino acid or residue thereof having the carboxyl group or other reactive groups protected and the free primary carboxyl group of another amino acid or residue thereof having the amino group or other reactive groups protected. In an exemplary procedure, the peptides of the present technology may be synthesized by solid-phase synthesis and purified according to methods known in the art. Any of a number of well-known procedures utilizing a variety of resins and reagents may be used to prepare the peptides of the present technology.
[1440] The process for synthesizing the peptides may be carried out by a procedure whereby each amino acid in the desired sequence is added one at a time in succession to another amino acid or residue thereof or by a procedure whereby peptide fragments with the desired amino acid sequence are first synthesized conventionally and then condensed to provide the desired peptide. The resulting peptide is then cyclized to yield a cyclic peptide.
[1441] Solid phase peptide synthesis methods are well known and practiced in the art. In such methods, the synthesis of peptides may be carried out by sequentially incorporating the desired amino acid residues one at a time into the growing peptide chain according to the general principles of solid phase methods. These methods are disclosed in numerous references, including Merrifield, Angew Chem. 24:799-810 (1985) and Barany et aL, The Peptides, Analysis, Synthesis and Biology, Vol. 2, Gross E. and Meienhofer J., Eds. Academic Press 1 -284 (1980).
[1442] In chemical syntheses of peptides, reactive side chain groups of the various amino acid residues are protected with suitable protecting groups, which prevent a chemical reaction from occurring at that site until the protecting group is removed. Also common is the protection of the alpha amino group of an amino acid residue or fragment while that entity reacts at the carboxyl group, followed by the selective removal of the alpha amino protecting group to allow a subsequent reaction to take place at that site. Specific protecting for solid phase synthesis methods and solution phase synthesis methods groups are known to those having ordinary skill in the art.
[1443] Alpha amino groups may be protected by a suitable protecting group, including a urethane-type protecting group, such as benzyloxycarbonyl (Z) and substituted benzyloxycarbonyl, such as p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, p-biphenyl-isopropoxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc) and p-methoxybenzyloxycarbonyl (Moz); aliphatic urethane-type protecting groups, such as t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropoxycarbonyl, and allyloxycarbonyl. Fmoc is useful for alpha amino protection.
[1444] Guanidino groups may be protected by a suitable protecting group, such as nitro, p-toluenesulfonyl (Tosyl), Z, pentamethylchromanesulfonyl (Pmc), adamantyloxycarbonyl, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) and Boc. Pmc is a useful protecting group for Arg.
[1445] Solid phase synthesis is commenced from the C-terminal end of the peptide by coupling a protected alpha amino acid to a suitable resin. Such starting material is prepared by attaching an alpha amino-protected amino acid by an ester linkage to a p- benzyloxybenzyl alcohol (Wang) resin or a 2-chlorotrityl chloride resin, by an amide bond between an Fmoc-Linker, such as p-[(R,S)-a-[1 -(9H-fluor-en-9-yl)-methoxyformamido]-2,4- dimethyloxybenzyl]-phenoxyacetic acid (Rink linker) to a benzhydrylamine (BHA) resin, or by other means well known in the art. Fmoc-Linker-BHA resin supports are commercially available and generally used when feasible. The resins are carried through repetitive cycles as necessary to add amino acids sequentially. The alpha amino Fmoc protecting groups are removed under basic conditions. Piperidine, piperazine, diethylamine, or morpholine (20-40% v/v) in N,N-dimethylformamide (DMF) may be used for this purpose.
[1446] Following removal of the alpha amino protecting group, the subsequent protected amino acids are coupled stepwise in the desired order to obtain an intermediate, protected peptide-resin. The activating reagents used for coupling of the amino acids in the solid phase synthesis of the peptides are well known in the art. After the peptide is synthesized, if desired, the orthogonally protected side chain protecting groups may be removed using methods well known in the art for further derivatization of the peptide.
[1447] Reactive groups in a peptide may be selectively modified, either during solid phase synthesis or after removal from the resin. For example, peptides may be modified to obtain N-terminus modifications, such as acetylation, while on resin, or may be removed from the resin by use of a cleaving reagent and then modified. Methods for N-terminus modification, such as acetylation, and for C-terminus modification, such as amidation, are known in the art. Similarly, methods for modifying side chains of amino acids are well known to those skilled in the art of peptide synthesis. The choice of modifications made to reactive groups present on the peptide will be determined, in part, by the characteristics that are desired in the peptide.
[1448] The peptide may be cyclized prior to cleavage from the peptide resin. For cyclization through reactive side chain moieties, the desired side chains are deprotected, and the peptide suspended in a suitable solvent and a cyclic coupling agent added. Suitable solvents include, for example DMF, dichloromethane (DOM) or 1 -methyl-2-pyrrolidone (NMP). Suitable cyclic coupling reagents include, for example, 2-(1 H-benzotriazol-1 -yl)- 1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TBTLI), 2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate (HBTU), benzotriazole-1 -yl-oxy- tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole-1 -yl-oxy- tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP), 2-(7-aza-1 H-benzotriazol-1 - yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TATLI), 2-(2-oxo-1 (2H)-pyridyl)-1 ,1 ,3,3- tetramethyluronium tetrafluoroborate (TPTU) or N,N'-dicyclohexylcarbodiimide/1 - hydroxybenzotriazole (DCCI/HOBt). Coupling is convention initiated by use of a suitable base, such as N,N-diispropylethylamine (DIPEA), sym-collidine or N-methylmorpholine (NMM).
[1449] Following cleavage of peptides from the solid phase following their synthesis, the peptide may be purified by any number of methods, such as reverse phase high performance liquid chromatography (RP-HPLC), using a suitable column, such as a C18 column. Other methods of separation or purification, such as methods based on the size or charge of the peptide, may also be employed. Once purified, the peptide may be characterized by any number of methods, such as high-performance liquid chromatograph (HPLC), amino acid analysis, mass spectrometry, and the like.
Salt Forms of Non-Naturally Occurring Melanocortin Analogs
[1450] The non-naturally occurring melanocortin analog peptides of the present technology may be in the form of any salt. The term “pharmaceutically acceptable salts” refers to salts prepared from non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Exemplary salts are the ammonium, calcium, lithium, magnesium, potassium, and sodium salts. Salts derived from organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
[1451] When the peptides of the present technology are basic, acid addition salts may be prepared from non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, carboxylic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric, pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric, tartaric, p-toluenesulfonic acid, trifluoroacetic acid, and the like. Acid addition salts of the peptides of the present technology are prepared in a suitable solvent from the peptide and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, citric, tartaric, maleic, succinic or methanesulfonic acid. The acetate salt form is especially useful. Where the peptides of the present technology include an acidic moiety, suitable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts.
Weight Loss Agents
[1452] The non-naturally occurring melanocortin analogs of the present technology may be administered before or after administration of a weight loss agent (e.g., a glucagon- like peptide-1 receptor agonist). In some embodiments, the non-naturally occurring melanocortin analogs are administered simultaneously to a weight loss agent. The non- naturally occurring melanocortin analog may be used to offset weight loss or reduce, prevent, or otherwise reverse lean mass loss attributed to use of the weight loss agent. The present technology is expected to be useful for subjects that may receive, have received, or are receiving one or more doses of a weight loss agent regardless of the underlying disease or condition that the subject has or develops.
Pharmaceutical Compositions, Formulations, and Administration
[1453] The non-naturally occurring melanocortin analogs of the present technology may be present in a pharmaceutical composition.
[1454] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 0.1 mg/mL to 50 mg/mL, relative to a total volume of the pharmaceutical composition. In some embodiments, the non- naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 0.1 mg/mL to 50 mg/mL, 0.5 mg/mL to 40 mg/mL, 1 mg/mL to 30 mg/mL, 2.5 mg/mL to 20 mg/mL, 5 mg/mL to 15 mg/mL, or 5 mg/mL to 10 mg/mL, relative to a total volume of the pharmaceutical composition. In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 10 mg/mL, relative to a total volume of the pharmaceutical composition.
[1455] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 0.1 mg/mL to about 50 mg/mL, relative to a total volume of the pharmaceutical composition. In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 0.1 mg/mL to about 50 mg/mL, about 0.5 mg/mL to about 40 mg/mL, about 1 mg/mL to about 30 mg/mL, about 2.5 mg/mL to about 20 mg/mL, about 5 mg/mL to about 15 mg/mL, or about 5 mg/mL to about 10 mg/mL, relative to a total volume of the pharmaceutical composition. In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 10 mg/mL, relative to a total volume of the pharmaceutical composition.
[1456] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of at least 0.1 mg/mL to at least 50 mg/mL, relative to a total volume of the pharmaceutical composition. In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of at least 0.1 mg/mL to at least 50 mg/mL, at least 0.5 mg/mL to at least 40 mg/mL, at least 1 mg/mL to at least 30 mg/mL, at least 2.5 mg/mL to at least 20 mg/mL, at least 5 mg/mL to at least 15 mg/mL, or at least 5 mg/mL to at least 10 mg/mL, relative to a total volume of the pharmaceutical composition. In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of at least 10 mg/mL, relative to a total volume of the pharmaceutical composition.
[1457] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of at least about 0.1 mg/mL to at least about 50 mg/mL, relative to a total volume of the pharmaceutical composition. In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of at least about 0.1 mg/mL to at least about 50 mg/mL, at least about 0.5 mg/mL to at least about 40 mg/mL, at least about 1 mg/mL to at least about 30 mg/mL, at least about 2.5 mg/mL to at least about 20 mg/mL, at least about 5 mg/mL to at least about 15 mg/mL, or at least about 5 mg/mL to at least about 10 mg/mL, relative to a total volume of the pharmaceutical composition. In some embodiments, the non- naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of at least about 10 mg/mL, relative to a total volume of the pharmaceutical composition.
Formulations
[1458] The pharmaceutical composition comprising the non-naturally occurring melanocortin analog may be formulated for intraperitoneal, intravenous, parenteral, depot, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration. In some embodiments, the pharmaceutical composition comprising the non-naturally occurring melanocortin analog is formulated for subcutaneous administration. In some embodiments, the pharmaceutical composition comprising the non-naturally occurring melanocortin analog is formulated for oral administration. In some embodiments, the pharmaceutical composition comprising the non-naturally occurring melanocortin analog is formulated for depot administration. [1459] In some embodiments, the pharmaceutical composition further comprises a pharmaceutical salt. Any pharmaceutical salt known in the art may be included in the pharmaceutical composition.
[1460] Pharmaceutical compositions comprising the non-naturally occurring melanocortin analog may be administered using any means known in the art, including orally, rectally, vaginally, ocularly, intranasally, topically, parenterally, or by injection. If administered by injection, the injection may be intravenous (IV), subcutaneous (SC), intramuscular (IM), intraperitoneal (IP), intracerebroventricular (ICV), or other means known in the art. Compositions administered by injection may be formulated for depot injection. Pharmaceutical compositions may be formulated by any means known in the art, including but not limited to formulation as tablets, capsules, caplets, suspensions, powders, lyophilized preparations, suppositories, pessaries, ocular drops, skin patches, orally soluble formulations, enteric formulations, solutions sprays, aerosols and the like, and may be mixed and formulated with buffers, binders, excipients, stabilizers, lubricants, oils, adjuvants, antioxidants and other agents known in the art. In general, any route of administration by which the compositions are introduced across an epidermal layer of cells may be employed. Administration includes topical delivery. Administration includes delivery across the epithelium. Administration includes delivery through the gastrointestinal tract. Administration includes delivery across the blood brain barrier. Administration includes delivery through mucous membranes, buccal administration, ophthalmic administration, oral administration, dermal administration, inhalation administration, nasal administration, urethral administration, vaginal administration, rectal administration, and the like.
[1461] In order to facilitate delivery of the active ingredients, to enhance dispersion, solubility, and stability of the active ingredients, and/or to reduce adverse injection site reactions, the pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers and/or excipients.
[1462] The pharmaceutical composition may comprise one or more pharmaceutically acceptable carriers and/or excipients such as, for example, buffers, binders, excipients, stabilizers, lubricants, oils, adjuvants, and antioxidants. For example, when the first pharmaceutical composition is formulated for subcutaneous administration, the one or more pharmaceutically acceptable carriers and/or excipients may comprise water.
[1463] In some embodiments, the first pharmaceutical composition contains 0.1 to 99.9999 wt.%, 1 to 99.999 wt.%, 5 to 99.99 wt.%, 10 to 99.9 wt.%, 15 to 99 wt.%, 20 to 90 wt.%, 30 to 85 wt.%, 40 to 80 wt.%, 50 to 75 wt.%, or 60 to 70 wt.% of the one or more pharmaceutically acceptable carriers and/or excipients relative to a total weight of the first pharmaceutical composition.
[1464] In some embodiments, the first pharmaceutical composition contains 0.1 to 99.9999 wt.%, 1 to 99.999 wt.%, 5 to 99.99 wt.%, 10 to 99.9 wt.%, 15 to 99 wt.%, 20 to 90 wt.%, 30 to 85 wt.%, 40 to 80 wt.%, 50 to 75 wt.%, or 60 to 70 wt.% of the one or more pharmaceutically acceptable carriers and/or excipients relative to a total weight of the first pharmaceutical composition.
[1465] In some embodiments, the first pharmaceutical composition contains at least 0.1 to at least 99.9999 wt.%, at least 1 to at least 99.999 wt.%, at least 5 to at least 99.99 wt.%, at least 10 to at least 99.9 wt.%, at least 15 to at least 99 wt.%, at least 20 to at least 90 wt.%, at least 30 to at least 85 wt.%, at least 40 to at least 80 wt.%, at least 50 to at least 75 wt.%, or at least 60 to at least 70 wt.% of the one or more pharmaceutically acceptable carriers and/or excipients relative to a total weight of the first pharmaceutical composition.
[1466] In some embodiments, the first pharmaceutical composition contains at least about 0.1 to at least about 99.9999 wt.%, at least about 1 to at least about 99.999 wt.%, at least about 5 to at least about 99.99 wt.%, at least about 10 to at least about 99.9 wt.%, at least about 15 to at least about 99 wt.%, at least about 20 to at least about 90 wt.%, at least about 30 to at least about 85 wt.%, at least about 40 to at least about 80 wt.%, at least about 50 to at least about 75 wt.%, or at least about 60 to at least about 70 wt.% of the one or more pharmaceutically acceptable carriers and/or excipients relative to a total weight of the first pharmaceutical composition.
[1467] Any pharmaceutically acceptable carriers and/or excipients known in the art may be included in the pharmaceutical composition. Non-limiting examples of pharmaceutically acceptable carriers and/or excipients include buffers, binders, excipients, stabilizers, lubricants, oils, adjuvants, preservatives, lipids, and antioxidants. The pharmaceutical composition may comprise any combination of the one or more pharmaceutically acceptable carriers and/or excipients previously described in relation to the first and pharmaceutical compositions. In some embodiments, the one or more pharmaceutically acceptable carriers and/or excipients comprise water.
[1468] To facilitate delivery of the non-naturally occurring melanocortin analog, the pharmaceutical composition may comprise one or more pharmaceutically acceptable carriers and/or excipients. Other pharmaceutically acceptable carriers and/or excipients may be included in the pharmaceutical composition to enhance dispersion, solubility, and stability of the non-naturally occurring melanocortin analog, and to reduce adverse injection site reactions.
[1469] In some embodiments, the one or more pharmaceutically acceptable carriers and/or excipients are isotonic.
[1470] In some embodiments, the salt is present in the pharmaceutical composition in a concentration of about 0.1 mg/mL to about 50 mg/mL, about 1 mg/mL to about 25 mg/mL, or about 5 mg/mL to about 10 mg/mL, relative to a total volume of the composition.
[1471] In some embodiments, the salt is present in the pharmaceutical composition in a concentration of at least 0.1 mg/mL to at least 50 mg/mL, at least 1 mg/mL to at least 25 mg/mL, or at least 5 mg/mL to at least 10 mg/mL, relative to a total volume of the composition
[1472] In order to achieve a desirable tonicity, the pharmaceutical composition may further include a salt such as sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride.
[1473] In some embodiments, the salt is present in the pharmaceutical composition in a concentration of at least about 0.1 mg/mL to at least about 50 mg/mL, at least about 1 mg/mL to at least about 25 mg/mL, or at least about 5 mg/mL to at least about 10 mg/mL, relative to a total volume of the composition.
[1474] Pharmaceutically acceptable carriers and/or excipients that may be included in the pharmaceutical composition generally include a pH buffered aqueous solution comprising one or more of the following components: (a) sodium acetate, (b) Tris, and (c) water. In some embodiments, all components are compatible with the non-naturally occurring melanocortin analog (i.e., do not react or cause the non-naturally occurring melanocortin analog to react) and are homogeneously dispersed or dissolved uniformly in the composition.
[1475] In the pH buffered solution of the pharmaceutical composition, the water may act as a diluent and include, without limitation, water for injection (WFI), sterile water, bacteriostatic water for injection (BWFI), distilled water, bidistilled water, deionized water, deionized distilled water, and reverse osmosis water. In some embodiments, the water present in the pH buffered aqueous solution is water for injection.
[1476] In some embodiments, the pharmaceutical composition includes water in an amount of about 1 wt% to about 90 wt%, about 10 wt% to about 75 wt%, or about 25 wt% to about 50 wt%, relative to a total weight of the composition.
[1477] In some embodiments, the pharmaceutical composition includes water in an amount of at least 1 wt% to at least 90 wt%, at least 10 wt% to at least 75 wt%, or at least 25 wt% to at least 50 wt%, relative to a total weight of the composition.
[1478] In some embodiments, the pharmaceutical composition includes water in an amount of at least about 1 wt% to at least about 90 wt%, at least about 10 wt% to at least about 75 wt%, or at least about 25 wt% to at least about 50 wt%, relative to a total weight of the composition. In some embodiments, sodium acetate is present in the pharmaceutical composition in a concentration of 0.5 mg/mL to 50 mg/mL, relative to a total volume of the composition. For example, sodium acetate may be present in the pharmaceutical composition in a concentration of 0.5 mg/mL to 50 mg/mL, 1 mg/mL to 40 mg/mL, 2 mg/mL to 30 mg/mL, 4 mg/mL to 20 mg/mL, 5 mg/mL to 15 mg/mL, 6 mg/mL to 12 mg/mL, or 8 mg/mL to 10 mg/mL, relative to a total volume of the composition.
[1479] In some embodiments, sodium acetate is present in the pharmaceutical composition in a concentration of about 6 mg/mL to about 8 mg/mL, relative to a total volume of the composition. For example, sodium acetate may be present in the pharmaceutical composition in a concentration of 6 mg/mL, 6.5 mg/mL, 7 mg/mL, 7.1 mg/mL, 7.5 mg/mL, or 8 mg/mL, relative to a total volume of the composition. [1480] In some embodiments, sodium acetate is present in the pharmaceutical composition in a molar concentration of 5 mM to 700 mM, relative to a total volume of the composition. For example, sodium acetate may be present in the pharmaceutical composition in a molar concentration of 5 mM to 700 mM, 10 mM to 600 mM, 20 mM to 500 mM, 30 mM to 400 mM, 40 mM to 300 mM, 50 mM to 200 mM, 60 mM to 100 mM, or 70 mM to 80 mM, relative to a total volume of the composition.
[1481] In some embodiments, sodium acetate is present in the pharmaceutical composition in a molar concentration of about 80 mM to about 100 mM, relative to a total volume of the composition. For example, sodium acetate may be present in the pharmaceutical composition in a molar concentration of 80 mM, 85 mM, 87 mM, 90 mM, 95 mM, or 100 mM, relative to a total volume of the composition.
[1482] The term “Tris” refers to tris(hydroxymethyl)aminomethane, which is also known as Tris buffer, Tris base, TRIS, tromethamine, tromethamine buffer, Trizma®, Trisamine, Trometamol, Tromethane, Trisaminol, or THAM. In some embodiments, Tris is present in the pharmaceutical composition in a concentration of 0.5 mg/mL to 50 mg/mL, relative to a total volume of the composition. For example, Tris may be present in the pharmaceutical composition in a concentration of 0.5 mg/mL to 50 mg/mL, 1 mg/mL to 40 mg/mL, 2 mg/mL to 30 mg/mL, 4 mg/mL to 20 mg/mL, 5 mg/mL to 15 mg/mL, 6 mg/mL to 12 mg/mL, or 8 mg/mL to 10 mg/mL, relative to a total volume of the composition.
[1483] In some embodiments, Tris is present in the pharmaceutical composition in a concentration of about 6 mg/mL to about 8 mg/mL, relative to a total volume of the composition. For example, Tris may be present in the pharmaceutical composition in a concentration of 6 mg/mL, 6.5 mg/mL, 7 mg/mL, 7.3 mg/mL, 7.6 mg/mL, or 8 mg/mL, relative to a total volume of the composition.
[1484] In some embodiments, Tris is present in the pharmaceutical composition in a molar concentration of 2 mM to 500 mM, relative to a total volume of the composition. For example, Tris may be present in the pharmaceutical composition in a molar concentration of 2 mM to 500 mM, 5 mM to 400 mM, 10 mM to 300 mM, 20 mM to 200 mM, 30 mM to 150 mM, 40 mM to 100 mM, 50 mM to 80 mM, or 60 mM to 70 mM, relative to a total volume of the composition. [1485] In some embodiments, Tris is present in the pharmaceutical composition in a molar concentration of about 50 mM to about 70 mM, relative to a total volume of the composition. For example, Tris may be present in the pharmaceutical composition in a molar concentration of 50 mM, 55 mM, 60 mM, 65 mM, or 70 mM, relative to a total volume of the composition.
[1486] In some embodiments, the pH buffered aqueous solution provides the pharmaceutical composition with a pH equivalent or close to the physiological pH levels. This may reduce adverse injection site reactions and also provide the non-naturally occurring melanocortin analog with enhanced stability and resistance to aggregation and degradation.
[1487] In some embodiments, a weight ratio of sodium acetate to Tris is about 1 :4 to about 4:1 , about 2:7 to about 7:2, about 1 :3 to about 3:1 , about 2:5 to about 5:2, about 1 :2 to about 2:1 , about 2:3 to about 3:2, or about 1 :1. In some embodiments, the weight ratio of sodium acetate to Tris is about 1 :1 .
[1488] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is about 1 :1 to about 20:1 , about 3:2 to about 15:1 , about 2:1 to about 12:1 , about 3:1 to about 10:1 , about 4:1 to about 9:1 , about 5:1 to about 8:1 , or about 6:1 to about 7:1 . In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is about 7:1 .
[1489] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to Tris is about 1 :1 to about 20:1 , about 3:2 to about 15:1 , about 2:1 to about 12:1 , about 3:1 to about 10:1 , about 4:1 to about 9:1 , about 5:1 to about 8:1 , or about 6:1 to about 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to Tris is about 7:1 .
[1490] In addition to sodium acetate and Tris, the pharmaceutical composition may include other buffering agents. Non-limiting examples of additional buffering agents include saline, phosphate, phosphoric acid, citrate, succinate, gluconate, histidine, acetic acid, ascorbate, tartartic acid, maleic acid, glycine, lactate, lactic acid, ascorbic acid, imidazole, bicarbonate, carbonic acid, succinic acid, sodium benzoate, benzoic acid, gluconate, edetate, malate, imidazole, and mixtures thereof. In some embodiments, the pharmaceutical composition comprises acetic acid as an additional buffering agent.
[1491] The pharmaceutical composition may further comprise one or more chelating agents. Suitable chelating agents include, but are not limited to edetate disodium dihydrate, calcium disodium edetate, sodium edetate, calcium versetamide sodium, calteridol, and diethylenetriaminepentaacetic acid. In some embodiments, the pharmaceutical composition further comprises edetate disodium dihydrate.
[1492] The pharmaceutical composition may further comprise a preservative agent. Exemplary preservative agents include, but are not limited to, ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, phenol, m-cresol, benzyl alcohol, alpha-tocopherol, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, benzalkonium chloride, phenoxyethanol, and methyl paraben. In some embodiments, when the pharmaceutical composition comprises a preservative agent, the preservative agent is phenol, benzyl alcohol, or a combination thereof.
[1493] If present in the pharmaceutical composition, the concentration of the preservative agent may range from 0.001 mg/mL to 50 mg/mL, 0.01 mg/mL to 25 mg/mL, 0.1 mg/mL to 10 mg/mL, or 1 mg/mL to 5 mg/mL, relative to a total volume of the composition.
[1494] The pharmaceutical composition may further comprise an emulsifier. Nonlimiting examples of emulsifiers that may be included in the pharmaceutical composition include sodium carboxymethylcellulose, cetyl alcohol, glycerol monostearate, methylcellulose, and stearic acid. In some embodiments, when the pharmaceutical composition comprises an emulsifier, the emulsifier is sodium carboxymethylcellulose.
[1495] The pharmaceutical composition may further comprise a lipid. Lipids may enhance solubility and/or improve permeability of the non-naturally occurring melanocortin analog. In some embodiments, the lipid is a phospholipid. Non-limiting examples of phospholipids that may be included in the pharmaceutical composition include egg phosphatidylcholine, hydrogenated soybean phoshphaditylcholine, glycerophosphocholine, lecithin, and N-(carbonyl-methoxypolyethylene glycol 2000)-1 ,2-distearoyl-glycero-3- phosphoethanolamine sodium salt. In some embodiments, when the pharmaceutical composition comprises a lipid, the lipid is N-(carbonyl-methoxypolyethylene glycol 2000)- 1 ,2-distearoyl-glycero-3-phosphoethanolamine sodium salt.
[1496] The pharmaceutical composition may further comprise a bulking agent. Inclusion of a bulking agent may increase the stability of the pharmaceutical composition. Non-limiting examples of bulking agents that may be included in the pharmaceutical composition include sucrose, lactose, trehalose, mannitol, sorbitol, glucose, raffinose, glycine, histidine, and polyvinyl pyrrolidone. In some embodiments, when the pharmaceutical composition comprises a bulking agent, the bulking agent is mannitol.
[1497] In some embodiments, the pharmaceutical composition is in the form of an aqueous solution or a suspension. In some embodiments, the pharmaceutical composition is in the form of an emulsion. In some embodiments, the pharmaceutical composition is in the form of an aqueous solution. In some embodiments, the pharmaceutical composition is in the form of an aqueous solution which is clear, colorless, and/or free of visible foreign matter.
[1498] In some embodiments, the pharmaceutical composition has a pH ranging from about 6.5 to about 8.5. In some embodiments, the pharmaceutical composition has a pH of about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 , 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1 , 8.2, 8.3,
8.4, or 8.5.
[1499] In some embodiments, the pharmaceutical composition is basic and has a pH of about 7.1 , 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1 , 8.2, 8.3, 8.4, or 8.5. In some embodiments, the pharmaceutical composition has a pH ranging from about 7.3 to about
7.4. In some embodiments, the pharmaceutical composition has a pH of 7.3 or 7.4.
[1500] In some embodiments, the pharmaceutical composition has an osmolality ranging from 250 mOsm/kg to 350 mOsm/kg. For example, the pharmaceutical composition may have an osmolality ranging from 250 mOsm/kg to 360 mOsm/kg, 260 mOsm/kg to 340 mOsm/kg, 270 mOsm/kg to 330 mOsm/kg, 280 mOsm/kg to 320 mOsm/kg, 290 mOsm/kg to 310 mOsm/kg, or about 300 mOsm/kg. In some embodiments, the pharmaceutical composition has an osmolarity of about 250 mOsm/kg, about 260 mOsm/kg, about 270 mOsm/kg, about 280 mOsm/kg, about 290 mOsm/kg, about 300 mOsm/kg, about 310 mOsm/kg, about 320 mOsm/kg, about 330 mOsm/kg, about 340 mOsm/kg, about 350 mOsm/kg, or about 360 mOsm/kg. In some embodiments, the pharmaceutical composition has an osmolality ranging from about 275 mOsm/kg to about 330 mOsm/kg. In some embodiments, the pharmaceutical composition has an osmolality of about 279 mOsm/kg, about 314 mOsm/kg, or about 329 mOsm/kg.
[1501] In some embodiments, the pharmaceutical composition has a viscosity ranging from about 0.5 cP to about 5 cP. For example, the pharmaceutical composition may have a viscosity ranging from about 0.5 cP to about 5 cP, about 0.75 cP to about 4.5 cP, about 1 .0 cP to about 4 cP, about 1 .2 cP to about 3.5 cP, about 1 .3 cP to about 3 cP, about 1 .4 cP to about 2.5 cP, about 1.5 cP to about 2 cP, or about 1.6 cP to about 1.8 cP. In some embodiments, the pharmaceutical composition has a viscosity of about 0.5 cP, 0.6 cP, 0.7 cP, 0.8 cP, 0.9 cP, 1 .0 cP, 1 .1 cP, 1 .2 cP, 1 .3 cP, 1 .4 cP, 1 .5 cP, 1 .6 cP, 1 .7 cP, 1 .8 cP, 1 .9 cP, or 2.0 cP. In some embodiments, the pharmaceutical composition has a viscosity of about 1 .4 cP or about 1 .6 cP.
[1502] In some embodiments, the pharmaceutical composition disclosed is formulated for parenteral administration, such as, for example, in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. The term “parenteral,” as used herein, includes subcutaneous, intravenous, intraperitoneal, intramuscular, and intralesional, or infusion techniques.
[1503] When the pharmaceutical composition is formulated for parenteral administration (e.g., subcutaneous administration), the active ingredient(s) (e.g., the non- naturally occurring melanocortin analog) may be dissolved or suspended in the aforementioned carrier and/or excipient. Additional aqueous or non-aqueous carriers that may facilitate dissolution of the active ingredient include, but are not limited to, ethanol, benzyl alcohol, DMSO, polyethylene glycol, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, and/or various buffers. [1504] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., subcutaneous administration) and comprises a non-naturally occurring melanocortin analog in a concentration of about 0.001 nmol, 0.005 nmol, 0.01 nmol, 0.02 nmol, 0.05 nmol, 0.1 nmol, 0.25 nmol, 0.5 nmol, 1 nmol, 2.5 nmol, 5 nmol, 10 nmol, 20 nmol, 25 nmol, 50 nmol, 100 nmol, 250 nmol, 500 nmol, or 1000 nmol, or even more, depending on the specific peptide selected, the desired therapeutic response, the route of administration, the formulation and other factors known to those of skill in the art.
[1505] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., subcutaneous administration) and comprises sodium acetate in a concentration of about 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 76 mM, 77 mM, 78 mM, 79 mM, 80 mM, 81 mM, 82 mM, 83 mM, 84 mM, 85 mM, 86 mM, 87 mM, 88 mM, 89 mM, 90 mM, 91 mM, 92 mM, 93 mM, 94 mM, 95 mM, 96 mM, 97 mM, 98 mM, 99 mM, 100 mM, 105 mM, 1 10 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, or 200 mM.
[1506] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., subcutaneous administration) and comprises Tris in a concentration of about 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 3 5mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, or 120 mM.
[1507] Alternatively, in some embodiments, the pharmaceutical composition is formulated for intranasal administration. When the pharmaceutical composition is formulated for intranasal administration, the composition may comprise one or more pharmaceutically acceptable carriers and/or excipients to facilitate delivery and enhance dispersion, solubility, and stability of the non-naturally occurring melanocortin analog.
[1508] The pharmaceutical composition may be formulated to be delivered by nose drop, spray device, or topical solution. In some embodiments, the pharmaceutical composition may be formulated as an aerosol, atomizer, inhalation, insufflation, metered- dose inhaler, or nebulizer. In some embodiments, the composition includes a propellant, such as hydrofluoroalkane. [1509] When the pharmaceutical composition is formulated for intranasal administration, the active ingredient(s) (e.g., the non-naturally occurring melanocortin analog) may be dissolved or suspended in the one or more pharmaceutically acceptable carriers and/or excipients. Additional aqueous or non-aqueous carriers that may facilitate dissolution of the active ingredient include, but are not limited to, ethanol, benzyl alcohol, DMSO, polyethylene glycol, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, and/or various buffers.
[1510] In some embodiments, the pharmaceutical composition is formulated for intranasal administration and comprises the non-naturally occurring melanocortin analog in a concentration of about 0.001 nmol, 0.005 nmol, 0.01 nmol, 0.02 nmol, 0.05 nmol, 0.1 nmol, 0.25 nmol, 0.5 nmol, 1 nmol, 2.5 nmol, 5 nmol, 10 nmol, 20 nmol, 25 nmol, 50 nmol, 100 nmol, 250 nmol, 500 nmol, or 1000 nmol, or even more, depending on the specific peptide selected, the desired therapeutic response, the route of administration, the formulation and other factors known to those of skill in the art.
[1511] In some embodiments, the pharmaceutical composition is formulated for intranasal administration and is configured to be administered using a spray device or nasal inhaler. The spray device or nasal inhaler may be configured to deliver about 1 mg to about 10Omg per spray. In some embodiments, the spray device or nasal inhaler is configured to deliver 1 mg to 100mg, 5mg to 90mg, 10mg to 80mg, 15mg to 70mg, 20mg to 60mg, 25mg, to 50mg, or 30mg to 40mg per spray.
[1512] In some embodiments, the pharmaceutical composition is formulated for intranasal administration and has a pH approximating the normal pH range of the nasal fluid. Accordingly, in some embodiments, the pharmaceutical composition has a pH ranging from about 5.5 to about 6.5. In some embodiments, the pharmaceutical composition has a pH of about 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1 , 6.2, 6.3, 6.4, or 6.5.
[1513] Pharmaceutically acceptable carriers and/or excipients that may be included in the pharmaceutical composition formulated for intranasal administration may generally include (i) one or more antioxidants, (ii) one or more preservatives, (iii) one or more buffers, (iv) one or more tonicity adjustors, (v) one or more surfactants, (vi) flavor, (vii) propellants, and/or (viii) a vehicle or solvent. In some embodiments, all components are compatible with the non-naturally occurring melanocortin analog (i.e., do not react or cause the non-naturally occurring melanocortin analog to react) and are homogeneously dispersed or dissolved uniformly in the composition.
[1514] In some embodiments, the pharmaceutically acceptable carriers and/or excipients are isotonic to nasal fluids.
[1515] In order to achieve a desirable tonicity, the pharmaceutical composition formulated for intranasal administration may further include a salt such as sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride. In some embodiments, the salt is present in the pharmaceutical composition in a concentration of 0.1 mg/mL to 50 mg/mL, 1 mg/mL to 25 mg/mL, or 5 mg/mL to 10 mg/mL, relative to a total volume of the composition. In some embodiments, the salt is sodium chloride and is present in a concentration of 0.9% by weight.
[1516] When the pharmaceutical composition is formulated for intranasal administration, the composition may comprise a pH buffered aqueous solution as previously described.
[1517] In some embodiments, the pharmaceutical composition is formulated for intranasal administration and comprises sodium acetate in a concentration of about 80 mM to about 100 mM. For example, sodium acetate may be present in the pharmaceutical composition in a molar concentration of 80 mM, 81 mM, 82 mM, 83 mM, 84 mM, 85 mM, 86 mM, 87 mM, 88 mM, 89 mM, 90 mM, 91 mM, 92 mM, 93 mM, 94 mM, 95 mM, 96 mM, 97 mM, 98 mM, 99 mM, or 100 mM.
[1518] In some embodiments, the pharmaceutical composition is formulated for intranasal administration and comprises Tris in a concentration of about 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 3 5mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 1 10 mM, or 120 mM.
[1519] Additionally, when the pharmaceutical composition is formulated for intranasal administration, the composition may further comprise a phosphate, e.g., sodium phosphate. In some embodiments, the pharmaceutical composition is formulated for intranasal administration and comprises sodium phosphate in a molar concentration of about 5 mM to about 700 mM, relative to a total volume of the composition. For example, sodium phosphate may be present in the pharmaceutical composition in a molar concentration of 5 mM to 700 mM, 10 mM to 600 mM, 20 mM to 500 mM, 30 mM to 400 mM, 40 mM to 300 mM, 50 mM to 200 mM, 60 mM to 100 mM, or 70 mM to 80 mM, relative to a total volume of the composition.
[1520] In some embodiments, the pharmaceutical composition comprises one or more antioxidants. For example, the pharmaceutical composition may comprise ascorbic acid, cysteine, sodium metabisulfite, propyl gallate, butylated hydroxytoluene, and/or butylated hydroxyanisole.
[1521] In some embodiments, the pharmaceutical composition comprises a surfactant, such as a sorbitan ester.
[1522] In some embodiments, the pharmaceutical composition comprises a flavoring or scent, such as an aromatic oil.
[1523] In some embodiments, the non-naturally occurring melanocortin analog is solubilized or suspended in a solvent or vehicle. The solvent or vehicle may be purified water, ethyl alcohol, and/or propylene glycol. In some embodiments, the pharmaceutical composition comprises between 0.03 wt% and 1 wt% melanocortin analog solubilized or suspended in a solvent or vehicle. For example, the pharmaceutical composition may comprise the non-naturally occurring melanocortin analog in an amount of about 0.03 wt%, about 0.05 wt%, about 0.1 wt%, about 0.15 wt%, about 0.2 wt%, about 0.25 wt%, about 0.3 wt%, about 0.35 wt%, about 0.4 wt%, about 0.45 wt%, about 0.5 wt%, about 0.55 wt%, about 0.6 wt%, about 0.65 wt%, about 0.7 wt%, about 0.75 wt%, about 0.8 wt%, about 0.85 wt%, about 0.9 wt%, about 0.95 wt%, or about 1 wt%.
[1524] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 0.1 mg/mL to about 50 mg/mL, relative to a total volume of the composition. In some embodiments, the non- naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 0.1 mg/mL to 50 mg/mL, 0.5 mg/mL to 40 mg/mL, 1 mg/mL to 30 mg/mL, 2.5 mg/mL to 20 mg/mL, 5 g/mL to 15 mg/mL, or 5 mg/mL to 10 mg/mL, relative to a total volume of the pharmaceutical composition. Any of the non-naturally occurring melanocortin analogs and corresponding concentrations described previously with reference to the pharmaceutical composition may be present in the pharmaceutical composition at the same or substantially similar concentrations.
Administration
[1525] The pharmaceutical compositions of the present technology may be administered once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day.
[1526] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 ml_ to 20 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day.
[1527] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition at a dose of about 10 mg in a dose volume of about 1 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, the administration is performed once per day. In other embodiments, the administration is performed once weekly. In some embodiments, the administration is performed once monthly.
[1528] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-12, 13-23, 24-27, 28-30, 31 -43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-11 1 , 1 15-122, 123-138, 139-157, 158-164, 165-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219-222, 224, 236-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, 344-350, 369, 426, 430- 432, 444-445, 487, 489, 493, 495, 497, 500, 507-510, 514, 516-517, 524-527, 529, 531 , 533-535, and 538-572and is present in the second pharmaceutical composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 ml_ to 20 ml_, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 2-7, 9-12, 13-23, 24-27, 28-30, 31 -43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-1 11 , 1 15-122, 123-138, 139-157, 158-164, 165-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219- 222, 224, 236-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327- 337, 344-350, 369, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-510, 514, 516-517, 524-527, 529, 531 , 533-535, and 538-572is present in the second pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to
10 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 2-7, 9-12, 13-23, 24-27, 28-30, 31 -43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 10S-
1 11 , 115-122, 123-138, 139-157, 158-164, 165-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219-222, 224, 236-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, 344-350, 369, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-510, 514, 516-517, 524-527, 529, 531 , 533-535, and 538-572is present in the second pharmaceutical composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 2-7, 9-12, 13-23, 24-27, 28-30, 31 -43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108- 1 11 , 115-122, 123-138, 139-157, 158-164, 165-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219-222, 224, 236-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, 344-350, 369, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-510, 514, 516-517, 524-527, 529, 531 , 533-535, and 538-572 is present in the second pharmaceutical composition at a dose of about 10 mg in a dose volume of about 1 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, the administration is performed once per day. In other embodiments, the administration is performed once weekly. In still other embodiments, the administration is performed once monthly.
[1529] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-10, 12-23, 24-27, 28-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-11 1 , 115-138, 139-157, 158-162, 164-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219, 221 -222, 224, 236-242, 244-245, 247-248, 250- 257, 259-267, 269-275, 282-283, 327-337, 344-350, 509-510, 525-527, 531 , 533-535, 538, 545-549, 551 -553, 555, 562-569, and 571 -572and is present in the second pharmaceutical composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 2-7, 9-10, 12-23, 24-27, 28-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-111 , 115- 138, 139-157, 158-162, 164-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219, 221 -222, 224, 236-242, 244-245, 247-248, 250-257, 259-267, 269-275, 282-283, 327- 337, 344-350, 509-510, 525-527, 531 , 533-535, 538, 545-549, 551 -553, 555, 562-569, and 571 -572 is present in the second pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 ml_, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 2-7, 9-10, 12-23, 24-27, 28-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-11 1 , 115-138, 139-157, 158-162, 164- 172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219, 221 -222, 224, 236-242, 244-245, 247-248, 250-257, 259-267, 269-275, 282-283, 327-337, 344-350, 509-510, 525- 527, 531 , 533-535, 538, 545-549, 551 -553, 555, 562-569, and 571 -572is present in the second pharmaceutical composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 2-7, 9-10, 12-23, 24-27, 28-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-111 , 115- 138, 139-157, 158-162, 164-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219, 221 -222, 224, 236-242, 244-245, 247-248, 250-257, 259-267, 269-275, 282-283, 327- 337, 344-350, 509-510, 525-527, 531 , 533-535, 538, 545-549, 551 -553, 555, 562-569, and 571 -572is present in the second pharmaceutical composition at a dose of about 10 mg in a dose volume of about 1 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, the administration is performed once per day. In other embodiments, the administration is performed once weekly. In still other embodiments, the administration is performed once monthly.
[1530] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-4, 13, 15-23, 24-32, 35-43, 48-55, 59, 64-69, 71 -76, 77-82, 86-87, 90, 92-93, 96, 102, 104-105, 108-11 1 , 115-138, 139-162, 164, 165-186, 195-197, 199-201 , 203, 215-217, 219, 221 -222, 224, 240-242, 244, 255-256, 259-267, 269-275, 327-328, 331 , 344-350, 525-527, 531 , 533-535, 538, 545, 547-549, 551 -553, 555, 562-569, and 571 -572 and is present in the second pharmaceutical composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 ml_, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 2-4, 13, 15-23, 24-32, 35-43, 48-55, 59, 64-69, 71 - 76, 77-82, 86-87, 90, 92-93, 96, 102, 104-105, 108-1 11 , 1 15-138, 139-162, 164, 165-186, 195-197, 199-201 , 203, 215-217, 219, 221 -222, 224, 240-242, 244, 255-256, 259-267, 269- 275, 327-328, 331 , 344-350, 525-527, 531 , 533-535, 538, 545, 547-549, 551 -553, 555, 562- 569, and 571 -572is present in the second pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 2-4, 13, 15-23, 24-32, 35-43, 48-55, 59, 64-69, 71 -76, 77-82, 86-87, 90, 92-93, 96, 102, 104-105, 108-111 , 1 15-138, 139-162, 164, 165-186, 195-197, 199-201 , 203, 215-217, 219, 221 -222, 224, 240-242, 244, 255-256, 259-267, 269-275, 327-328, 331 , 344-350, 525-527, 531 , 533-535, 538, 545, 547-549, 551 - 553, 555, 562-569, and 571 -572is present in the second pharmaceutical composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 2-4, 13, 15-23, 24-32, 35-43, 48-55, 59, 64-69, 71 - 76, 77-82, 86-87, 90, 92-93, 96, 102, 104-105, 108-1 11 , 1 15-138, 139-162, 164, 165-186, 195-197, 199-201 , 203, 215-217, 219, 221 -222, 224, 240-242, 244, 255-256, 259-267, 269- 275, 327-328, 331 , 344-350, 525-527, 531 , 533-535, 538, 545, 547-549, 551 -553, 555, 562- 569, and 571 -572 is present in the second pharmaceutical composition at a dose of about
-I SO- 10 mg in a dose volume of about 1 ml_, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, the administration is performed once per day. In other embodiments, the administration is performed once weekly. In still other embodiments, the administration is performed once monthly.
[1531] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-10, 12-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-11 1 , 115-138, 139-162, 164, 165-186, 194-197, 199-201 , 203-206, 239-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, and 344-350 and is present in the second pharmaceutical composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 ml_, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 2-7, 9-10, 12-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-1 11 , 115-138, 139-162, 164, 165-186, 194-197, 199- 201 , 203-206, 239-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, and 344-350 is present in the second pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 2-7, 9-10, 12-43, 48-55, 59, 64-69, 71 - 76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-111 , 115-138, 139-162, 164, 165-186, 194- 197, 199-201 , 203-206, 239-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, and 344-350 is present in the second pharmaceutical composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 2-7, 9-10, 12-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-1 11 , 115-138, 139-162, 164, 165-186, 194-197, 199- 201 , 203-206, 239-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, and 344-350 is present in the second pharmaceutical composition at a dose of about 10 mg in a dose volume of about 1 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, the administration is performed once per day. In other embodiments, the administration is performed once weekly. In still other embodiments, the administration is performed once monthly.
[1532] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 215-217, 219-222, 224, 236-238, 497, 500, 507-510, 514, 516-517, 535, and 538-561 and is present in the second pharmaceutical composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 215-217, 219-222, 224, 236-238, 497, 500, 507-510, 514, 516-517, 535, and 538-561 is present in the second pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 215-217, 219- 222, 224, 236-238, 497, 500, 507-510, 514, 516-517, 535, and 538-561 is present in the second pharmaceutical composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 215-217, 219- 222, 224, 236-238, 497, 500, 507-510, 514, 516-517, 535, and 538-561 is present in the second pharmaceutical composition at a dose of about 10 mg in a dose volume of about 1 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, the administration is performed once per day. In other embodiments, the administration is performed once weekly. In still other embodiments, the administration is performed once monthly.
[1533] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 220, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-508, 514, 516-517, 524, 529, 539-544, 550, 554, and 556-561 and is present in the second pharmaceutical composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 220, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-508, 514, 516-517, 524, 529, 539-544, 550, 554, and 556-561 is present in the second pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 220, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-508, 514, 516-517, 524, 529, 539-544, 550, 554, and 556-561 is present in the second pharmaceutical composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, any one of SEQ ID NOs: 220, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-508, 514, 516-517, 524, 529, 539-544, 550, 554, and 556-561 is present in the second pharmaceutical composition at a dose of about 10 mg in a dose volume of about 1 ml_, and wherein the administration is performed once monthly, once every three weeks, once every two weeks, once per week, twice per week, 3 times per week, 4 times per week, 5 times per week, once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, or 10 times per day. In some embodiments, the administration is performed once per day. In other embodiments, the administration is performed once weekly. In still other embodiments, the administration is performed once monthly.
[1534] In some embodiments, the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof is administered hourly (such as every hour, every 2 hours, every 4 hours, every 8 hours, etc.), once a day, or twice a day. In some embodiments, the non-naturally occurring melanocortin analog is administered every morning, every evening, or every afternoon. In some embodiments, the non-naturally occurring melanocortin analog is administered before a meal, after a meal, or with a meal.
[1535] In some embodiments, the non-naturally occurring melanocortin analog or pharmaceutical composition thereof may be administered as a dosing regimen comprising once, twice, or three times daily administration on a (i) weekly; (ii) every other week; (iii) one week of therapy followed by two, three or four weeks off; (iv) two weeks of therapy followed by one, two, three or four weeks off; (v) three weeks of therapy followed by one, two, three, four or five week off; (vi) four weeks of therapy followed by one, two, three, four or five week off; (vii) five weeks of therapy followed by one, two, three, four or five week off; or (viii) monthly schedule. The (i)-(viii) schedules may be repeated 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 times or more. In some embodiments, the non-naturally occurring melanocortin analog or pharmaceutical composition thereof is administered at various dosages during the dosing regimen (e.g., a first dose with an effective amount of 10 mg/kg and a second dose with an effective amount of 5 mg/kg).
[1536] In some embodiments, the non-naturally occurring melanocortin analog or pharmaceutical composition thereof is administered once every other day, once every 2 or 3 days, once every third day, once per week, once every other week, once every third week, once every month, once every six weeks, once every other month, once every three months, once every six months, or once per year. Administration of the non-naturally occurring melanocortin analog or pharmaceutical composition thereof at any of the dosing frequencies of the present technology may be repeated for a total of at least 2 dosages, at least 3 dosages, at least 4 dosages, at least 5 dosages, at least 10 dosages, at least 15 dosages, at least 20 dosages, at least 30 dosages, at least 40 dosages, at least 50 dosages or more. In some embodiments, the frequency of dosages of the non-naturally occurring melanocortin analog or pharmaceutical composition thereof is the same during a treatment regimen. In other embodiments, the frequency of dosages of the non-naturally occurring melanocortin analog or pharmaceutical composition thereof is different during a treatment regimen. The non-naturally occurring melanocortin analog or the pharmaceutical composition thereof may be administered even less frequently. Alternatively, the dosage regimen may be decreased or increased from an initial dosing regimen for days, weeks, months, or years. In some embodiments, the dosing regimen is repeated at other intervals.
Dosing
[1537] In some embodiments, the pharmaceutical compositions of the present technology are formulated to provide a dose of about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg of the non-naturally occurring melanocortin analog to the subject in need thereof.
[1538] In some embodiments, the pharmaceutical compositions of the present technology are formulated to provide a dose of at least 1 mg, at least 2 mg, at least 3 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 40 mg, at least 50 mg, at least 60 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, or at least 500 mg of the non-naturally occurring melanocortin analog to the subject in need thereof. [1539] In some embodiments, the pharmaceutical compositions of the present technology are formulated to provide a dose of at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 75 mg, at least about 100 mg, at least about 125 mg, at least about 150 mg, at least about 175 mg, at least about 200 mg, at least about 225 mg, at least about 250 mg, at least about 275 mg, at least about 300 mg, at least about 325 mg, at least about 350 mg, at least about 375 mg, at least about 400 mg, at least about 425 mg, at least about 450 mg, at least about 475 mg, or at least about 500 mg of the non- naturally occurring melanocortin analog to the subject in need thereof.
[1540] In some embodiments, the compositions of the present technology are administered to the subject at a dose that is based on the subject’s BMI. In some embodiments, two or more doses of the compositions of the present technology are administered to the subject, wherein the two or more doses are titrated (e.g., inversely titrated) based on the subject’s BMI at the time of each administration.
[1541] In some embodiments, the pharmaceutical compositions of the present technology are formulated to provide a dose of about 0.001 mg/kg, about 0.005 mg/kg, about 0.01 mg/kg, about 0.05 mg/kg, about 0.10 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 40 mg/kg, about 50 mg/kg, about 60 mg/kg, about 75 mg/kg, about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200 mg/kg, about 225 mg/kg, about 250 mg/kg, about 275 mg/kg, about 300 mg/kg, about 325 mg/kg, about 350 mg/kg, about 375 mg/kg, about 400 mg/kg, about 425 mg/kg, about 450 mg/kg, about 475 mg/kg, or about 500 mg/kg of the non-naturally occurring melanocortin analog to the subject in need thereof.
[1542] In some embodiments, the pharmaceutical compositions of the present technology are formulated to provide a dose of at least 0.001 mg/kg, at least 0.005 mg/kg, at least 0.01 mg/kg, at least 0.05 mg/kg, at least 0.10 mg/kg, at least 0.5 mg/kg, at least 1 mg/kg, at least 2 mg/kg, at least 3 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 15 mg/kg, at least 20 mg/kg, at least 25 mg/kg, at least 30 mg/kg, at least 40 mg/kg, at least 50 mg/kg, at least 60 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, at least 175 mg/kg, at least 200 mg/kg, at least 225 mg/kg, at least 250 mg/kg, at least 275 mg/kg, at least 300 mg/kg, at least 325 mg/kg, at least 350 mg/kg, at least 375 mg/kg, at least 400 mg/kg, at least 425 mg/kg, at least 450 mg/kg, at least 475 mg/kg, or at least 500 mg/kg of the non-naturally occurring melanocortin analog to the subject in need thereof.
[1543] In some embodiments, the pharmaceutical compositions of the present technology are formulated to provide a dose of at least about 0.001 mg/kg, at least about 0.005 mg/kg, at least about 0.01 mg/kg, at least about 0.05 mg/kg, at least about 0.10 mg/kg, at least about 0.5 mg/kg, at least about 1 mg/kg, at least about 2 mg/kg, at least about 3 mg/kg, at least about 5 mg/kg, at least about 10 mg/kg, at least about 15 mg/kg, at least about 20 mg/kg, at least about 25 mg/kg, at least about 30 mg/kg, at least about 40 mg/kg, at least about 50 mg/kg, at least about 60 mg/kg, at least about 75 mg/kg, at least about 100 mg/kg, at least about 125 mg/kg, at least about 150 mg/kg, at least about 175 mg/kg, at least about 200 mg/kg, at least about 225 mg/kg, at least about 250 mg/kg, at least about 275 mg/kg, at least about 300 mg/kg, at least about 325 mg/kg, at least about 350 mg/kg, at least about 375 mg/kg, at least about 400 mg/kg, at least about 425 mg/kg, at least about 450 mg/kg, at least about 475 mg/kg, or at least about 500 mg/kg of the non-naturally occurring melanocortin analog to the subject in need thereof.
[1544] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg/kg to about 500 mg/kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg/kg to about 250 mg/kg per body weight of the subject once daily. In some embodiments, non-naturally occurring melanocortin analog is administered at a dose of about 15 mg/kg to about 100 mg/kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 20 mg/kg to about 75 mg/kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 30 mg/kg or 60 mg/kg per body weight of the subject once daily. [1545] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 5 mg/kg to at least 500 mg/kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 10 mg/kg to at least 250 mg/kg per body weight of the subject once daily. In some embodiments, non-naturally occurring melanocortin analog is administered at a dose of at least 15 mg/kg to at least 100 mg/kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 20 mg/kg to at least 75 mg/kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 30 mg/kg or 60 mg/kg per body weight of the subject once daily.
[1546] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 5 mg/kg to at least about 500 mg/kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 10 mg/kg to at least about 250 mg/kg per body weight of the subject once daily. In some embodiments, non-naturally occurring melanocortin analog is administered at a dose of at least about 15 mg/kg to at least about 100 mg/kg per body weight of the subject once daily. In some embodiments, the non- naturally occurring melanocortin analog is administered at a dose of at least about 20 mg/kg to at least about 75 mg/kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 30 mg/kg or 60 mg/kg per body weight of the subject once daily.
[1547] In some embodiments, the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.001 mg/kg to 25 mg/kg, 0.01 mg/kg to 20 mg/kg, 0.05 mg/kg to 15 mg/kg, 0.075 mg/kg to 10 mg/kg, 0.1 mg/kg to 8 mg/kg, 0.2 mg/kg to 6 mg/kg, 0.3 mg/kg to 4 mg/kg, 0.4 mg/kg to 2 mg/kg, or 0.5 mg/kg to 1 mg/kg per body weight of the subject.
[1548] In some embodiments, the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from about 0.5 mg/kg to about 10 mg/kg, about 1 mg/kg to about 7.5 mg/kg, or about 2.5 mg/kg to about 5 mg/kg per body weight of the subject.
[1549] In some embodiments, the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from at least 0.5 mg/kg to at least 10 mg/kg, at least 1 mg/kg to at least 7.5 mg/kg, or at least 2.5 mg/kg to at least 5 mg/kg per body weight of the subject.
[1550] In some embodiments, the non-naturally occurring melanocortin analog is administered about once daily in an amount ranging from about 0.5 mg/kg to about 10 mg/kg, about 1 mg/kg to about 7.5 mg/kg, or about 2.5 mg/kg to about 5 mg/kg per body weight of the subject.
[1551] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg , about 40 mg/kg, about 50 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200 mg/kg, about 250 mg/kg, about 300 mg/kg, about 350 mg/kg, about 400 mg/kg, about 450 mg/kg, or about 500 mg/kg per body weight of the subject once daily.
[1552] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 5 mg/kg, at least 10 mg/kg, at least 15 mg/kg, at least 20 mg/kg, at least 25 mg/kg, at least 30 mg/kg, at least 35 mg/kg , at least 40 mg/kg, at least 50 mg/kg, at least 65 mg/kg, at least 70 mg/kg, at least 75 mg/kg, at least 80 mg/kg, at least 85 mg/kg, at least 90 mg/kg, at least 95 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, at least 175 mg/kg, at least 200 mg/kg, at least 250 mg/kg, at least 300 mg/kg, at least 350 mg/kg, at least 400 mg/kg, at least 450 mg/kg, or at least 500 mg/kg per body weight of the subject once daily.
[1553] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 5 mg/kg, at least about 10 mg/kg, at least about 15 mg/kg, at least about 20 mg/kg, at least about 25 mg/kg, at least about 30 mg/kg, at least about 35 mg/kg , at least about 40 mg/kg, at least about 50 mg/kg, at least about 65 mg/kg, at least about 70 mg/kg, at least about 75 mg/kg, at least about 80 mg/kg, at least about 85 mg/kg, at least about 90 mg/kg, at least about 95 mg/kg, at least about 100 mg/kg, at least about 125 mg/kg, at least about 150 mg/kg, at least about 175 mg/kg, at least about 200 mg/kg, at least about 250 mg/kg, at least about 300 mg/kg, at least about 350 mg/kg, at least about 400 mg/kg, at least about 450 mg/kg, or at least about 500 mg/kg per body weight of the subject once daily.
[1554] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg/kg per body weight of the subject once daily.
[1555] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 5 mg/kg per body weight of the subject once daily.
[1556] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 5 mg/kg per body weight of the subject once daily.
[1557] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg/kg per body weight of the subject once daily.
[1558] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 10 mg/kg per body weight of the subject once daily.
[1559] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 10 mg/kg per body weight of the subject once daily.
[1560] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 15 mg/kg per body weight of the subject once daily.
[1561] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 15 mg/kg per body weight of the subject once daily.
[1562] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 15 mg/kg per body weight of the subject once daily.
[1563] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 20 mg/kg per body weight of the subject once daily.
[1564] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 20 mg/kg per body weight of the subject once daily. [1565] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 20 mg/kg per body weight of the subject once daily.
[1566] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 25 mg/kg per body weight of the subject once daily.
[1567] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 25 mg/kg per body weight of the subject once daily.
[1568] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 25 mg/kg per body weight of the subject once daily.
[1569] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 30 mg/kg per body weight of the subject once daily.
[1570] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 30 mg/kg per body weight of the subject once daily.
[1571] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 30 mg/kg per body weight of the subject once daily.
[1572] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 35 mg/kg per body weight of the subject once daily.
[1573] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 35 mg/kg per body weight of the subject once daily.
[1574] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 35 mg/kg per body weight of the subject once daily.
[1575] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 40 mg/kg per body weight of the subject once daily.
[1576] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 40 mg/kg per body weight of the subject once daily.
[1577] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 40 mg/kg per body weight of the subject once daily. [1578] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 50 mg/kg per body weight of the subject once daily.
[1579] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 50 mg/kg per body weight of the subject once daily.
[1580] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 50 mg/kg per body weight of the subject once daily.
[1581] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg , about 40 mg/kg, about 50 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200 mg/kg, about 250 mg/kg, about 300 mg/kg, about 350 mg/kg, about 400 mg/kg, about 450 mg/kg, or about 500 mg/kg per body weight of the subject twice daily.
[1582] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 5 mg/kg, at least 10 mg/kg, at least 15 mg/kg, at least 20 mg/kg, at least 25 mg/kg, at least 30 mg/kg, at least 35 mg/kg , at least 40 mg/kg, at least 50 mg/kg, at least 65 mg/kg, at least 70 mg/kg, at least 75 mg/kg, at least 80 mg/kg, at least 85 mg/kg, at least 90 mg/kg, at least 95 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, at least 175 mg/kg, at least 200 mg/kg, at least 250 mg/kg, at least 300 mg/kg, at least 350 mg/kg, at least 400 mg/kg, at least 450 mg/kg, or at least 500 mg/kg per body weight of the subject twice daily.
[1583] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 5 mg/kg, at least about 10 mg/kg, at least about 15 mg/kg, at least about 20 mg/kg, at least about 25 mg/kg, at least about 30 mg/kg, at least about 35 mg/kg , at least about 40 mg/kg, at least about 50 mg/kg, at least about 65 mg/kg, at least about 70 mg/kg, at least about 75 mg/kg, at least about 80 mg/kg, at least about 85 mg/kg, at least about 90 mg/kg, at least about 95 mg/kg, at least about 100 mg/kg, at least about 125 mg/kg, at least about 150 mg/kg, at least about 175 mg/kg, at least about 200 mg/kg, at least about 250 mg/kg, at least about 300 mg/kg, at least about 350 mg/kg, at least about 400 mg/kg, at least about 450 mg/kg, or at least about 500 mg/kg per body weight of the subject twice daily.
[1584] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg/kg per body weight of the subject twice daily.
[1585] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg/kg per body weight of the subject twice daily.
[1586] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 15 mg/kg per body weight of the subject twice daily.
[1587] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 20 mg/kg per body weight of the subject twice daily.
[1588] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 25 mg/kg per body weight of the subject twice daily.
[1589] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 30 mg/kg per body weight of the subject twice daily.
[1590] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 35 mg/kg per body weight of the subject twice daily.
[1591] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 40 mg/kg per body weight of the subject twice daily.
[1592] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 50 mg/kg per body weight of the subject twice daily.
[1593] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg/kg per body weight of the subject twice daily.
[1594] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg/kg per body weight of the subject twice daily.
[1595] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 15 mg/kg per body weight of the subject twice daily. [1596] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 20 mg/kg per body weight of the subject twice daily.
[1597] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 25 mg/kg per body weight of the subject twice daily.
[1598] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 30 mg/kg per body weight of the subject twice daily.
[1599] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 35 mg/kg per body weight of the subject twice daily.
[1600] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 40 mg/kg per body weight of the subject twice daily.
[1601] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 50 mg/kg per body weight of the subject twice daily.
[1602] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 5 mg/kg per body weight of the subject twice daily.
[1603] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 10 mg/kg per body weight of the subject twice daily.
[1604] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 15 mg/kg per body weight of the subject twice daily.
[1605] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 20 mg/kg per body weight of the subject twice daily.
[1606] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 25 mg/kg per body weight of the subject twice daily.
[1607] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 30 mg/kg per body weight of the subject twice daily.
[1608] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 35 mg/kg per body weight of the subject twice daily. [1609] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 40 mg/kg per body weight of the subject twice daily.
[1610] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 50 mg/kg per body weight of the subject twice daily.
[1611] In some embodiments, the non-naturally occurring melanocortin analog is administered at one or more doses. In some embodiments, the non-naturally occurring melanocortin analog is administered at two or more doses.
[1612] In some embodiments, the non-naturally occurring melanocortin analog is administered at a first dose once daily or twice daily. In some embodiments, the non- naturally occurring melanocortin analog is administered at a second dose once daily or twice daily.
[1613] In some embodiments, the non-naturally occurring melanocortin analog is administered at a first dose once daily for about 5 days to about 10 days. In some embodiments, the non-naturally occurring melanocortin analog is administered at a second dose once daily for about 5 days to about 10 days, after administration of the first dose. In some embodiments, the non-naturally occurring melanocortin analog is administered at a third dose twice daily for about 7 days to about 21 days, after administration of the second dose. In some embodiments, the second dose is greater than the first dose. In some embodiments, the third dose comprises a cumulative dose that is greater than the second dose.
[1614] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg/kg to about 20 mg/kg administered once a day for about 5 days to about 10 days; (ii) at a second dose of about 10 mg/kg to about 40 mg/kg administered once a day after administration of the first dose for about 5 days to about 10 days; (iii) at a third dose of about 5 mg/kg to about 30 mg/kg administered twice a day after administration of the second dose for at least about 5 days to about 10 days. In some embodiments, the third dose is administered twice a day for at least about 7 days or more.
[1615] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, or about 20 mg/kg administered once a day for about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, or about 10 days; (ii) at a second dose of about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, or about 40 mg/kg administered once a day after administration of the first dose about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, or about 10 days; (iii) at a third dose of about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, or about 30 mg/kg administered twice a day after administration of the second dose for at least about 5 days, about, 6 days, about 7 days, about 8 days, about 9 days, or about 10 days. In some embodiments, the third dose is administered twice a day for at least about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days or more.
[1616] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg/kg administered once a day for about 7 days; (ii) at a second dose of about 15 mg/kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 10 mg/kg administered twice a day after administration of the second dose for at least about 7 days. In some embodiments, the third dose is administered twice a day for at least about 14 days or more.
[1617] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 10 mg/kg administered once a day for about 7 days; (ii) at a second dose of about 20 mg/kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 15 mg/kg administered twice a day after administration of the second dose for at least about 7 days. In some embodiments, the third dose is administered twice a day for at least about 14 days or more.
[1618] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 15 mg/kg administered once a day for about 7 days; (ii) at a second dose of about 25 mg/kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 20 mg/kg administered twice a day after administration of the second dose for at least about 7 days. In some embodiments, the third dose is administered twice a day for at least about 14 days or more. [1619] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-12, 13-23, 24-27, 28-30, 31 -43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-11 1 , 1 15-122, 123-138, 139-157, 158-164, 165-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219-222, 224, 236-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, 344-350, 369, 426, 430- 432, 444-445, 487, 489, 493, 495, 497, 500, 507-510, 514, 516-517, 524-527, 529, 531 , 533-535, and 538-572and is administered at least once daily in an amount ranging from 0.001 mg/kg to 25 mg/kg, 0.01 mg/kg to 20 mg/kg, 0.05 mg/kg to 15 mg/kg, 0.075 mg/kg to 10 mg/kg, 0.1 mg/kg to 8 mg/kg, 0.2 mg/kg to 6 mg/kg, 0.3 mg/kg to 4 mg/kg, 0.4 mg/kg to 2 mg/kg, or 0.5 mg/kg to 1 mg/kg per body weight of the subject. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-12, 13- 23, 24-27, 28-30, 31 -43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108- 1 11 , 115-122, 123-138, 139-157, 158-164, 165-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219-222, 224, 236-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, 344-350, 369, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-510, 514, 516-517, 524-527, 529, 531 , 533-535, and 538-572and is administered at least once daily in an amount ranging from about 0.5 mg/kg to about 10 mg/kg, about 1 mg/kg to about 7.5 mg/kg, or about 2.5 mg/kg to about 5 mg/kg per body weight of the subject.
[1620] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-10, 12-23, 24-27, 28-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-11 1 , 115-138, 139-157, 158-162, 164-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219, 221 -222, 224, 236-242, 244-245, 247-248, 250- 257, 259-267, 269-275, 282-283, 327-337, 344-350, 509-510, 525-527, 531 , 533-535, 538, 545-549, 551 -553, 555, 562-569, and 571 -572and is administered at least once daily in an amount ranging from 0.001 mg/kg to 25 mg/kg, 0.01 mg/kg to 20 mg/kg, 0.05 mg/kg to 15 mg/kg, 0.075 mg/kg to 10 mg/kg, 0.1 mg/kg to 8 mg/kg, 0.2 mg/kg to 6 mg/kg, 0.3 mg/kg to 4 mg/kg, 0.4 mg/kg to 2 mg/kg, or 0.5 mg/kg to 1 mg/kg per body weight of the subject. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-10, 12-23, 24-27, 28-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-11 1 , 115-138, 139-157, 158-162, 164-172, 173-182, 183-186, 194-197, 199- 201 , 203-206, 215-217, 219, 221 -222, 224, 236-242, 244-245, 247-248, 250-257, 259-267, 269-275, 282-283, 327-337, 344-350, 509-510, 525-527, 531 , 533-535, 538, 545-549, 551 - 553, 555, 562-569, and 571 -572and is administered at least once daily in an amount ranging from about 0.5 mg/kg to about 10 mg/kg, about 1 mg/kg to about 7.5 mg/kg, or about 2.5 mg/kg to about 5 mg/kg per body weight of the subject.
[1621] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-4, 13, 15-23, 24-32, 35-43, 48-55, 59, 64-69, 71 -76, 77-82, 86-87, 90, 92-93, 96, 102, 104-105, 108-11 1 , 115-138, 139-162, 164, 165-186, 195-197, 199-201 , 203, 215-217, 219, 221 -222, 224, 240-242, 244, 255-256, 259-267, 269-275, 327-328, 331 , 344-350, 525-527, 531 , 533-535, 538, 545, 547-549, 551 -553, 555, 562-569, and 571 -572 and is administered at least once daily in an amount ranging from 0.001 mg/kg to 25 mg/kg, 0.01 mg/kg to 20 mg/kg, 0.05 mg/kg to 15 mg/kg, 0.075 mg/kg to 10 mg/kg, 0.1 mg/kg to 8 mg/kg, 0.2 mg/kg to 6 mg/kg, 0.3 mg/kg to 4 mg/kg, 0.4 mg/kg to 2 mg/kg, or 0.5 mg/kg to 1 mg/kg per body weight of the subject. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-4, 13, 15-23, 24-32, 35-43, 48-55, 59, 64- 69, 71 -76, 77-82, 86-87, 90, 92-93, 96, 102, 104-105, 108-1 11 , 115-138, 139-162, 164, 165- 186, 195-197, 199-201 , 203, 215-217, 219, 221 -222, 224, 240-242, 244, 255-256, 259-267, 269-275, 327-328, 331 , 344-350, 525-527, 531 , 533-535, 538, 545, 547-549, 551 -553, 555, 562-569, and 571 -572 and is administered at least once daily in an amount ranging from about 0.5 mg/kg to about 10 mg/kg, about 1 mg/kg to about 7.5 mg/kg, or about 2.5 mg/kg to about 5 mg/kg per body weight of the subject.
[1622] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-10, 12-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-11 1 , 115-138, 139-162, 164, 165-186, 194-197, 199-201 , 203-206, 239-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, and 344-350 and is administered at least once daily in an amount ranging from 0.001 mg/kg to 25 mg/kg, 0.01 mg/kg to 20 mg/kg, 0.05 mg/kg to 15 mg/kg, 0.075 mg/kg to 10 mg/kg, 0.1 mg/kg to 8 mg/kg, 0.2 mg/kg to 6 mg/kg, 0.3 mg/kg to 4 mg/kg, 0.4 mg/kg to 2 mg/kg, or 0.5 mg/kg to 1 mg/kg per body weight of the subject. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-10, 12-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-1 1 1 , 115-138, 139-162, 164, 165-186, 194-197, 199-201 , 203-206, 239-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282- 283, 327-337, and 344-350 and is administered at least once daily in an amount ranging from about 0.5 mg/kg to about 10 mg/kg, about 1 mg/kg to about 7.5 mg/kg, or about 2.5 mg/kg to about 5 mg/kg per body weight of the subject.
[1623] In some embodiments, the non-naturally occurring melanocortin analog is any one Of SEQ ID NOs: 215-217, 219-222, 224, 236-238, 497, 500, 507-510, 514, 516-517, 535, and 538-561 and is administered at least once daily in an amount ranging from 0.001 mg/kg to 25 mg/kg, 0.01 mg/kg to 20 mg/kg, 0.05 mg/kg to 15 mg/kg, 0.075 mg/kg to 10 mg/kg, 0.1 mg/kg to 8 mg/kg, 0.2 mg/kg to 6 mg/kg, 0.3 mg/kg to 4 mg/kg, 0.4 mg/kg to 2 mg/kg, or 0.5 mg/kg to 1 mg/kg per body weight of the subject. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 215-217, 219-222, 224, 236-238, 497, 500, 507-510, 514, 516-517, 535, and 538-561 and is administered at least once daily in an amount ranging from about 0.5 mg/kg to about 10 mg/kg, about 1 mg/kg to about 7.5 mg/kg, or about 2.5 mg/kg to about 5 mg/kg per body weight of the subject.
[1624] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 220, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-508, 514, 516-517, 524, 529, 539-544, 550, 554, and 556-561 and is administered at least once daily in an amount ranging from 0.001 mg/kg to 25 mg/kg, 0.01 mg/kg to 20 mg/kg, 0.05 mg/kg to 15 mg/kg, 0.075 mg/kg to 10 mg/kg, 0.1 mg/kg to 8 mg/kg, 0.2 mg/kg to 6 mg/kg, 0.3 mg/kg to 4 mg/kg, 0.4 mg/kg to 2 mg/kg, or 0.5 mg/kg to 1 mg/kg per body weight of the subject. In some embodiments, the non-naturally occurring melanocortin analog is any one Of SEQ ID NOs: 220, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-508, 514, 516-517, 524, 529, 539-544, 550, 554, and 556-561 and is administered at least once daily in an amount ranging from about 0.5 mg/kg to about 10 mg/kg, about 1 mg/kg to about 7.5 mg/kg, or about 2.5 mg/kg to about 5 mg/kg per body weight of the subject.
[1625] In some embodiments, the non-naturally occurring melanocortin analog is administered at least once daily in an amount of about 0.1 mg to about 100 mg, 0.5 mg to about 50 mg, about 1 mg to about 40 mg, about 2.5 mg to about 30 mg, about 5 to about 20 mg, or about 7.5 to about 15 mg. In some embodiments, the non-naturally occurring melanocortin analog is administered once daily in an amount of about 10 mg. In some embodiments, the non-naturally occurring melanocortin analog is administered at least once daily in an amount of about 1 mg to about 100 mg, about 5 mg to about 95 mg, about 10 mg to about 90 mg, about 15 mg to about 85 mg, about 20 mg to about 80 mg, about 25 mg to about 75 mg, about 30 mg to about 70 mg, about 35 mg to about 65 mg, about 40 to about 60 mg, or about 45 to about 55 mg. In some embodiments, the non-naturally occurring melanocortin analog is administered at least once daily in an amount of about 50 mg.
[1626] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-12, 13-23, 24-27, 28-30, 31 -43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-11 1 , 1 15-122, 123-138, 139-157, 158-164, 165-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219-222, 224, 236-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, 344-350, 369, 426, 430- 432, 444-445, 487, 489, 493, 495, 497, 500, 507-510, 514, 516-517, 524-527, 529, 531 , 533-535, and 538-572 and is administered at least once daily in an amount of about 0.1 mg to about 100 mg, 0.5 mg to about 50 mg, about 1 mg to about 40 mg, about 2.5 mg to about 30 mg, about 5 to about 20 mg, or about 7.5 to about 15 mg. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-12, 13-23, 24-27, 28-30, 31 -43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 10S- 1 11 , 115-122, 123-138, 139-157, 158-164, 165-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219-222, 224, 236-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, 344-350, 369, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-510, 514, 516-517, 524-527, 529, 531 , 533-535, and 538-572and is administered once daily in an amount of about 10 mg. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-12, 13-23, 24-27, 28-30, 31 -43, 48- 55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-11 1 , 115-122, 123-138, 139-157, 158-164, 165-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219- 222, 224, 236-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327- 337, 344-350, 369, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-510, 514, 516-517, 524-527, 529, 531 , 533-535, and 538-572and is administered at least once daily in an amount of about 1 mg to about 100 mg, about 5 mg to about 95 mg, about 10 mg to about 90 mg, about 15 mg to about 85 mg, about 20 mg to about 80 mg, about 25 mg to about 75 mg, about 30 mg to about 70 mg, about 35 mg to about 65 mg, about 40 to about 60 mg, or about 45 to about 55 mg. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-12, 13-23, 24-27, 28-30, 31 -43, 48- 55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-11 1 , 115-122, 123-138, 139-157, 158-164, 165-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219- 222, 224, 236-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327- 337, 344-350, 369, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-510, 514, 516-517, 524-527, 529, 531 , 533-535, and 538-572 and is administered at least once daily in an amount of about 50 mg.
[1627] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-10, 12-23, 24-27, 28-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-11 1 , 115-138, 139-157, 158-162, 164-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219, 221 -222, 224, 236-242, 244-245, 247-248, 250- 257, 259-267, 269-275, 282-283, 327-337, 344-350, 509-510, 525-527, 531 , 533-535, 538, 545-549, 551 -553, 555, 562-569, and 571 -572and is administered at least once daily in an amount of about 0.1 mg to about 100 mg, 0.5 mg to about 50 mg, about 1 mg to about 40 mg, about 2.5 mg to about 30 mg, about 5 to about 20 mg, or about 7.5 to about 15 mg. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-10, 12-23, 24-27, 28-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-11 1 , 115-138, 139-157, 158-162, 164-172, 173-182, 183-186, 194-197, 199- 201 , 203-206, 215-217, 219, 221 -222, 224, 236-242, 244-245, 247-248, 250-257, 259-267, 269-275, 282-283, 327-337, 344-350, 509-510, 525-527, 531 , 533-535, 538, 545-549, 551 - 553, 555, 562-569, and 571 -572and is administered once daily in an amount of about 10 mg. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-10, 12-23, 24-27, 28-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92- 93, 96, 102-105, 108-11 1 , 115-138, 139-157, 158-162, 164-172, 173-182, 183-186, 194- 197, 199-201 , 203-206, 215-217, 219, 221 -222, 224, 236-242, 244-245, 247-248, 250-257, 259-267, 269-275, 282-283, 327-337, 344-350, 509-510, 525-527, 531 , 533-535, 538, 545- 549, 551 -553, 555, 562-569, and 571 -572and is administered at least once daily in an amount of about 1 mg to about 100 mg, about 5 mg to about 95 mg, about 10 mg to about 90 mg, about 15 mg to about 85 mg, about 20 mg to about 80 mg, about 25 mg to about 75 mg, about 30 mg to about 70 mg, about 35 mg to about 65 mg, about 40 to about 60 mg, or about 45 to about 55 mg. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-10, 12-23, 24-27, 28-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-1 11 , 1 15-138, 139-157, 158-162, 164-172, 173- 182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219, 221 -222, 224, 236-242, 244-245, 247-248, 250-257, 259-267, 269-275, 282-283, 327-337, 344-350, 509-510, 525-527, 531 , 533-535, 538, 545-549, 551 -553, 555, 562-569, and 571 -572 and is administered at least once daily in an amount of about 50 mg.
[1628] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-4, 13, 15-23, 24-32, 35-43, 48-55, 59, 64-69, 71 -76, 77-82, 86-87, 90, 92-93, 96, 102, 104-105, 108-11 1 , 115-138, 139-162, 164, 165-186, 195-197, 199-201 , 203, 215-217, 219, 221 -222, 224, 240-242, 244, 255-256, 259-267, 269-275, 327-328, 331 , 344-350, 525-527, 531 , 533-535, 538, 545, 547-549, 551 -553, 555, 562-569, and 571 -572 and is administered at least once daily in an amount of about 0.1 mg to about 100 mg, 0.5 mg to about 50 mg, about 1 mg to about 40 mg, about 2.5 mg to about 30 mg, about 5 to about 20 mg, or about 7.5 to about 15 mg. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-4, 13, 15-23, 24-32, 35-43, 48-55, 59, 64- 69, 71 -76, 77-82, 86-87, 90, 92-93, 96, 102, 104-105, 108-1 11 , 115-138, 139-162, 164, 165- 186, 195-197, 199-201 , 203, 215-217, 219, 221 -222, 224, 240-242, 244, 255-256, 259-267, 269-275, 327-328, 331 , 344-350, 525-527, 531 , 533-535, 538, 545, 547-549, 551 -553, 555, 562-569, and 571 -572 and is administered once daily in an amount of about 10 mg. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-4, 13, 15-23, 24-32, 35-43, 48-55, 59, 64-69, 71 -76, 77-82, 86-87, 90, 92-93, 96, 102, 104- 105, 108-111 , 115-138, 139-162, 164, 165-186, 195-197, 199-201 , 203, 215-217, 219, 221 - 222, 224, 240-242, 244, 255-256, 259-267, 269-275, 327-328, 331 , 344-350, 525-527, 531 , 533-535, 538, 545, 547-549, 551 -553, 555, 562-569, and 571 -572 and is administered at least once daily in an amount of about 1 mg to about 100 mg, about 5 mg to about 95 mg, about 10 mg to about 90 mg, about 15 mg to about 85 mg, about 20 mg to about 80 mg, about 25 mg to about 75 mg, about 30 mg to about 70 mg, about 35 mg to about 65 mg, about 40 to about 60 mg, or about 45 to about 55 mg. In some embodiments, the non- naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-4, 13, 15-23, 24-32, 35-43, 48-55, 59, 64-69, 71 -76, 77-82, 86-87, 90, 92-93, 96, 102, 104-105, 108-1 1 1 , 115- 138, 139-162, 164, 165-186, 195-197, 199-201 , 203, 215-217, 219, 221 -222, 224, 240-242, 244, 255-256, 259-267, 269-275, 327-328, 331 , 344-350, 525-527, 531 , 533-535, 538, 545, 547-549, 551 -553, 555, 562-569, and 571 -572 and is administered at least once daily in an amount of about 50 mg.
[1629] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-10, 12-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-11 1 , 115-138, 139-162, 164, 165-186, 194-197, 199-201 , 203-206, 239-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, and 344-350 and is administered at least once daily in an amount of about 0.1 mg to about 100 mg, 0.5 mg to about 50 mg, about 1 mg to about 40 mg, about 2.5 mg to about 30 mg, about 5 to about 20 mg, or about 7.5 to about 15 mg. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-10, 12-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-1 1 1 , 115-138, 139-162, 164, 165-186, 194-197, 199-201 , 203-206, 239-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282- 283, 327-337, and 344-350 and is administered once daily in an amount of about 10 mg. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-10, 12-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-111 , 115-138, 139-162, 164, 165-186, 194-197, 199-201 , 203-206, 239-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, and 344-350 and is administered at least once daily in an amount of about 1 mg to about 100 mg, about 5 mg to about 95 mg, about 10 mg to about 90 mg, about 15 mg to about 85 mg, about 20 mg to about 80 mg, about 25 mg to about 75 mg, about 30 mg to about 70 mg, about 35 mg to about 65 mg, about 40 to about 60 mg, or about 45 to about 55 mg. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 2-7, 9-10, 12- 43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-111 , 115-138, 139- 162, 164, 165-186, 194-197, 199-201 , 203-206, 239-242, 244-245, 247-248, 250-251 , 253- 257, 259-267, 269-275, 282-283, 327-337, and 344-350 and is administered at least once daily in an amount of about 50 mg. [1630] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 215-217, 219-222, 224, 236-238, 497, 500, 507-510, 514, 516-517, 535, and 538-561 and is administered at least once daily in an amount of about 0.1 mg to about 100 mg, 0.5 mg to about 50 mg, about 1 mg to about 40 mg, about 2.5 mg to about 30 mg, about 5 to about 20 mg, or about 7.5 to about 15 mg. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 215-217, 219-222, 224, 236-238, 497, 500, 507-510, 514, 516-517, 535, and 538-561 and is administered once daily in an amount of about 10 mg. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 215-217, 219-222, 224, 236-238, 497, 500, 507-510, 514, 516-517, 535, and 538-561 and is administered at least once daily in an amount of about 1 mg to about 100 mg, about 5 mg to about 95 mg, about 10 mg to about 90 mg, about 15 mg to about 85 mg, about 20 mg to about 80 mg, about 25 mg to about 75 mg, about 30 mg to about 70 mg, about 35 mg to about 65 mg, about 40 to about 60 mg, or about 45 to about 55 mg. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 215-217, 219-222, 224, 236-238, 497, 500, 507-510, 514, 516-517, 535, and 538-561 and is administered at least once daily in an amount of about 50 mg.
[1631] In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 220, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-508, 514, 516-517, 524, 529, 539-544, 550, 554, and 556-561 and is administered at least once daily in an amount of about 0.1 mg to about 100 mg, 0.5 mg to about 50 mg, about 1 mg to about 40 mg, about 2.5 mg to about 30 mg, about 5 to about 20 mg, or about 7.5 to about 15 mg. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 220, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-508, 514, 516-517, 524, 529, 539-544, 550, 554, and 556-561 and is administered once daily in an amount of about 10 mg. In some embodiments, the non-naturally occurring melanocortin analog is any one of SEQ ID NOs: 220, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-508, 514, 516-517, 524, 529, 539-544, 550, 554, and 556-561 and is administered at least once daily in an amount of about 1 mg to about 100 mg, about 5 mg to about 95 mg, about 10 mg to about 90 mg, about 15 mg to about 85 mg, about 20 mg to about 80 mg, about 25 mg to about 75 mg, about 30 mg to about 70 mg, about 35 mg to about 65 mg, about 40 to about 60 mg, or about 45 to about 55 mg. In some embodiments, the non- naturally occurring melanocortin analog is any one of SEQ ID NOs: 220, 426, 430-432, 444- 445, 487, 489, 493, 495, 497, 500, 507-508, 514, 516-517, 524, 529, 539-544, 550, 554, and 556-561 and is administered at least once daily in an amount of about 50 mg.
[1632] In some embodiments, administration of the non-naturally occurring melanocortin analog comprises delivery across the blood brain barrier. In some embodiments, administration of the non-naturally occurring melanocortin analog comprises delivery across the epithelium. In some embodiments, administration of the non-naturally occurring melanocortin analog comprises delivery across the epithelium and the blood brain barrier. In some embodiments, administration of the non-naturally occurring melanocortin analog comprises delivery through the gastrointestinal tract.
Methods
[1633] The present technology comprises methods of treating, preventing, reducing, or otherwise ameliorating one or more symptoms or conditions that may benefit from weight gain or a reduction in weight loss. The methods comprise administering a non-naturally occurring melanocortin analog of the present technology to a subject in need thereof. The methods may promote fat gain (e.g., epididymal fat or perirenal fat), increase muscle mass, increase body weight, accelerate weight gain, increase fat mass to lean mass ratio, improve body composition and/or BMI (e.g., for underweight conditions), increase waist circumference, increase cardiac mass, increase brain mass, or any combination thereof, relative to a control. In some embodiments, the methods of the present technology increase a fat mass or a lean mass (e.g., muscle, organ, and bone mass) in the subject, relative to a control.
[1634] In some embodiments, the methods of the present technology reduce a loss in or a rate of loss in fat (e.g., epididymal fat or perirenal fat), muscle mass, body weight, weight gain, fat mass to lean mass ratio, BMI, a BMI durability, waist circumference, cardiac mass, brain mass, or any combination thereof, relative to a control.
[1635] In some embodiments, the present technology comprises methods of treating, preventing, reducing, or otherwise ameliorating one or more symptoms or conditions associated with cachexia, anorexia, or other conditions benefiting from weight gain in a subject by administering a non-naturally occurring melanocortin analog to the subject. The methods may promote lean mass gain, increase lean mass, maintain healthy lean mass, maintain a mass, or reduce a mass loss in the subject. The methods of the present technology may increase a cardiac mass, relative to a control. In some embodiments, the method improves gastrointestinal function and nutrient absorption
[1636] The subject of the methods of the present technology may have cachexia, anorexia, or another condition for which a therapeutic benefit is provided by weight gain or reduced rates of weight loss. In some embodiments, the subject is underweight. In some embodiments, the subject has a metabolic dysfunction or disorder, including, but not limited to, impaired glucose metabolism. In some embodiments, the subject has muscle wasting or sarcopenia.
[1637] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence according to any one of Formulae (l)-(ID). In some embodiments, the non-naturally occurring analog comprises a sequence of any one of SEQ ID NOs: 2-7, 9-12, 13-23, 24-27, 28-30, 31 -43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102- 105, 108-111 , 1 15-122, 123-138, 139-157, 158-164, 165-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219-222, 224, 236-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, 344-350, 369, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-510, 514, 516-517, 524-527, 529, 531 , 533-535, and 538-572. In some embodiments, the non-naturally occurring analog comprises a sequence of any one of SEQ ID NOs: -7, 9-10, 12-23, 24-27, 28-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-11 1 , 115-138, 139-157, 158-162, 164-172, 173-182, 183-186, 194-197, 199- 201 , 203-206, 215-217, 219, 221 -222, 224, 236-242, 244-245, 247-248, 250-257, 259-267, 269-275, 282-283, 327-337, 344-350, 509-510, 525-527, 531 , 533-535, 538, 545-549, 551 - 553, 555, 562-569, and 571 -572. In some embodiments, the non-naturally occurring analog comprises a sequence of any one of SEQ ID NOs: 2-4, 13, 15-23, 24-32, 35-43, 48-55, 59, 64-69, 71 -76, 77-82, 86-87, 90, 92-93, 96, 102, 104-105, 108-111 , 1 15-138, 139-162, 164, 165-186, 195-197, 199-201 , 203, 215-217, 219, 221 -222, 224, 240-242, 244, 255-256, 259- 267, 269-275, 327-328, 331 , 344-350, 525-527, 531 , 533-535, 538, 545, 547-549, 551 -553, 555, 562-569, and 571 -572ln some embodiments, the non-naturally occurring analog comprises a sequence of any one of SEQ ID NOs: 2-7, 9-10, 12-43, 48-55, 59, 64-69, 71 - 76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-111 , 115-138, 139-162, 164, 165-186, 194- 197, 199-201 , 203-206, 239-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, and 344-350. In some embodiments, the non-naturally occurring analog comprises any one of SEQ ID NOs: 215-217, 219-222, 224, 236-238, 497, 500, 507-510, 514, 516-517, 535, and 538-561 . In some embodiments, the non-naturally occurring analog comprises any one of SEQ ID NOs: 220, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-508, 514, 516-517, 524, 529, 539-544, 550, 554, and 556-561.
[1638] In some embodiments, the methods of the present technology the risk or incidence of adverse cardiovascular events, such as, cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, angina, sinus tachycardia, coronary artery bypass grafting, percutaneous coronary intervention, heart failure, carotid endarterectomy, peripheral vascular disease, or any combination thereof, and/or decrease gastrointestinal effects such as, nausea, vomiting, and diarrhea that are associated with use of a conventional non-naturally occurring melanocortin analog. The methods may also treat, prevent, or reduce one or more side effects associated with the use of a conventional non- naturally occurring melanocortin analog. For example, methods of reducing lean mass loss, maintaining lean mass, or promoting lean mass gain may prevent or reduce the risk or incidence of adverse cardiovascular events associated with the use of a conventional non- naturally melanocortin agonist, such as sinus tachycardia. Additionally, such methods may reduce hemoglobin A1 c levels, decrease inflammation, regulate plasma insulin and/or preserve or improve kidney function in the subject.
[1639] In some embodiments, the present technology comprises methods of increasing, maintaining, or reducing a loss (e.g., a rate of loss or an absolute loss) of muscle mass. In some embodiments, the muscle mass is cardiac muscle mass, skeletal muscle mass, or both. In some embodiments, the cardiac muscle mass is determined by measuring change in heart weight. In some embodiments, the skeletal muscle mass is determined by measuring change in gastrocnemius tissue weight. In related embodiments, the muscle mass change is cardiac muscle mass change, skeletal muscle mass change, or both. In some embodiments, cardiac muscle is determined by heart weight. In some embodiments, skeletal muscle mass is determined by gastrocnemius tissue weight. In some embodiments, the muscle mass changes may be assessed by using magnetic resonance imaging (MRI) and/or or nuclear magnetic resonance (NMR).
[1640] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence according to any one of Formulae (l)-(ID). In some embodiments, the non-naturally occurring analog comprises a sequence of any one of SEQ ID NOs: 2-7, 9-12, 13-23, 24-27, 28-30, 31 -43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102- 105, 108-111 , 1 15-122, 123-138, 139-157, 158-164, 165-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219-222, 224, 236-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, 344-350, 369, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-510, 514, 516-517, 524-527, 529, 531 , 533-535, and 538-572. In some embodiments, the non-naturally occurring analog comprises a sequence of any one of SEQ ID NOs: -7, 9-10, 12-23, 24-27, 28-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-11 1 , 115-138, 139-157, 158-162, 164-172, 173-182, 183-186, 194-197, 199- 201 , 203-206, 215-217, 219, 221 -222, 224, 236-242, 244-245, 247-248, 250-257, 259-267, 269-275, 282-283, 327-337, 344-350, 509-510, 525-527, 531 , 533-535, 538, 545-549, 551 - 553, 555, 562-569, and 571 -572. In some embodiments, the non-naturally occurring analog comprises a sequence of any one of SEQ ID NOs: 2-4, 13, 15-23, 24-32, 35-43, 48-55, 59, 64-69, 71 -76, 77-82, 86-87, 90, 92-93, 96, 102, 104-105, 108-111 , 1 15-138, 139-162, 164, 165-186, 195-197, 199-201 , 203, 215-217, 219, 221 -222, 224, 240-242, 244, 255-256, 259- 267, 269-275, 327-328, 331 , 344-350, 525-527, 531 , 533-535, 538, 545, 547-549, 551 -553, 555, 562-569, and 571 -572ln some embodiments, the non-naturally occurring analog comprises a sequence of any one of SEQ ID NOs: 2-7, 9-10, 12-43, 48-55, 59, 64-69, 71 - 76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-111 , 115-138, 139-162, 164, 165-186, 194- 197, 199-201 , 203-206, 239-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, and 344-350. In some embodiments, the non-naturally occurring analog comprises any one of SEQ ID NOs: 215-217, 219-222, 224, 236-238, 497, 500, 507-510, 514, 516-517, 535, and 538-561 . In some embodiments, the non-naturally occurring analog comprises any one of SEQ ID NOs: 220, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-508, 514, 516-517, 524, 529, 539-544, 550, 554, and 556-561. [1641] The methods of the present technology may be performed on the subject for about 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years. In some embodiments, the pharmaceutical composition is administered to the subject for about 1 day, about 2 days, about 5 days, about 6 days, about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, about 1 year, about 2 years, about 3 years, about 4 years, or about 5 years.
[1642] In some embodiments, a method of the present technology is performed on the subject for about 1 day, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.
[1643] The methods of the present technology may be performed on the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years. In some embodiments, the pharmaceutical composition is administered to the subject for at least 1 day, at least 2 days, at least 5 days, at least 6 days, at least 1 week, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 9 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years.
[1644] In some embodiments, a method of the present technology is performed on the subject for at least 1 day, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.
[1645] The methods of the present technology may be performed on the subject for at least about 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years. In some embodiments, the pharmaceutical composition is administered to the subject for at least about 1 day, at least about 2 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years.
[1646] In some embodiments, a method of the present technology is performed on the subject for at least about 1 day, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days. Maintenance Doses
[1647] In some embodiments, a maintenance dose of the non-naturally occurring melanocortin analog is administered to the subject to maintain weight and/or continue weight increase.
Subjects
[1648] In some embodiments, the subject is a mammal, including but not limited to a human, a non-human primate such as a chimpanzee, a domestic livestock or a farm animal such as a cow, a bison, sheep, a pig, a goat, a horse, a chicken, and a rooster, a domestic pet animal such as a dog, a cat, a rat, a mouse, and a rabbit, and a laboratory subject such as a rodent, including a rat, a mouse, and a guinea pig. In some embodiments, the subject is a human. In some embodiments, the subject is an animal such as a rat or a dog.
[1649] In some embodiments, the subject has a body mass index (BMI) of 18.5 kg/m2 to 35 kg/m2. In some embodiments, the subject has a BMI of less than 35 kg/m2. In some embodiments, the subject has a BMI of less than 18.5 kg/m2.
[1650] In some embodiments, the subject is an underweight subject. Underweight subjects include those having a body weight about 3%, 5% or less, 10% or less, 20% or less, or 30% or less, than the lower end of “normal” BMI (e.g., 18.5 kg/m2).
[1651] In some embodiments, the subject has a metabolic dysfunction.
Controls
[1652] The controls of the present technology may comprise the subject at baseline. In some embodiments, the controls of the methods of the present technology comprise a subject that is not administered a non-naturally occurring melanocortin analog of the present technology or a subject subjected to a method lacking one or more steps of the methods of the present technology.
EXAMPLES
[1653] The following examples are intended to illustrate various embodiments of the present technology. As such, the specific embodiments discussed are not to be construed as limitations on the scope of the present technology. It will be apparent to one skilled in the art that various equivalents, changes, and modifications may be made without departing from the scope of present technology, and it is understood that such equivalent embodiments, are to be included herein. Further, all references cited herein are hereby incorporated by reference in their entirety, as if fully set forth herein.
Example 1 : Peptide Synthesis-Generic
[1654] The non-naturally occurring melanocortin analogs of the present technology were synthesized by conventional procedures (e.g., solution-phase procedure, solid-phase synthesis) for the formation of a peptide linkage between amino acids. The solution-phase procedure involved a condensation between the free alpha amino group of an amino acid or derivative thereof having the carboxyl group or other reactive groups protected and the free primary carboxyl group of another amino acid or derivative thereof having the amino group or other reactive groups protected. The solid-phase synthesis utilized a variety of resins and reagents and may involve additional purification steps.
[1655] The process for synthesizing the non-naturally occurring melanocortin analogs was generally performed by a procedure as follows. Each amino acid in the desired sequence of the non-naturally occurring melanocortin analogs was added one at a time in succession to another amino acid or derivative thereof or by a procedure whereby peptide fragments with the desired amino acid sequence were first synthesized conventionally and then condensed to provide the desired peptide. In most cases, the resulting peptide was then cyclized to yield a cyclic peptide.
[1656] Solid-phase peptide synthesis was carried out by sequentially incorporating the desired amino acid residues one at a time into the growing peptide chain coupled to a solidphase support according to the general principles of solid phase methods (see Merrifield, Angew Chem. 24:799-810 (1985) and Barany et al. , The Peptides, Analysis, Synthesis and Biology, Vol. 2, Gross E. and Meienhofer J., Eds. Academic Press 1 -284 (1980)). An exemplary solid-phase synthesis of non-naturally occurring melanocortin analogs is provided below. [1657] Initially, the C-terminal amino acid residue of the non-naturally occurring melanocortin analog was coupled to a solid-phase support, e.g., a solid-phase resin. Coupling of the C-terminal amino acid residue and the solid-phase support may be carried out according to any method know in the art. Depending on the coupling method, the alphaamine of the C-terminal amino acid residue may or may not be protected with an amine protecting group, as described below. Likewise, the carboxyl group of the amino acid residue may or may not be activated prior to coupling to the solid-phase support in order to increase its electrophilicity. Some methods of coupling rely on the formation of an ester bond between the carboxyl group of the amino acid and a reactive handle on the solid-phase resin. For example, an amino acid residue may be coupled to a p-benzyloxybenzyl alcohol resin (Wang) or a 2-chlorotrityl chloride resin via an ester linkage. Some methods of coupling rely on the formation of an amide bond between the carboxyl group of the amino acid and a reactive handle on the solid-phase resin For example, an amino acid residue may be coupled to a benzhydrylamine (BHA) resin through an Fmoc-linker such as, for example, p- [(R,S)-a-[1 -(9H-fluor-en-9-yl)-methoxyformamido]-2,4-dimethyloxybenzyl]-phenoxyacetic acid (Rink linker) via an amide linkage.
[1658] The non-naturally occurring melanocortin analog was then synthesized by sequential amino acid addition or combination of peptide fragments. Subsequently, the peptide was cleaved from the solid-phase support and purified by methods known in the art, such as, for example, reverse phase high performance liquid chromatography (RP-HPLC) using a suitable column, such as a C18 column. Additionally, or alternatively, other methods of separation or purification were employed, including, but not limited to, methods based on the size or charge of the peptide. Once purified, the peptide was characterized by methods such as high-performance liquid chromatograph (HPLC), amino acid analysis, mass spectrometry, and the like.
Example 2: Peptide Synthesis-Protecting Groups
[1659] During synthesis of the non-naturally occurring melanocortin analogs, reactive side chain groups of the various amino acid residues were protected with suitable protecting groups, which prevented undesirable chemical reaction from occurring at that site until the protecting group was removed. [1660] Additionally, protection of the alpha amino group of an amino acid residue or fragment was performed while that entity reacting with the carboxyl group, followed by the selective removal of the alpha amino protecting group to allow a subsequent reaction to take place at that site. Specific protecting groups for solid phase synthesis methods and solution phase synthesis methods are known to those having ordinary skill in the art. Alpha amino groups were protected by a suitable protecting group, including a urethane-type protecting group, such as benzyloxycarbonyl (Z) and substituted benzyloxycarbonyl, such as p- chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p- biphenyl-isopropoxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc) and p- methoxybenzyloxycarbonyl (Moz); aliphatic urethane-type protecting groups, such as t- butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropoxycarbonyl, and allyloxycarbonyl. Fmoc was also used for alpha amino protection. Guanidino groups, if present, were protected by a suitable protecting group, such as nitro, p-toluenesulfonyl (Tos), Z, pentamethylchromanesulfonyl (Pmc), adamantyloxycarbonyl, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) and Boc. Pmc was used as a protecting group for Arg.
[1661] Alpha aminoprotecting groups may be removed under basic conditions, such as, for example, using a solution of piperidine, piperazine, diethylamine, or morpholine (20- 40% v/v) in N,N-dimethylformamide (DMF). In synthesis methods in which alpha amino protecting groups were used, protecting groups were removed after synthesis of the peptide and before or after cleavage of the solid-phase support.
Example 3: Peptide Synthesis-Additional Modifications
[1662] If necessary, the peptides were further modified to obtain N-terminus modifications, such as acetylation, while on resin, or were removed from the resin by use of a cleaving reagent and then modified. Likewise, C-terminus modification (e.g., amidation), was performed if needed.
[1663] Additionally, the cyclized peptide structures were obtained prior to cleavage from the peptide resin. For cyclization through reactive side chain moieties, the desired side chains were deprotected, and the peptide suspended in a suitable solvent and a cyclic coupling agent added. Suitable solvents, for example DMF, dichloromethane (DCM) or 1 - methyl-2-pyrrolidone (NMP), were used for the cyclization. Suitable cyclic coupling reagents (e.g., 2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TBTLI), 2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (HBTLI), benzotriazole- 1 -yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole-1 -yl- oxy-tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP), 2-(7-aza-1 H-benzotriazol- 1 -yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TATU), 2-(2-oxo-1 (2H)-pyridyl)-1 ,1 ,3,3- tetramethyluronium tetrafluoroborate (TPTLI), N,N'-dicyclohexylcarbodiimide/1 - hydroxybenzotriazole (DCCI/HOBt)) were also used for the cyclization. Coupling was initiated by a suitable base, such as N,N-diispropylethylamine (DIPEA), sym-collidine or N- methylmorpholine (NMM).
Example 4: Biological Data
[1664] The agonist and antagonist activity of exemplary non-naturally occurring melanocortin analogs at the melanocortin receptors (e.g., MC1 R, MC3R, MC4R, and MC5R) were measured via cAMP accumulation assay, according to the following procedure. Experimental design and execution were conducted by Epics Therapeutics S.A. EuroscreenFast (Bruxelles, Belgium).
Compound Handing
[1665] Compounds were delivered as powder (1 mg) or 10 mM solutions (100 pl) in 100% DMSO. Powders were solubilized in 100% DMSO at a concentration of 10 mM (master solution) in a solvent volume defined. Serial dilutions were performed from master solution in 100% DMSO to obtain intermediate concentrations 200-, 300- or 400-fold higher than the concentrations to be tested, depending on the assay. Each sample was diluted 100- fold in the assay buffer and dispensed in a test plate. Amounts, solvents, and dilutions were estimated based on standard small-molecule drugs. Cell lines used for functional assays are shown in Table 1 . un Table 1. Cell lines
Figure imgf000216_0001
Compound Testing
[1666] Compounds were tested for (i) agonist and/or antagonist activity at the human MC3 (FAST-0232C) and MC4 (FAST-0233C) receptors, (ii) agonist activity at the human MC1 (FAST-0232C) receptor, and/or (iii) agonist activity at the human MC5 (FAST-0233C) receptor at the following nanomolar concentrations, in duplicate: 0.0001 , 0.001 , 0.01 , 0.03, 0.1 , 0.3, 1 , 10, 100, and 1 ,000.
Testing Protocol
[1667] Cyclic AMP (cAMP) Homogenous Time-Resolved Fluorescence (HTRF) assay for Gs coupled receptor:
[1668] CHO-K1 cells expressing recombinant human receptor grown prior to the test in media without antibiotic were detached by gentle flushing with PBS-EDTA (5 mM EDTA), recovered by centrifugation and resuspended in assay buffer (KRH: 5 mM KCI, 1.25 mM MgSO4, 124 mM NaCI, 25 mM HEPES, 13.3 mM Glucose, 1.25 mM KH2PO4, 1.45 mM CaCI2, 0.5 g/l BSA, supplemented with 1 mM IBMX or 25pM Rolipram).
[1669] Dose response curves were performed in parallel with the reference compounds.
[1670] For agonist test (384well): 5 pl of cells were mixed with 5 pl of the test compound at increasing concentrations and then incubated 30 min at room temperature. After addition of the lysis buffer containing cAMP-d2 and anti-cAMP cryptate detection reagents, plates were incubated 1 -hour at room temperature, and fluorescence ratios were measured according to the manufacturer specification, with the HTRF kit. [1671] For antagonist test (384well): 5 pl of cells were mixed in the wells of an assay plate with 5 pl of a mix of test compound at increasing concentrations and reference agonist for a final concentration corresponding to the historical EC80. The plates were then incubated 30 min at room temperature. After addition of the lysis buffer containing cAMP-d2 and anti-cAMP cryptate detection reagents, plates were incubated 1 -hour at room temperature, and fluorescence ratios were measured according to the manufacturer specification, with the HTRF kit.
Quality Control for Compound Testing
[1672] On each day of experimentation and prior to the testing of compounds, reference compounds were tested at several concentrations in duplicate (n=2) to obtain a dose-response curve and an estimated EC50 and/or IC50 values.
[1673] Reference values thus obtained for the test were compared to historical values obtained from the same receptor and used to validate the experimental session.
[1674] A session was considered as valid only if the reference value was found to be within a 0.5 logs interval from the historical value.
[1675] For replicate determinations, the maximum variability tolerated in the test was of +/-20% around the average of the replicates.
Non-naturally occurring melanocortin analog grouping
[1676] Non-naturally occurring melanocortin analogs were grouped based on structural similarities. Group A included non-naturally occurring melanocortin analogs A1 and A2, both of which are linear peptides comprising the motif Pro-dNal(2’)-Arg-Trp. Group A peptides are provided in Table 2.
Table 2. Group A non-naturally occurring melanocortin analogs
Figure imgf000217_0001
Figure imgf000218_0001
[1677] Group D included non-naturally occurring melanocortin analogs D1 to D5, and known MC3R/MC4R antagonists B02 and B07, all of which are cyclic peptides comprising the motif Pro-dNal(2’)-Arg-Trp, cyclized through a lactam bond between Asp and Lys, or a derivative thereof. The non-naturally occurring melanocortin analogs in Group D are derived from known MC3R/MC4R antagonist B07. Group D non-naturally occurring melanocortin analogs are provided in Table 3.
Table 3. Group D non-naturally occurring melanocortin analogs
Figure imgf000218_0002
[1678] Group E included non-naturally occurring melanocortin analogs E1 through E24, all of which are cyclic peptides comprising the motif Pro-dNal(2’)-Arg-Trp, cyclized by a lactam bond between Asp and Lys, and a C-terminal dVal-dPro moiety. Group E non- naturally occurring melanocortin analogs are provided in Table 4.
Table 4. Group E non-naturally occurring melanocortin analogs
Figure imgf000218_0003
Figure imgf000219_0001
[1679] Group F included non-naturally occurring melanocortin analogs F1 through F29, all of which are peptides cyclized through a bridge other than a bridge between Asp and Lys. Group F non-naturally occurring melanocortin analogs are provided in Table 5.
Table 5. Group F non-naturally occurring melanocortin analogs
Figure imgf000220_0001
Figure imgf000221_0001
[1680] Group G included non-naturally occurring melanocortin analogs G1 through G24, all of which are cyclic peptides comprising the motif R3-dNal(2’)-Arg-Trp, where R3 is not Pro. Group G non-naturally occurring melanocortin analogs are provided in Table 6.
Table 6. Group G non-naturally occurring melanocortin analogs
Figure imgf000221_0002
Figure imgf000222_0001
[1681] Group H included non-naturally occurring melanocortin analogs H1 through H15, all of which are cyclic peptides comprising the motif Pro-dNal(2’)-R5-Trp, where R5 is not Arg. Group H non-naturally occurring melanocortin analogs are provided in Table 7.
Table 7. Group H non-naturally occurring melanocortin analogs
Figure imgf000222_0002
Figure imgf000223_0001
[1682] Group I included non-naturally occurring melanocortin analogs 11 through 113, all of which are cyclic peptides comprising the motif Pro-dNal(2’)-Arg-R6, where R6 is not Trp. Group I non-naturally occurring melanocortin analogs are provided in Table 8.
Table 8. Group I non-naturally occurring melanocortin analogs
Figure imgf000223_0002
[1683] Group J included non-naturally occurring melanocortin analogs J1 through J69, all of which are cyclic peptides comprising the motif Pro-dNal(2’)-Arg-Trp, cyclized by a lactam bond between Asp and Lys, and a C-terminus other than dVal-dPro-NH2. Group J non-naturally occurring melanocortin analogs are provided in Table 9.
Table 9. Group J non-naturally occurring melanocortin analogs
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
[1684] Group K included non-naturally occurring melanocortin analogs K1 through K37, all of which are cyclic peptides comprising the motif Pro-p(X)dPhe-Arg-Trp, where X is Cl, I, Br, or CF3, or a derivative thereof. Group K non-naturally occurring melanocortin analogs are provided in Table 10.
Table 10. Group K non-naturally occurring melanocortin analogs
Figure imgf000227_0002
Figure imgf000228_0001
Figure imgf000229_0001
[1685] Group L included non-naturally occurring melanocortin analogs L1 through L3, all of which are cyclic peptides comprising the Pro at one or more of R2, R3, and R7. Group L non-naturally occurring melanocortin analogs are provided in Table 1 1 .
Table 11 . Group L non-naturally occurring melanocortin analogs
Figure imgf000229_0002
[1686] Group M included non-naturally occurring melanocortin analogs M1 through M5, all of which are cyclic peptides comprising the motif Glu-dNal(2')-Arg-Trp or a derivative thereof. Group M non-naturally occurring melanocortin analogs are provided in Table 12.
Table 12. Group M non-naturally occurring melanocortin analogs
Figure imgf000230_0001
[1687] Group N included non-naturally occurring melanocortin analogs N7 through
N1 1 , all of which are cyclic peptides comprising the motif dNal(2')-Arg-Trp-Gly or a derivative thereof and/or a C-terminal dPro-dPro-Lys-Asp, or a derivative thereof. Group N non- naturally occurring melanocortin analogs are provided in Table 13.
Table 13. Group M non-naturally occurring melanocortin analogs
Figure imgf000230_0002
Figure imgf000231_0001
[1688] Group O included non-naturally occurring melanocortin analogs 01 through 08, all of which are cyclic peptides comprising the motif dAla-His-dNal(2’)-Arg or a derivative thereof. The inclusion of dAla in Group O may promote and stabilize b-turns in the Group O peptides. Group O non-naturally occurring melanocortin analogs are provided in Table 14.
Table 14. Group N non-naturally occurring melanocortin analogs
Figure imgf000231_0002
[1689] Group P included non-naturally occurring melanocortin analog P1 , which is a cyclic peptides comprising the motif dBip-dPhe-Arg-Trp. The group P non-naturally occurring melanocortin analog is provided in Table 15.
Table 15. Group P non-naturally occurring melanocortin analogs
Figure imgf000232_0001
[1690] Group Q included non-naturally occurring melanocortin analogs Q1 to Q34, all of which are cyclic peptides comprising the motif His-p(X)dPhe-Arg-Trp or a derivative thereof. Further, group Q peptides have partial agonist activity on at least the MC4R. Group Q non-naturally occurring melanocortin analogs are provided in Table 16.
Table 16. Group Q non-naturally occurring melanocortin analogs
Figure imgf000232_0002
Figure imgf000233_0001
Figure imgf000234_0001
Agonist activity of melanocortin analogs on melanocortin 1 and 5 receptors
[1691] Administration of some non-naturally occurring melanocortin analogs activated melanocortin 1 receptor (MC1 R) and/or melanocortin 5 receptor (MC5R) activity, as measured by cAMP levels (Table 17).
Table 17. Dose-response results of melanocortin agonist analogs and control against the melanocortin 1 receptor (MC1 R) and melanocortin 5 receptor (MC5R)
Figure imgf000234_0002
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
Agonist activity of melanocortin analogs on melanocortin 3 receptor and melanocortin 4 receptor
[1692] Administration of some non-naturally occurring melanocortin analogs activated melanocortin 3 receptor (MC3R) activity and/or melanocortin 4 receptor (MC4R) activity, as measured by cAMP levels (Table 18).
Table 18. Dose-response results of melanocortin agonist analogs and control against the melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R)
Figure imgf000243_0002
Figure imgf000244_0001
Figure imgf000245_0001
Antagonist activity of melanocortin analogs on melanocortin 3 receptor and melanocortin 4 receptor
[1693] Administration of some non-naturally occurring melanocortin analogs inhibited melanocortin 3 receptor (MC3R) and/or melanocortin 4 receptor (MC4R) activity, as measured by cAMP levels. (Table 19).
Table 19. Dose-response results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) and the melanocortin 4 receptor (4)
Figure imgf000245_0002
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Additional Embodiments
[1694] Various embodiments of the present technology are set forth below in paragraphs [1695] to [3223]:
[1695] 1. A method of increasing body weight in a subject in need thereof, comprising administering to the subject
[1696] a non-naturally occurring melanocortin analog comprising a sequence of Formula (I):
[1697] X1 -X2-X3- R1 - R2- R3- R4- R5- R6- R7- R8- R9-Y1 - Y2- Y3-Y4- Y5-Y6- Y7 ( I) ,
[1698] wherein:
[1699] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[1700] X2 is absent, phenylalanine (Phe), or Nle;
[1701] X3 is absent, Phe, or Nle; [1702] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), frans-4-guanidinyl-proline (fransPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys);
[1703] R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s-CH=CH-CO, proline (Pro), and tryptophan (Trp);
[1704] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), transPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino- 1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
[1705] R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
[1706] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fransPro(guan); [1707] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
[1708] R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[1709] R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
[1710] R9 is absent or Lys;
[1711] Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro,
Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[1712] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[1713] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[1714] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[1715] Y5 is absent or dVal;
[1716] Y6 is absent or dVal;
[1717] Y7 is absent or dPro; and
[1718] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[1719] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[1720] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and [1721] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[1722] provided that:
[1723] when R3 is dTrp or Phe, then R4 is not dNal(2’) and R6 is not dPhe;
[1724] when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii)
R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7;
[1725] when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either
R5 is Lys or R6 is dNal(2’) or Nal(2’);
[1726] when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent;
[1727] when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and
[1728] when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
[1729] 2. Use of a non-naturally occurring melanocortin analog for increasing body weight in a subject in need thereof, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I):
[1730] X1 -X2-X3- R1 - R2- R3- R4- R5- R6- R7- R8- R9-Y1 - Y2- Y3-Y4- Y5-Y6- Y7 ( I) ,
[1731] wherein:
[1732] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[1733] X2 is absent, phenylalanine (Phe), or Nle;
[1734] X3 is absent, Phe, or Nle;
[1735] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), tra/?s-4-guanidinyl-proline (f/'ansPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys);
[1736] R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s-CH=CH-CO, proline (Pro), and tryptophan (Trp);
[1737] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, czsPro(guan), tra/?sPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[ 1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino- 1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
[1738] R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
[1739] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fransPro(guan);
[1740] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’)); [1741] R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[1742] R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
[1743] R9 is absent or Lys;
[1744] Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro,
Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[1745] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[1746] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[1747] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[1748] Y5 is absent or dVal;
[1749] Y6 is absent or dVal;
[1750] Y7 is absent or dPro; and
[1751] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[1752] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[1753] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and
[1754] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[1755] provided that: [1756] when R3 is dTrp or Phe, then R4 is not dNal(2’) and R6 is not dPhe;
[1757] when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii)
R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7;
[1758] when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2’) or Nal(2’);
[1759] when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent;
[1760] when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and
[1761] when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
[1762] 3. The method or the use of embodiment 1 or 2, wherein the method further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject.
[1763] 4. The method of the use of embodiment 3, wherein the lean mass is lean muscle mass.
[1764] 5. The method or the use of any one of embodiments 1 to 4, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 0.5 mg/kg to about 10 mg/kg per body weight of the subject once daily.
[1765] 6. The method or the use of embodiment 5, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 1 mg/kg or 3 mg/kg per body weight of the subject once daily.
[1766] 7. The method or the use of any one of embodiments 1 to 4, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily. [1767] 8. The method or the use of any one of embodiments 1 to 4, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily.
[1768] 9. The method or the use of any one of embodiments 1 to 6, wherein the non-naturally occurring melanocortin analog is an antagonist of a melanocortin 4 receptor.
[1769] 10. The method or the use of embodiment 9, wherein the non-naturally occurring melanocortin analog is a full antagonist of the melanocortin 4 receptor.
[1770] 11. The method or the use of embodiment 9, wherein the non-naturally occurring melanocortin analog is a partial antagonist of the melanocortin 4 receptor.
[1771] 11. The method or the use of embodiment 9, wherein the non-naturally occurring melanocortin analog is a partial antagonist of the melanocortin 4 receptor.
[1772] 12. The method or the use of any one of embodiments 1 to 1 1 , wherein the non-naturally occurring melanocortin analog is an antagonist of a melanocortin 3 receptor.
[1773] 13. The method or the use of embodiment 12, wherein the non-naturally occurring melanocortin analog is a full antagonist of the melanocortin 3 receptor.
[1774] 14. The method or the use of embodiment 12, wherein the non-naturally occurring melanocortin analog is a partial antagonist of the melanocortin 3 receptor.
[1775] 15. The method or the use of any one of embodiments 1 to 1 1 , wherein the non-naturally occurring melanocortin analog is an agonist of the melanocortin 3 receptor.
[1776] 16. The method or the use of embodiment 15, wherein the non-naturally occurring melanocortin analog is a full agonist of the melanocortin 3 receptor.
[1777] 17. The method or the use of embodiment 15, wherein the non-naturally occurring melanocortin analog is a partial agonist of the melanocortin 3 receptor.
[1778] 18. The method or the use of embodiment 15, wherein the non-naturally occurring melanocortin analog has no melanocortin 3 receptor activity. [1779] 19. The method or the use of any one of embodiments 1 to 18, wherein the method or the use further comprises preventing or reducing one or more side effects associated with a metabolic disorder, relative to a control.
[1780] 20. A method of preventing or reducing cachexia in a subject in need thereof relative to a control, comprising administering to the subject:
[1781] a non-naturally occurring melanocortin analog comprising a sequence of Formula (I):
[1782] X1 -X2-X3- R1 - R2- R3- R4- R5- R6- R7- R8- R9-Y1 - Y2- Y3-Y4- Y5-Y6- Y7 ( I) ,
[1783] wherein:
[1784] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[1785] X2 is absent, phenylalanine (Phe), or Nle;
[1786] X3 is absent, Phe, or Nle;
[1787] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), frans-4-guanidinyl-proline (fransPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys);
[1788] R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s-CH=CH-CO, proline (Pro), and tryptophan (Trp);
[1789] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), fra/?sPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[ 1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino- 1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
[1790] R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
[1791] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fransPro(guan);
[1792] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
[1793] R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[1794] R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
[1795] R9 is absent or Lys;
[1796] Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro,
Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[1797] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[1798] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[1799] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp; [1800] Y5 is absent or dVal;
[1801] Y6 is absent or dVal;
[1802] Y7 is absent or dPro; and
[1803] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[1804] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[1805] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and
[1806] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[1807] provided that:
[1808] when R3 is dTrp or Phe, then R4 is not dNal(2’) and R6 is not dPhe;
[1809] when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii)
R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7;
[1810] when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2’) or Nal(2’);
[1811] when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent;
[1812] when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and
[1813] when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu. [1814] 21 . Use of a non-naturally occurring melanocortin analog for preventing or reducing cachexia in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I):
[1815] X1 -X2-X3- R1 - R2- R3- R4- R5- R6- R7- R8- R9-Y1 - Y2- Y3-Y4- Y5-Y6- Y7 ( I) ,
[1816] wherein:
[1817] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[1818] X2 is absent, phenylalanine (Phe), or Nle;
[1819] X3 is absent, Phe, or Nle;
[1820] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), trans-4-guanidinyl-proline (tra/?sPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys);
[1821] R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s-CH=CH-CO, proline (Pro), and tryptophan (Trp);
[1822] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, czsPro(guan), fra/?sPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[ 1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino- 1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
[1823] R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
[1824] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and tra/?sPro(guan);
[1825] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
[1826] R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[1827] R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
[1828] R9 is absent or Lys;
[1829] Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro,
Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[1830] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[1831] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[1832] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[1833] Y5 is absent or dVal;
[1834] Y6 is absent or dVal;
[1835] Y7 is absent or dPro; and [1836] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[1837] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[1838] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and
[1839] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[1840] provided that:
[1841] when R3 is dTrp or Phe, then R4 is not dNal(2’) and R6 is not dPhe;
[1842] when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7;
[1843] when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2’) or Nal(2’);
[1844] when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent;
[1845] when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and
[1846] when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
[1847] 22. A method of preventing or reducing anorexia in a subject in need thereof relative to a control, comprising administering to the subject: [1848] a non-naturally occurring melanocortin analog comprising a sequence of Formula (I):
[1849] X1 -X2-X3- R1 - R2- R3- R4- R5- R6- R7- R8- R9-Y1 - Y2- Y3-Y4- Y5-Y6- Y7 (I),
[1850] wherein:
[1851] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[1852] X2 is absent, phenylalanine (Phe), or Nle;
[1853] X3 is absent, Phe, or Nle;
[1854] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), frans-4-guanidinyl-proline (fransPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys);
[1855] R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s-CH=CH-CO, proline (Pro), and tryptophan (Trp);
[1856] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), transP ro (guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[ 1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino- 1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
[1857] R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
[1858] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and tra/?sPro(guan);
[1859] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
[1860] R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[1861] R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
[1862] R9 is absent or Lys;
[1863] Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro,
Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[1864] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[1865] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[1866] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[1867] Y5 is absent or dVal;
[1868] Y6 is absent or dVal;
[1869] Y7 is absent or dPro; and [1870] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[1871] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[1872] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and
[1873] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[1874] provided that:
[1875] when R3 is dTrp or Phe, then R4 is not dNal(2’) and R6 is not dPhe;
[1876] when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7;
[1877] when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2’) or Nal(2’);
[1878] when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent;
[1879] when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and
[1880] when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
[1881] 23. Use of a non-naturally occurring melanocortin analog for preventing or reducing anorexia in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I): [1882] X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4-Y5-Y6-Y7 (I),
[1883] wherein:
[1884] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[1885] X2 is absent, phenylalanine (Phe), or Nle;
[1886] X3 is absent, Phe, or Nle;
[1887] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), frans-4-guanidinyl-proline (fransPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys);
[1888] R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s-CH=CH-CO, proline (Pro), and tryptophan (Trp);
[1889] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), transP ro (guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[ 1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino- 1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip); [1890] R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
[1891] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fransPro(guan);
[1892] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
[1893] R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[1894] R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
[1895] R9 is absent or Lys;
[1896] Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro,
Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[1897] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[1898] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[1899] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[1900] Y5 is absent or dVal;
[1901] Y6 is absent or dVal;
[1902] Y7 is absent or dPro; and
[1903] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: [1904] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[1905] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and
[1906] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[1907] provided that:
[1908] when R3 is dTrp or Phe, then R4 is not dNal(2’) and R6 is not dPhe;
[1909] when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii)
R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7;
[1910] when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2’) or Nal(2’);
[1911] when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent;
[1912] when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and
[1913] when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
[1914] 24. A method of increasing, maintaining, or reducing a loss in a body mass index (BMI) level in a subject in need thereof relative to a control, comprising administering to the subject:
[1915] a non-naturally occurring melanocortin analog comprising a sequence of Formula (I): [1916] X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4-Y5-Y6-Y7 (I),
[1917] wherein:
[1918] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[1919] X2 is absent, phenylalanine (Phe), or Nle;
[1920] X3 is absent, Phe, or Nle;
[1921] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), frans-4-guanidinyl-proline (fransPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys);
[1922] R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s-CH=CH-CO, proline (Pro), and tryptophan (Trp);
[1923] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), transP ro (guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[ 1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino- 1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip); [1924] R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
[1925] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fransPro(guan);
[1926] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
[1927] R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[1928] R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
[1929] R9 is absent or Lys;
[1930] Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro,
Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[1931] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[1932] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[1933] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[1934] Y5 is absent or dVal;
[1935] Y6 is absent or dVal;
[1936] Y7 is absent or dPro; and
[1937] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: [1938] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[1939] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and
[1940] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[1941] provided that:
[1942] when R3 is dTrp or Phe, then R4 is not dNal(2’) and R6 is not dPhe;
[1943] when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7;
[1944] when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2’) or Nal(2’);
[1945] when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent;
[1946] when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and
[1947] when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
[1948] 25. Use of a non-naturally occurring melanocortin analog for increasing, maintaining, or reducing a loss in a BMI level in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I):
[1949] X1 -X2-X3- R1 - R2- R3- R4- R5- R6- R7- R8- R9-Y1 - Y2- Y3-Y4- Y5-Y6- Y7 ( I) ,
[1950] wherein: [1951] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[1952] X2 is absent, phenylalanine (Phe), or Nle;
[1953] X3 is absent, Phe, or Nle;
[1954] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), frans-4-guanidinyl-proline (fransPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys);
[1955] R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s-CH=CH-CO, proline (Pro), and tryptophan (Trp);
[1956] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), transP ro (guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[ 1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino- 1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
[1957] R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe); [1958] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fransPro(guan);
[1959] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
[1960] R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[1961] R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
[1962] R9 is absent or Lys;
[1963] Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro,
Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[1964] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[1965] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[1966] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[1967] Y5 is absent or dVal;
[1968] Y6 is absent or dVal;
[1969] Y7 is absent or dPro; and
[1970] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[1971] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; [1972] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and
[1973] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[1974] provided that:
[1975] when R3 is dTrp or Phe, then R4 is not dNal(2’) and R6 is not dPhe;
[1976] when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii)
R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7;
[1977] when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2’) or Nal(2’);
[1978] when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent;
[1979] when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and
[1980] when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
[1981] 26. The method or the use of any one of embodiments 1 -25, wherein the method or the use prevents fat mass gain after administration of the non-naturally occurring melanocortin analog, relative to a control.
[1982] 27. The method or the use of any one of embodiments 1 -26, wherein the method or the use reduces increases a fat mass level after administration of the non- naturally occurring melanocortin analog, relative to a control.
[1983] 28. The method or the use of any one of embodiments 1 -27, wherein the method or the use maintains or increases brain mass in the subject during or after administration of the non-naturally occurring melanocortin analog, relative to a control. [1984] 29. The method or the use of any one of embodiments 1 -27, wherein the method or the use prevents or reduces brain mass loss in the subject during or after administration of the non-naturally occurring melanocortin analog, relative to a control.
[1985] 30. The method or the use of any one of embodiments 1 -29, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I):
[1986] X1 -X2-X3- R1 - R2- R3- R4- R5- R6- R7- R8- R9-Y1 - Y2- Y3-Y4- Y5-Y6- Y7 ( I) ,
[1987] wherein:
[1988] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[1989] X2 is absent, phenylalanine (Phe), or Nle;
[1990] X3 is absent, Phe, or Nle;
[1991] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), trans-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys);
[1992] R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s-CH=CH-CO, proline (Pro), and tryptophan (Trp);
[1993] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), transP ro (guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[ 1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino- 1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
[1994] R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
[1995] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and transPro(guan);
[1996] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and T- naphthylalanine (Nal(1 ’));
[1997] R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[1998] R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
[1999] R9 is absent or Lys;
[2000] Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro,
Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[2001] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[2002] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[2003] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[2004] Y5 is absent or dVal; [2005] Y6 is absent or dVal;
[2006] Y7 is absent or dPro; and
[2007] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[2008] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[2009] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and
[2010] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[2011] provided that:
[2012] when R3 is dTrp or Phe, then R4 is not dNal(2’) and R6 is not dPhe;
[2013] when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii)
R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7;
[2014] when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2’) or Nal(2’);
[2015] when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent;
[2016] when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and
[2017] when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu. [2018] 31 . The method or the use of any one of embodiments 1 -29, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I), wherein:
[2019] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[2020] X2 is absent, phenylalanine (Phe), or Nle;
[2021] X3 is absent, Phe, or Nle;
[2022] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), tra/?s-4-guanidinyl-proline (f/'ansPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys)
[2023] R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s-CH=CH-CO, proline (Pro), and tryptophan (Trp);
[2024] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, czsPro(guan), tra/?sPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[ 1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino- 1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip); [2025] R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
[2026] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fransPro(guan);
[2027] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
[2028] R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[2029] R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
[2030] R9 is absent or Lys;
[2031] Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro,
Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[2032] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[2033] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[2034] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[2035] Y5 is absent or dVal;
[2036] Y6 is absent or dVal;
[2037] Y7 is absent or dPro; and
[2038] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: [2039] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[2040] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn;
[2041] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[2042] provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:
[2043] Ac-Nle-c[Asp-dTrp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 83);
[2044] Ac-Nle-c[Asp-Phe-Phe-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID
NO: 420);
[2045] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 223);
[2046] Ac-Nle-c[dCys-His-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 460);
[2047] Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 464);
[2048] Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 465);
[2049] Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 466);
[2050] Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 467);
[2051] Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 468);
[2052] Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
469);
[2053] Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 470);
[2054] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 474); [2055] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
475);
[2056] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 476);
[2057] Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
477);
[2058] Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 478);
[2059] Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 481 );
[2060] Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 482);
[2061] Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 483);
[2062] Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 484);
[2063] Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 485);
[2064] Ac-Nle-c[Cys-His-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 459);
[2065] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 472);
[2066] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
471 );
[2067] Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 463);
[2068] Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 462);
[2069] Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 479);
[2070] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO:
473);
[2071] Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 480);
[2072] Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 486);
[2073] Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 491 );
[2074] Ac-Nle-c[dCys-His-p(F)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 461 ); [2075] Ac-Nle-c[Asp-dGln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 492);
[2076] Ac-Nle-c[Asp-dTyr-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 496);
[2077] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 218);
[2078] Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
442);
[2079] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 449);
[2080] Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 455);
[2081] Ac-Nle-c[Asp-Pro-p(F)dP e-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 447);
[2082] Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 438);
[2083] Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
450);
[2084] Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 435);
[2085] Ac-dl_ys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 439);
[2086] Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 441 );
[2087] Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 436);
[2088] Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 454);
[2089] Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 452);
[2090] Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 451 );
[2091] Ac-dl_ys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 456);
[2092] Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 437);
[2093] Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 440);
[2094] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
448); [2095] Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 457);
[2096] Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 453);
[2097] Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 458);
[2098] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO:
446);
[2099] Ac-Nle-c[dCys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 433);
[2100] Ac-Nle-c[dCys-Pro-p(F)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 434);
[2101] Ac-Nle-c[Asp-dPhe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 488);
[2102] Ac-Nle-c[Asp-dBip-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 490);
[2103] Ac-Nle-c[Asp-dTrp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 494);
[2104] Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 443);
[2105] Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 268);
[2106] Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 363);
[2107] Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 365);
[2108] Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 370);
[2109] Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 378);
[2110] Ac-dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 379);
[2111] Ac-Nle-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 380);
[2112] Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 418);
[2113] Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 621 );
[2114] Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 666);
[2115] Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 297);
[2116] Ac-Nle-c[Asp-His-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
228); [2117] Ac-Nle-c[Asp-His-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 229);
[2118] Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 281 );
[2119] Ac-Nle-c[Asp-Leu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 355);
[2120] Ac-Nle-c[Asp-Tic-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 362);
[2121] Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 424);
[2122] Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 366);
[2123] Ac-Nle-c[Asp-Bip-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 368);
[2124] Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dLeu-dPro-NH2 (SEQ ID NO: 422);
[2125] Ac-Nle-c[Asp-Trp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 372);
[2126] Ac-Nle-c[Asp-Tyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 374);
[2127] Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
639);
[2128] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dPro-dPro-Lys-Asp-NH2 (SEQ ID
NO: 352);
[2129] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 351 );
[2130] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Trp-NH2 (SEQ ID NO: 600);
[2131] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 322);
[2132] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dAsn-NH2 (SEQ ID NO: 605);
[2133] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Gly-Gly-NH2 (SEQ ID NO: 610);
[2134] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Arg-NH2 (SEQ ID NO: 581 );
[2135] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dPro-dPro-dl_ys-dAsp-NH2 (SEQ ID
NO: 353);
[2136] Ac-Nle-c[dCys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 319);
[2137] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asn-dPro-NH2 (SEQ ID NO: 607); [2138] Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 638);
[2139] Ac-Nle-c[Asp-Pro-His-Phe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 295);
[2140] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 575);
[2141] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH2 (SEQ ID NO: 587);
[2142] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-NH2 (SEQ ID NO: 582);
[2143] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Arg-Pro-Val-NH2 (SEQ ID NO: 588);
[2144] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAsn-dPro-NH2 (SEQ ID NO: 612);
[2145] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-Pro-Val-NH2 (SEQ ID NO: 583);
[2146] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Ala-Ala-NH2 (SEQ ID NO: 609);
[2147] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 594);
[2148] Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 631 );
[2149] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Arg-Val-Pro-NH2 (SEQ ID NO: 589);
[2150] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO:
597);
[2151] Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 628);
[2152] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-l_ys]-dTle-dPro-NH2 (SEQ ID NO: 591 );
[2153] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 590);
[2154] Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 311 );
[2155] Ac-Nle-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
629);
[2156] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-Hyp-NH2 (SEQ ID NO: 574);
[2157] Ac-dPhe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 303);
[2158] Ac-Nle-c[Asp-Oic-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 360);
[2159] Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 313); [2160] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 291 );
[2161] Ac-dAla-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 299);
[2162] Phe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 305);
[2163] His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 306);
[2164] Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 312);
[2165] Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 314);
[2166] Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 315);
[2167] Ac-Nle-c[dCys-Pro-dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 321 );
[2168] Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 423);
[2169] Ac-Nle-Phe-Phe-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID
NO: 421 );
[2170] Ac-Nle-c[Cys-Trp-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 383);
[2171] Ac-Nle-c[dCys-Trp-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 384);
[2172] Ac-Lys-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 387);
[2173] Ac-Arg-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 389);
[2174] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
403);
[2175] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 407);
[2176] Ac-Nle-c[Asp-Trp-Leu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 395);
[2177] Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 633);
[2178] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Val-Pro-NH2 (SEQ ID NO: 573);
[2179] Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 643);
[2180] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Val-NH2 (SEQ ID NO: 576);
[2181] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Pro-NH2 (SEQ ID NO: 577); [2182] dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 309);
[2183] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 593);
[2184] Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH2 (SEQ ID NO: 632);
[2185] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asp-NH2 (SEQ ID NO: 603);
[2186] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 617);
[2187] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 620);
[2188] Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dPro-NH2 (SEQ ID NO: 634);
[2189] Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 635);
[2190] Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 644);
[2191] Ac-dTyr-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 304);
[2192] Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 642);
[2193] dPhe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 308);
[2194] Ac-Nle-c[Asp-Atc-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 212);
[2195] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 226);
[2196] Ac-Nle-c[dPen-Pro-dPhe-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 320);
[2197] Ac-Nle-c[Cys-dPhe-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 324);
[2198] Ac-Nle-c[Asp-Cpe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 358);
[2199] Ac-Nle-c[Asp-Che-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 359);
[2200] Ac-Nle-c[Asp-dPhe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 367);
[2201] Ac-Nle-c[Asp-dGln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 371 );
[2202] Ac-Nle-c[Asp-dTrp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 373);
[2203] Ac-Nle-c[Asp-dTyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 375);
[2204] Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 381 );
[2205] Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 382); [2206] Ac-Nle-c[dCys-Trp-Pro-dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 385);
[2207] Ac-Ala-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 386);
[2208] Ac-dLys-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 388);
[2209] Ac-dArg-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 390);
[2210] Ac-dHis-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 391 );
[2211] Ac-His-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 392);
[2212] Ac-Nle-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
393);
[2213] Ac-Nle-c[Asp-Trp-Ala-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 394);
[2214] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO:
405);
[2215] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dl_ys-dVal-dPro-NH2 (SEQ ID NO:
406);
[2216] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dl_ys-dPro-NH2 (SEQ ID NO: 408);
[2217] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 409);
[2218] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 410);
[2219] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 411 );
[2220] Ac-Nle-c[Asp-Phe-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 412);
[2221] Ac-Nle-c[Asp-His-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 413);
[2222] Ac-Nle-c[Asp-Tyr-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 414);
[2223] Ac-Nle-c[Asp-dPhe-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 415);
[2224] Ac-Nle-c[Asp-dHis-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 416);
[2225] Ac-Nle-c[Asp-dTyr-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 417);
[2226] Ac-Nle-c[Asp-Hyp-dPhe-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 419); [2227] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 596);
[2228] Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-dPro-dVal-NH2 (SEQ ID NO: 622);
[2229] Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 645);
[2230] Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 646);
[2231] Ac-dLeu-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 298);
[2232] Ac-Nle-c[Asp-Ala-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 354);
[2233] Ac-Nle-c[Asp-Hyp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 364);
[2234] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-Arg-NH2 (SEQ ID NO: 578);
[2235] Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 300);
[2236] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dArg-NH2 (SEQ ID NO: 579);
[2237] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 580);
[2238] Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 640);
[2239] Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 641 );
[2240] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dPro-NH2 (SEQ ID NO: 584);
[2241] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-Val-Pro-NH2 (SEQ ID NO: 585);
[2242] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-dVal-dPro-NH2 (SEQ ID NO: 586);
[2243] Ac-dNle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 301 );
[2244] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 595);
[2245] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-d al-dPro-NH2 (SEQ ID NO:
598);
[2246] Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 302);
[2247] Ac-Nle-Nle-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
630);
[2248] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-dPro-dVal-NH2 (SEQ ID NO: 601 ); [2249] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAla-dAla-NH2 (SEQ ID NO: 602);
[2250] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dHyp-NH2 (SEQ ID NO: 604);
[2251] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-Asp-NH2 (SEQ ID NO: 606);
[2252] Ac-Nle-c[Cys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 318);
[2253] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Hyp-NH2 (SEQ ID NO: 608);
[2254] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asp-dPro-NH2 (SEQ ID NO: 61 1 );
[2255] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asn-NH2 (SEQ ID NO: 613);
[2256] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAsp-NH2 (SEQ ID NO: 614);
[2257] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAsn-NH2 (SEQ ID NO: 615);
[2258] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-dPro-NH2 (SEQ ID NO: 616);
[2259] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dVal-dVal-dVal-dPro-
NH2 (SEQ ID NO: 599);
[2260] Ac-Nle-c[Asp-Pro-His-Phe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 296);
[2261] Ac-Nle-c[Asp-Aba-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 198);
[2262] Ac-Nle-c[Asp-Aia-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 207);
[2263] Ac-Nle-c[Asp-Ata-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 208);
[2264] Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 225);
[2265] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 592);
[2266] Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 425);
[2267] Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(1 ’)-Lys]-dVal-dPro-NH2 (SEQ ID NO: 427);
[2268] Ac-Nle-c[Asp-Pro-dPhe-Arg-Phe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 429);
[2269] Ac-Nle-c[Pen-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 325);
[2270] Ac-Nle-c[dPen-dPhe-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 326);
[2271] Ac-Nle-c[Asp-dlle-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 356); [2272] Ac-Nle-c[Asp-dVal-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 357);
[2273] Ac-Arg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 376);
[2274] Ac-dArg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-d al-dPro-NH2 (SEQ ID NO: 377);
[2275] Ac-Nle-c[Asp-Trp-dLeu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 396);
[2276] Ac-Nle-c[Asp-Trp-dVal-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 397);
[2277] Ac-Nle-c[Asp-Trp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 398);
[2278] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-dNal(1')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
400);
[2279] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Phe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 401 );
[2280] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-dPhe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 402);
[2281] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Nal(1 ')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 399);
[2282] Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 404);
[2283] Ac-Nle-c[Asp-Pro-dPhe-Arg-dTrp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 187);
[2284] Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
231 );
[2285] Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
232);
[2286] Ac-Nle-c[Asp-Pro-dPhe-Arg-Aia-Lys]-dVal-dPro-NH2 (SEQ ID NO: 233);
[2287] Ac-Nle-c[Asp-Pro-dPhe-Arg-Aba-Lys]-dVal-dPro-NH2 (SEQ ID NO: 234);
[2288] Ac-Nle-c[Asp-Pro-dPhe-Arg-Ata-Lys]-dVal-dPro-NH2 (SEQ ID NO: 235);
[2289] Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(1 ’)-Lys]-dVal-dPro-NH2 (SEQ ID NO: 428);
[2290] Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 520);
[2291] Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 522);
[2292] Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 523);
[2293] Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 518); [2294] Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 503);
[2295] Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 505);
[2296] Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 502);
[2297] Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 519);
[2298] Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 506);
[2299] Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 501 );
[2300] Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 521 );
[2301] Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 504);
[2302] Ac-Nle-c[Asp-dBip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 528);
[2303] Ac-Nle-c[Asp-dGln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 530);
[2304] Ac-Nle-c[Asp-dTrp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 532);
[2305] Ac-Nle-c[Asp-Aba-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 209);
[2306] Ac-Nle-c[Asp-Aia-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 210);
[2307] Ac-Nle-c[Asp-Ata-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 211 );
[2308] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 512);
[2309] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
513);
[2310] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO:
511 );
[2311] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
515);
[2312] Ac-Nle-c[dPen-Ala-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 338);
[2313] Ac-Nle-c[dPen-Leu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 339);
[2314] Ac-Nle-c[dPen-dl_eu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 340); [2315] Ac-Nle-c[dPen-dVal-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 341 );
[2316] Ac-Nle-c[dPen-Gly-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 342);
[2317] Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 536);
[2318] Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 498);
[2319] Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO:
499);
[2320] Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO:
537);
[2321] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 44);
[2322] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 45);
[2323] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 46);
[2324] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 47);
[2325] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 56);
[2326] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 57);
[2327] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 58);
[2328] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 60);
[2329] Ac-Nle-c[dPen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 61 );
[2330] Ac-Nle-c[dPen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 62);
[2331] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 63);
[2332] Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 8); and
[2333] Ac-Nle-c[Asp-Pro-Glu-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO:
258). [2334] 32. The method or the use of any one of embodiments 1 -30, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IA):
[2335] X1 -X2-X3- R1 - R2- R3- R4- R5- R6- R7- R8- Y1 - Y2- Y3- Y4- Y5-Y6- Y7 ( I A) ,
[2336] wherein:
[2337] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[2338] X2 is absent, phenylalanine (Phe), or Nle;
[2339] X3 is absent, Phe, or Nle;
[2340] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), trans-4-guanidinyl-proline (fra/?sPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys)
[2341] R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s-CH=CH-CO, proline (Pro), and tryptophan (Trp);
[2342] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, Tyr, dTyr, c/sPro(guan), f/'ansPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2 ,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
[2343] R4 is selected from the group consisting of 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);
[2344] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and tra/?sPro(guan);
[2345] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
[2346] R7 is absent or is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[2347] R8 is Lys or d Pen;
[2348] Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[2349] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[2350] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[2351] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[2352] Y5 is absent or dVal;
[2353] Y6 is absent or dVal;
[2354] Y7 is absent or dPro; and [2355] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[2356] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[2357] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn;
[2358] a lactam bridge between R1 and R7 or R8 when R1 is Asp and R7 or R8 is Lys;
[2359] provided that:
[2360] when R4 is p(Br)dPhe, then R1 is Nle or Ala, Y4-Y7 are absent, and at least one of X1 and Y3 is absent;
[2361] when R4 is p(CI)dPhe, then (i) R3 is selected from Phe, dPhe, Bip, Trp, Tyr, dTyr, and Pro or (ii) R3 is His and R6 is not Trp;
[2362] when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and
[2363] when R7 is Pro or Gly, then (i) R3 is not His or (ii) R2 is not Pro.
[2364] 33. The method or the use of any one of embodiments 1 -29 and 31 , wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IA), wherein:
[2365] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[2366] X2 is absent, phenylalanine (Phe), or Nle;
[2367] X3 is absent, Phe, or Nle;
[2368] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), tra/?s-4-guanidinyl-proline (f/'ansPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys)
[2369] R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s-CH=CH-CO, proline (Pro), and tryptophan (Trp);
[2370] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, Tyr, dTyr, c/sPro(guan), f/'ansPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
[2371] R4 is selected from the group consisting of 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);
[2372] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fransPro(guan);
[2373] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’)); [2374] R7 is absent or is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[2375] R8 is Lys or dPen;
[2376] Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[2377] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[2378] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[2379] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[2380] Y5 is absent or dVal;
[2381] Y6 is absent or dVal;
[2382] Y7 is absent or dPro; and
[2383] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[2384] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[2385] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn;
[2386] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[2387] provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: [2388] Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 539);
[2389] Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 540);
[2390] Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 541 );
[2391] Ac-dl_ys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 542);
[2392] Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 543);
[2393] Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 544);
[2394] Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 556);
[2395] Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 557);
[2396] Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 558);
[2397] Ac-dl_ys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 559);
[2398] Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 560);
[2399] Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 561 );
[2400] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 550);
[2401] Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 554);
[2402] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 220);
[2403] Ac-Nle-c[Cys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 497);
[2404] Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 500);
[2405] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
507);
[2406] Ac-Nle-c[Asp-His-p(CI)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 508);
[2407] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 514);
[2408] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 516); [2409] Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 517);
[2410] Ac-Nle-c[Asp-dHis-p(CI)dPhe-Arg-Trp-Lys]-d\Zal-dPro-NH2 (SEQ ID NO: 524);
[2411] Ac-Nle-c[Asp-Gln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 529);
[2412] Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 520);
[2413] Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 522);
[2414] Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 523);
[2415] Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 518);
[2416] Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 503);
[2417] Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 505);
[2418] Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 502);
[2419] Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 519);
[2420] Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 506);
[2421] Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 501 );
[2422] Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 521 );
[2423] Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 504);
[2424] Ac-Nle-c[Asp-dBip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 528);
[2425] Ac-Nle-c[Asp-dGln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 530);
[2426] Ac-Nle-c[Asp-Aba-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 209);
[2427] Ac-Nle-c[Asp-Aia-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 210);
[2428] Ac-Nle-c[Asp-Ata-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 211 );
[2429] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 512);
[2430] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
513); [2431] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO:
511 );
[2432] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
515);
[2433] Ac-Nle-c[dPen-Ala-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 338);
[2434] Ac-Nle-c[dPen-Leu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 339);
[2435] Ac-Nle-c[dPen-dLeu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 340);
[2436] Ac-Nle-c[dPen-dVal-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 341 );
[2437] Ac-Nle-c[dPen-Gly-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 342);
[2438] Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 536);
[2439] Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 498);
[2440] Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO:
499);
[2441] Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO:
537);
[2442] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 44);
[2443] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 45);
[2444] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 46);
[2445] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 47);
[2446] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 56);
[2447] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 57);
[2448] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 58);
[2449] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 60);
[2450] Ac-Nle-c[dPen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 61 );
[2451] Ac-Nle-c[dPen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 62); [2452] Ac-Nle-c[Pen-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 63);
[2453] Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 8); and
[2454] Ac-Nle-c[Asp-Pro-Glu-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO:
258).
[2455] 34. The method or the use of any one of embodiments 1 -30 and 32, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IA), wherein:
[2456] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[2457] X2 is absent or Nle;
[2458] X3 is absent or Nle;
[2459] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), and glutamic acid (Glu);
[2460] R2 is selected from the group consisting of dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s- CH=CH-CO, and tryptophan (Trp);
[2461] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, Tyr, dTyr, 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), and D-biphenylalanine (dBip); [2462] R4 is selected from the group consisting of 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);
[2463] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, and ornithine (Orn);
[2464] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
[2465] R7 is selected from the group consisting of Gly, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[2466] R8 is Lys or dPen;
[2467] Y1 is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[2468] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[2469] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[2470] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[2471] Y5 is absent or dVal;
[2472] Y6 is absent or dVal;
[2473] Y7 is absent or dPro; and
[2474] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: [2475] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[2476] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn;
[2477] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[2478] provided that:
[2479] when R4 is p(Br)dPhe, then R1 is Nle or Ala, R5 is Arg, Y4-Y7 are absent, and at least one of X1 and Y3 is absent;
[2480] when R4 is p(CI)dPhe, then R3 is selected from Phe, dPhe, Bip, Trp, Tyr, dTyr, and Pro; and
[2481] when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro and R1 is not dArg, Arg, dTyr, or Ala, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys.
[2482] 35. The method or the use of any one of embodiments 1 -29 and 33, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IA), wherein:
[2483] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[2484] X2 is absent or Nle;
[2485] X3 is absent or Nle;
[2486] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), and glutamic acid (Glu);
[2487] R2 is selected from the group consisting of dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s- CH=CH-CO, and tryptophan (Trp);
[2488] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, Tyr, dTyr, 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), and D-biphenylalanine (dBip);
[2489] R4 is selected from the group consisting of 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);
[2490] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, and ornithine (Orn);
[2491] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
[2492] R7 is selected from the group consisting of Gly, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[2493] R8 is Lys or d Pen;
[2494] Y1 is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp; [2495] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[2496] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[2497] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[2498] Y5 is absent or dVal;
[2499] Y6 is absent or dVal;
[2500] Y7 is absent or dPro; and
[2501] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[2502] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[2503] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn;
[2504] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[2505] provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:
[2506] Ac-Nle-c[Asp-His-p(Br)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 546);
[2507] Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 539);
[2508] Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 540);
[2509] Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 556);
[2510] Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 557); [2511] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 550);
[2512] Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 554);
[2513] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
509);
[2514] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
510);
[2515] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 220);
[2516] Ac-Nle-c[Cys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 497);
[2517] Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 500);
[2518] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
507);
[2519] Ac-Nle-c[Asp-His-p(CI)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 508);
[2520] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 514);
[2521] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 516);
[2522] Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 517);
[2523] Ac-Nle-c[Asp-dHis-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 524);
[2524] Ac-Nle-c[Asp-Gln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 529);
[2525] Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 518);
[2526] Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 502);
[2527] Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 519);
[2528] Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 501 );
[2529] Ac-Nle-c[Asp-dBip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 528); [2530] Ac-Nle-c[Asp-dGln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 530);
[2531] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 512);
[2532] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
513);
[2533] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO:
511 );
[2534] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
515);
[2535] Ac-dArg-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 329);
[2536] Ac-Arg-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 330);
[2537] Ac-dTyr-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 332);
[2538] Ac-Ala-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 333);
[2539] Ac-Nle-c[dPen-Ala-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 338);
[2540] Ac-Nle-c[dPen-Leu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 339);
[2541] Ac-Nle-c[dPen-dLeu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 340);
[2542] Ac-Nle-c[dPen-dVal-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 341 );
[2543] Ac-Nle-c[dPen-Gly-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 342);
[2544] Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 536);
[2545] Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 498);
[2546] Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO:
499);
[2547] Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO:
537);
[2548] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 44); [2549] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 45);
[2550] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 46);
[2551] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 47);
[2552] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 56);
[2553] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 57);
[2554] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 58);
[2555] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 60);
[2556] Ac-Nle-c[dPen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 61 );
[2557] Ac-Nle-c[dPen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 62); and
[2558] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 63).
[2559] 36. The method or the use of any one of embodiments 1 -30, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IB):
[2560] X1 -X2-X3- R1 - R2- R3-d Nal (2’)- R5- R6- R7- R8-Y1 - Y2- Y3-Y4- Y5-Y6- Y7 (IB),
[2561] wherein:
[2562] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[2563] X2 is absent, phenylalanine (Phe), or Nle;
[2564] X3 is absent, Phe, or Nle;
[2565] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), frans-4-guanidinyl-proline (fransPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys)
[2566] R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s-CH=CH-CO, proline (Pro), and tryptophan (Trp);
[2567] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, c/sPro(guan), transPro(guan), 4-amino- 1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 - aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5- a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), and 1 -amino-1 -cyclopentane carboxylic (Cpe);
[2568] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fransPro(guan);
[2569] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’-naphthylalanine (Nal(T));
[2570] R7 is absent or is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[2571] R8 is absent or is Lys or dPen;
[2572] Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[2573] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[2574] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys; [2575] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[2576] Y5 is absent or dVal;
[2577] Y6 is absent or dVal;
[2578] Y7 is absent or dPro; and
[2579] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[2580] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[2581] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn;
[2582] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[2583] provided that:
[2584] when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is not Ala, Leu, dLeu, dVal, or Gly, and if R3 is absent, then R2 is Pen and R7 is dCys; and
[2585] when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
[2586] 37. The method or the use of any one of embodiments 1 -29 and 31 , wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IB), wherein:
[2587] X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
[2588] X2 is absent, phenylalanine (Phe), or Nle;
[2589] X3 is absent, Phe, or Nle; [2590] R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D- norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D-valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), frans-4-guanidinyl-proline (fransPro(guan)), cysteine (Cys), D-cysteine (dCys), D-phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D-glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys)
[2591] R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s-CH=CH-CO, proline (Pro), and tryptophan (Trp);
[2592] R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, c/sPro(guan), transPro(guan), 4-amino- 1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 - aminocyclo-propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5- a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), and 1 -amino-1 -cyclopentane carboxylic (Cpe);
[2593] R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and transP ro (guan);
[2594] R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’-naphthylalanine (Nal(T));
[2595] R7 is absent or is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
[2596] R8 is absent or is Lys or dPen; [2597] Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D-hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
[2598] Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
[2599] Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
[2600] Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
[2601] Y5 is absent or dVal;
[2602] Y6 is absent or dVal;
[2603] Y7 is absent or dPro; and
[2604] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[2605] a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or
R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen;
[2606] a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and
[2607] a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys;
[2608] provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:
[2609] Ac-Nle-c[dPen-Ala-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 338);
[2610] Ac-Nle-c[dPen-Leu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 339);
[2611] Ac-Nle-c[dPen-dLeu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 340); [2612] Ac-Nle-c[dPen-dVal-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 341 );
[2613] Ac-Nle-c[dPen-Gly-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 342);
[2614] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 44);
[2615] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 45);
[2616] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 46);
[2617] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 47);
[2618] Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 56);
[2619] Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 57);
[2620] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 58);
[2621] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 60);
[2622] Ac-Nle-c[dPen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 61 );
[2623] Ac-Nle-c[dPen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 62);
[2624] Ac-Nle-c[Pen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 63);
[2625] Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 8); and
[2626] Ac-Nle-c[Asp-Pro-Glu-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO:
258).
[2627] 38. The method or the use of any one of embodiments 1 -30, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IC):
[2628] X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4 (IC),
[2629] wherein:
[2630] X1 is absent or norleucine (Nle)
[2631] R1 is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys); [2632] R2 is aspartic acid (Asp) or cysteine (Cys);
[2633] R3 is His or proline (Pro);
[2634] R4 is selected from the group consisting of para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);
[2635] R5 is Arg or His;
[2636] R6 is selected from the group consisting of tryptophan (Trp), 4-amino-1 ,2,4,5- tetrahydro-2-benzazepin-3-one (Aba), 3- 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5- a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), 2’-D-naphthylalanine dNal(2’), and 2’-naphthylalanine (Nal(2’));
[2637] R7 is Lys or Cys;
[2638] Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle);
[2639] Y2 is selected from the group consisting of dVal, dPro, and dTle;
[2640] Y3 is absent or is dVal or dPro;
[2641] Y4 is absent or dPro; and
[2642] the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of:
[2643] a disulfide bond between Cys at R2 and Cys R7; and
[2644] a lactam bridge between Asp at R2 and Lys at R7;
[2645] provided that:
[2646] when R4 is p(CI)dPhe, then R1 is Nle or Ala, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent.
[2647] 39. The method or the use of any one of embodiments 1 -29 and 31 , wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IC), wherein: [2648] X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4 (IC),
[2649] wherein:
[2650] X1 is absent or norleucine (Nle)
[2651] R1 is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys);
[2652] R2 is aspartic acid (Asp) or cysteine (Cys);
[2653] R3 is His or proline (Pro);
[2654] R4 is selected from the group consisting of para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe);
[2655] R5 is Arg or His;
[2656] R6 is selected from the group consisting of tryptophan (Trp), 4-amino-1 ,2,4,5- tetrahydro-2-benzazepin-3-one (Aba), 3- 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5- a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), 2’-D-naphthylalanine dNal(2’), and 2’-naphthylalanine (Nal(2’));
[2657] R7 is Lys or Cys;
[2658] Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle);
[2659] Y2 is selected from the group consisting of dVal, dPro, and dTle;
[2660] Y3 is absent or is dVal or dPro;
[2661] Y4 is absent or dPro; and
[2662] the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of:
[2663] a disulfide bond between Cys at R2 and Cys R7; and
[2664] a lactam bridge between Asp at R2 and Lys at R7; [2665] provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:
[2666] Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 520);
[2667] Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 522);
[2668] Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 523);
[2669] Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 518);
[2670] Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 503);
[2671] Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 505);
[2672] Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 502);
[2673] Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 519);
[2674] Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 506);
[2675] Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 501 );
[2676] Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 521 );
[2677] Ac-dl_ys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 504);
[2678] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 512);
[2679] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
513);
[2680] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO:
511 ); and
[2681] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
515).
[2682] 40. The method or the use of any one of embodiments 1 -30, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (ID):
[2683] X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4 (ID), [2684] wherein:
[2685] X1 is absent or norleucine (Nle);
[2686] R1 is absent or is selected from the group consisting of Nle, arginine (Arg), D- arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys)
[2687] R2 is aspartic acid (Asp) or cysteine (Cys);
[2688] R3 is selected from the group consisting of His, D-histidine (dHis), proline (Pro), phenylalanine (Phe), tryptophan (Trp), tyrosine (Tyr), glutamine (Gin), and biphenylalanine (Bip);
[2689] R4 is selected from the group consisting of dPhe, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
[2690] R5 is selected from the group consisting of Arg, Lys, and His;
[2691] R6 is selected from the group consisting of Trp, 2’-D-naphthylalanine (dNal(2’)), and 2’-naphthylalanine (Nal(2’));
[2692] R7 is Lys or Cys;
[2693] Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle);
[2694] Y2 is dVal or dPro;
[2695] Y3 is absent, dVal, or dPro;
[2696] Y4 is absent or dPro; and
[2697] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[2698] a disulfide bond between Cys at R2 and Cys at R7; and
[2699] a lactam bridge between Asp at R2 and Lys at R7;
[2700] provided that: [2701] when R4 is p(Br)dPhe and R1 is Nle or Ala, then the C-terminus is not dVal-dPro or dTle-dPro and if the C-terminus is dPro-dVal-dPro, then X1 is present.
[2702] when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7;
[2703] when R4 is dPhe, then R3 is Pro and either R5 is Lys or R6 is dNal(2’) or Nal(2’); and
[2704] when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, and Gin, R6 is Trp, and either X1 and Y3 are both present or X1 and Y3 are both absent.
[2705] 41 . The method or the use of any one of embodiments 1 -29 and 31 , wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (ID), wherein:
[2706] R1 is absent or is selected from the group consisting of Nle, arginine (Arg), D- arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys)
[2707] R2 is aspartic acid (Asp) or cysteine (Cys);
[2708] R3 is selected from the group consisting of His, D-histidine (dHis), proline (Pro), phenylalanine (Phe), tryptophan (Trp), tyrosine (Tyr), glutamine (Gin), and biphenylalanine (Bip);
[2709] R4 is selected from the group consisting of dPhe, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
[2710] R5 is selected from the group consisting of Arg, Lys, and His;
[2711] R6 is selected from the group consisting of Trp, 2’-D-naphthylalanine (dNal(2’)), and 2’-naphthylalanine (Nal(2’));
[2712] R7 is Lys or Cys;
[2713] Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle); [2714] Y2 is dVal or dPro;
[2715] Y3 is absent, dVal, or dPro;
[2716] Y4 is absent or dPro; and
[2717] the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
[2718] a disulfide bond between Cys at R2 and Cys at R7; and
[2719] a lactam bridge between Asp at R2 and Lys at R7;
[2720] provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:
[2721] Ac-Nle-c[Asp-Pro-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 217);
[2722] Ac-Nle-c[Asp-dHis-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 562);
[2723] Ac-Nle-c[Asp-Phe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 563);
[2724] Ac-Nle-c[Asp-Bip-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 565);
[2725] Ac-Nle-c[Asp-Gln-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 567);
[2726] Ac-Nle-c[Asp-Trp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 569);
[2727] Ac-Nle-c[Asp-Tyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 571 );
[2728] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 222);
[2729] Ac-Nle-c[Cys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 535);
[2730] Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 538);
[2731] Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
545);
[2732] Ac-Nle-c[Asp-His-p(Br)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 546);
[2733] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
547); [2734] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 548);
[2735] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 552);
[2736] Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
553);
[2737] Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 555);
[2738] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
551 );
[2739] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 223);
[2740] Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 464);
[2741] Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 465);
[2742] Ac-dl_ys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 466);
[2743] Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 467);
[2744] Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 468);
[2745] Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
469);
[2746] Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 470);
[2747] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 474);
[2748] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
475);
[2749] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 476);
[2750] Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
477);
[2751] Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 478); [2752] Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 481 );
[2753] Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 482);
[2754] Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 483);
[2755] Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 484);
[2756] Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 485);
[2757] Ac-Nle-c[Cys-His-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 459);
[2758] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 472);
[2759] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
471 );
[2760] Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 463);
[2761] Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 462);
[2762] Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 479);
[2763] Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO:
473);
[2764] Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 480);
[2765] Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 486);
[2766] Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 491 );
[2767] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 218);
[2768] Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
442);
[2769] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 449);
[2770] Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 455);
[2771] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 447);
[2772] Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 438); [2773] Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
450);
[2774] Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 435);
[2775] Ac-dl_ys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 439);
[2776] Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 441 );
[2777] Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 436);
[2778] Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 454);
[2779] Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 452);
[2780] Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 451 );
[2781] Ac-dl_ys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 456);
[2782] Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 437);
[2783] Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 440);
[2784] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
448);
[2785] Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 457);
[2786] Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 453);
[2787] Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 458);
[2788] Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 443);
[2789] Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 363);
[2790] Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 365);
[2791] Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 370);
[2792] Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 621 );
[2793] Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 297);
[2794] Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 366); [2795] Ac-Nle-c[Asp-Bip-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 368);
[2796] Ac-Nle-c[Asp-Trp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 372);
[2797] Ac-Nle-c[Asp-Tyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 374);
[2798] Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
639);
[2799] Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 638);
[2800] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 295);
[2801] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO:
597);
[2802] Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 628);
[2803] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 591 );
[2804] Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 311 );
[2805] Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 313);
[2806] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 291 );
[2807] Ac-dAla-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 299);
[2808] His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 306);
[2809] Ac-dl_ys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 312);
[2810] Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 314);
[2811] Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 315);
[2812] Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 643);
[2813] dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 309);
[2814] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 617);
[2815] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 620);
[2816] Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 644); [2817] Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 642);
[2818] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 596);
[2819] Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 645);
[2820] Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 646);
[2821] Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 300);
[2822] Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 640);
[2823] Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 641 );
[2824] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 595);
[2825] Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO:
598);
[2826] Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 302);
[2827] Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 425);
[2828] Ac-Nle-c[Cys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 318);
[2829] Ac-Nle-c[Asp-Pro-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 215);
[2830] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
509);
[2831] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
510);
[2832] Ac-Nle-c[Asp-Phe-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 525);
[2833] Ac-Nle-c[Asp-Bip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 527);
[2834] Ac-Nle-c[Asp-Trp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 531 );
[2835] Ac-Nle-c[Asp-Tyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 533);
[2836] Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 520);
[2837] Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 522);
[2838] Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 523); [2839] Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 518);
[2840] Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 503);
[2841] Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 505);
[2842] Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 502);
[2843] Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 519);
[2844] Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 506);
[2845] Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 501 );
[2846] Ac-dl_ys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 521 );
[2847] Ac-dl_ys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 504);
[2848] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 512);
[2849] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
513); and
[2850] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
515).
[2851] 42. The method or the use of any one of embodiments 1 -41 , wherein an N- terminus of the non-naturally occurring melanocortin analog, if present, is modified by an acyl group.
[2852] 43. The method or the use of embodiment 42, wherein the acyl group is an acetyl group.
[2853] 44. The method or the use of any one of embodiments 1 -41 , wherein an N- terminus of the non-naturally occurring melanocortin analog, if present, is not modified.
[2854] 45. The method or the use of any one of embodiments 1 -44, wherein a C- terminus of the non-naturally occurring melanocortin analog is modified by an amide group.
[2855] 46. The method or the use of any one of embodiments 1 -44, wherein a C- terminus of the non-naturally occurring melanocortin analog is not modified. [2856] 47. The method or the use of any one of embodiments 1-46, wherein R4 is dNal(2’).
[2857] 48. The method or the use of any one of embodiments 1 -47, wherein the non-naturally occurring melanocortin analog comprises a sequence cyclized.
[2858] 49. The method or the use of any one of embodiments 1 -48, wherein R3 is
Pro, Hyp, or His.
[2859] 50. The method or the use of any one of embodiments 1 -49, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[2860] Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro (SEQ ID NO: 2);
[2861] Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 3);
[2862] Ac-Nle-c[Asp-Hyp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 4);
[2863] Ac-Nle-c[Asp-Pro-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 5);
[2864] Ac-Nle-c[Asp-Phe-His-dNal(2')-Arg-Trp-Lys]-dLeu-dPro-NH2 (SEQ ID NO: 6);
[2865] Ac-Nle-c[Asp-Phe-His-dNal(2')-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 7);
[2866] Ac-Nle-c[Asp-Hyp-dNal(2’)-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 9); and
[2867] Ac-Nle-c[Asp-Pro-His-dNal(2’)-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 10),
[2868] wherein c represents cyclization through R1 or R2 and R7 via a lactam bond.
[2869] 51 . The method or the use of any one of embodiments 1-48, wherein R9 is present.
[2870] 52. The method or the use of any one of embodiments 1 -48 and 51 , wherein the sequence of any one of Formulae (l)-(ID) is: Ac-Nle-c[Asp-Phe-Phe-Pro-His-dNal(2')- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 1 1 ), wherein c represents cyclization through R1 and R9via a lactam bond.
[2871] 53. The method or the use of any one of embodiments 1 -48, wherein R9 is absent and X1-X3 are present. [2872] 54. The method or the use of any one of embodiments 1 -48 and 53, wherein the sequence of any one of Formulae (l)-(ID) is: Ac-Nle-Phe-Phe-c[Asp-Phe-His-dNal(2')- Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 12), wherein c represents cyclization through R1 and R8via a lactam bond.
[2873] 55. The method or the use of any one of embodiments 1 -48, wherein the non-naturally occurring melanocortin analog comprises a sequence cyclized between R2 and R7 via a lactam bond or a disulfide bond.
[2874] 56. The method or the use of any one of embodiments 1 -48 and 55, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[2875] Ac-Nle-c[dAsp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 38);
[2876] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-dLys]-dVal-dPro-NH2 (SEQ ID NO: 39);
[2877] Ac-Nle-c[Cys-Pro-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 40);
[2878] Ac-Nle-c[dCys-Pro-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 41 );
[2879] Ac-Nle-c[Cys-Pro-dNal(2’)-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 42);
[2880] Ac-Nle-c[dCys-Pro-dNal(2’)-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 43);
[2881] Ac-Nle-c[Cys-Pro-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 48);
[2882] Ac-Nle-c[dCys-Pro-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 49);
[2883] Ac-Nle-c[Pen-Pro-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 50);
[2884] Ac-Nle-c[Pen-Pro-dNal(2’)-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 51 );
[2885] Ac-Nle-c[Pen-Pro-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 52);
[2886] Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 53);
[2887] Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 54);
[2888] Ac-Nle-c[Pen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 55);
[2889] Ac-Nle-c[Pen-dNal(2’)-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 59);
[2890] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 64); [2891] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-dOrn]-dVal-dPro-NH2 (SEQ ID NO: 65);
[2892] Ac-Nle-c[Glu-Pro-dNal(2’)-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 66);
[2893] Ac-Nle-c[Glu-Pro-dNal(2’)-Arg-Trp-dOrn]-dVal-dPro-NH2 (SEQ ID NO: 67); and
[2894] c[CO-cis-CH = CH-CO-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 197),
[2895] wherein c represents cyclization through R1 or R2 and R7 via a lactam bond or a disulfide bond.
[2896] 57. The method or the use of any one of embodiments 1 -48, wherein the non-naturally occurring melanocortin analog comprises a sequence cyclized through a lactam bond between Asp at R1 or R2 and Lys at R7.
[2897] 58. The method or the use of any one of embodiments 1 -48 and 57, wherein
R1 is selected from the group consisting of dArg, dMet, d He, dLeu, dVal, dAla, Ala, Tie, dTle, dNIe, Nva, Gly, dPro, dCys, dPhe, dGIn, dAsn, fransPro(guan), c/sPro(guan), dTyr, Tyr, and Dmt.
[2898] 59. The method or the use of any one of embodiments 1 -48, 57, and 58, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[2899] Ac-dArg-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 15);
[2900] Ac-dMet-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 16);
[2901] Ac-dlle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 17);
[2902] Ac-dl_eu-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 18);
[2903] Ac-dVal-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 19);
[2904] Ac-dAla-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 20);
[2905] Ac-Ala-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 21 );
[2906] Ac-Tle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 22);
[2907] Ac-dTle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 23); [2908] Ac-dNle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 24);
[2909] Ac-Nva-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 25);
[2910] Ac-Gly-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 26);
[2911] Ac-dPro-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 27);
[2912] Ac-dCys-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 28);
[2913] Ac-dPhe-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 29);
[2914] Ac-dTyr-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 30);
[2915] Ac-dGln-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 31 );
[2916] Ac-dAsn-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 32);
[2917] Ac-fransPro(guan)-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID
NO: 33);
[2918] Ac-c/sPro(guan)-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
34);
[2919] dTyr-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 35);
[2920] Tyr-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 36); and
[2921] Dmt-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 37),
[2922] wherein c represents cyclization through R2 and R7 via a lactam bond.
[2923] 60. The method or the use of any one of embodiments 1 -48 and 57, wherein
R3 is absent or selected from the group consisting of Ala, dAla, dMet, Gly, Leu, He, Vai, dLeu, dlle, dVal, Trp, fransPro(guan), c/sPro(guan), b-Ala, Mamb, Acpc, Aba, Aia, Aic, Cpe, Che, Oic, Tic, and Glu.
[2924] 61 . The method or the use of any one of embodiments 1 -48, 57, and 60, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[2925] Ac-Nle-c[Asp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 68);
[2926] Ac-Nle-c[Asp-Ala-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 69); [2927] Ac-Nle-c[Asp-dAla-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 71 );
[2928] Ac-Nle-c[Asp-dMet-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 72);
[2929] Ac-Nle-c[Asp-Pro-Gly-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 73);
[2930] Ac-Nle-c[Asp-Gly-Gly-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 74);
[2931] Ac-Nle-c[Asp-Gly-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 75);
[2932] Ac-Nle-c[Asp-Leu-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 76);
[2933] Ac-Nle-c[Asp-lle-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 77);
[2934] Ac-Nle-c[Asp-Val-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 78);
[2935] Ac-Nle-c[Asp-dLeu-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 79);
[2936] Ac-Nle-c[Asp-dlle-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 80);
[2937] Ac-Nle-c[Asp-dVal-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 81 );
[2938] Ac-Nle-c[Asp-Trp-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 82);
[2939] Ac-Nle-c[Asp-^ansPro(guan)-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID
NO: 84);
[2940] Ac-Nle-c[Asp-c/sPro(guan)-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
85),
[2941] Ac-Nle-c[Asp-p-Ala-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 199);
[2942] Ac-Nle-c[Asp-Mamb-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 200);
[2943] Ac-Nle-c[Asp-Acpc-dNal(2') Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 201 );
[2944] Ac-Nle-c[Asp-Aba-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 204);
[2945] Ac-Nle-c[Asp-Aia-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 205);
[2946] Ac-Nle-c[Asp-Aic-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 239);
[2947] Ac-Nle-c[Asp-Cpe-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 240);
[2948] Ac-Nle-c[Asp-Che-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 241 ); [2949] Ac-Nle-c[Asp-Oic-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 242);
[2950] Ac-Nle-c[Asp-Tic-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 244); and
[2951] Ac-Nle-c[Asp-Glu-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 255),
[2952] wherein c represents cyclization through R1 or R2 and R7 via a lactam bond.
[2953] 62. The method or the use of any one of embodiments 1 -48 and 57, wherein
R5 is absent or selected from the group consisting of Lys, Orn, His, Ala, fransPro(guan), c/sPro(guan), and Glu.
[2954]
[2955] 63. The method or the use of any one of embodiments 1 -48, 57, and 62, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[2956] Ac-Nle-c[Asp-Pro-dNal(2’)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 86);
[2957] Ac-Nle-c[Asp-Pro-dNal(2’)-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 87);
[2958] Ac-Nle-c[Asp-Pro-dNal(2’)-Orn-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 90);
[2959] Ac-Nle-c[Asp-Pro-dNal(2’)-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 92);
[2960] Ac-Nle-c[Asp-Pro-dNal(2’)-Ala-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 93);
[2961] Ac-Nle-c[Asp-Pro-dNal(2’)-Glu-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 96);
[2962] Ac-Nle-c[Asp-His-dNal(2’)-fransPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID
NO: 247);
[2963] Ac-Nle-c[Asp-His-dNal(2’)-c/sPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 248);
[2964] Ac-Nle-c[Asp-Pro-dNal(2’)-fra/?sPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID
NO: 250); and
[2965] Ac-Nle-c[Asp-Pro-dNal(2’)-c/sPro(guan)Pro-Trp-Lys]-dVal-dPro-NH2 (SEQ ID
NO: 251 ),
[2966] wherein c represents cyclization through R2 and R7 via a lactam bond. [2967] 64. The method or the use of any one of embodiments 1 -48 and 57, wherein
R6 is selected from the group consisting of Nal(1 ’), dNal(1 ’), Aia, Phe, dPhe, Tyr, dTyr, dNal(2’), dTrp, Aba, and Ata.
[2968] 65. The method or the use of any one of embodiments 1 -48, 57, and 64, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[2969] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Nal(1 ’)-Lys]-dVal-dPro-NH2 (SEQ ID NO: 102);
[2970] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Aia-Lys]-dVal-dPro-NH2 (SEQ ID NO: 103);
[2971] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Phe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 104);
[2972] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Tyr-Lys]-dVal-dPro-NH2 (SEQ ID NO: 105);
[2973] Ac-Nle-c[Asp-Rro-dNal(2’)-Arg-dNal(1 ’)-Lys]-dVal-dPro-NH2 (SEQ ID NO:
108);
[2974] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dPhe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 109);
[2975] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dNal(2’]-Lys]-dVal-dPro-NH2 (SEQ ID NO: 1 10);
[2976] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dTyr-Lys]-dVal-dPro-NH2 (SEQ ID NO: 111 );
[2977] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dTrp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 196);
[2978] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Aba-Lys]-dVal-dPro-NH2 (SEQ ID NO: 253); and
[2979] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Ata-Lys]-dVal-dPro-NH2 (SEQ ID NO: 254),
[2980] wherein c represents cyclization through R2 and R7 via a lactam bond.
[2981] 66. The method or the use of any one of embodiments 1 -48 and 57, wherein:
[2982] (i) Y1 is selected from dPro, Vai, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, Lys, dLys, Trp, and dTle and Y2 is absent or selected from dVal, Vai, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, and dTle; or [2983] (ii) Y1 is dVal, Y2 is dPro, and the C-terminus of the non-naturally occurring melanocortin analog is not modified.
[2984] 67. The method or the use of any one of embodiments 1 -48, 57, and 66, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[2985] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Val-Pro-NH2 (SEQ ID NO: 115);
[2986] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 1 16);
[2987] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 1 17);
[2988] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-Hyp-NH2 (SEQ ID NO: 1 18);
[2989] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 1 19);
[2990] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Val-Hyp-NH2 (SEQ ID NO: 120);
[2991] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Val-dHyp-NH2 (SEQ ID NO: 121 );
[2992] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Hyp-dVal-NH2 (SEQ ID NO: 122);
[2993] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dHyp-dVal-NH2 (SEQ ID NO: 123);
[2994] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Hyp-Val-NH2 (SEQ ID NO: 124);
[2995] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dHyp-Val-NH2 (SEQ ID NO: 125);
[2996] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dVal-NH2 (SEQ ID NO: 126);
[2997] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-dPro-NH2 (SEQ ID NO: 127);
[2998] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-NH2 (SEQ ID NO: 128);
[2999] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-NH2 (SEQ ID NO: 129);
[3000] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Val-NH2 (SEQ ID NO: 130);
[3001] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Pro-NH2 (SEQ ID NO: 131 );
[3002] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Ala-NH2 (SEQ ID NO: 132);
[3003] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAla-NH2 (SEQ ID NO: 133);
[3004] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dHyp-NH2 (SEQ ID NO: 134); [3005] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Hyp-NH2 (SEQ ID NO: 135);
[3006] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAla-dAla-NH2 (SEQ ID NO: 136);
[3007] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Ala-Ala-NH2 (SEQ ID NO: 137);
[3008] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Gly-Gly-NH2 (SEQ ID NO: 138);
[3009] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-Asp-NH2 (SEQ ID NO: 139);
[3010] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-Arg-NH2 (SEQ ID NO: 140);
[3011] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-Asn-NH2 (SEQ ID NO: 141 );
[3012] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dAsp-NH2 (SEQ ID NO: 142);
[3013] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dArg-NH2 (SEQ ID NO: 143);
[3014] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dAsn-NH2 (SEQ ID NO: 144);
[3015] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Asp-dPro-NH2 (SEQ ID NO: 145);
[3016] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-dPro-NH2 (SEQ ID NO: 146);
[3017] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Asn-dPro-NH2 (SEQ ID NO: 147);
[3018] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAsp-dPro-NH2 (SEQ ID NO: 148);
[3019] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 149);
[3020] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAsn-dPro-NH2 (SEQ ID NO: 150);
[3021] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Asp-NH2 (SEQ ID NO: 151 );
[3022] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-NH2 (SEQ ID NO: 152);
[3023] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Asn-NH2 (SEQ ID NO: 153);
[3024] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAsp-NH2 (SEQ ID NO: 154);
[3025] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dArg-NH2 (SEQ ID NO: 155);
[3026] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAsn-NH2 (SEQ ID NO: 156);
[3027] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-Pro-Val-NH2 (SEQ ID NO: 157);
[3028] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-dPro-dVal-NH2 (SEQ ID NO: 158); [3029] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dLys-dPro-dVal-NH2 (SEQ ID NO: 159);
[3030] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-dPro-NH2 (SEQ ID NO: 160);
[3031] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dLys-dPro-NH2 (SEQ ID NO: 161 );
[3032] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-Val-Pro-NH2 (SEQ ID NO: 162);
[3033] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-dVal-dPro-NH2 (SEQ ID NO: 163);
[3034] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dLys-dVal-dPro-NH2 (SEQ ID NO: 164);
[3035] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-Pro-Val-NH2 (SEQ ID NO: 165);
[3036] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-dPro-dVal-NH2 (SEQ ID NO: 166);
[3037] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dArg-dPro-dVal-NH2 (SEQ ID NO: 167);
[3038] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-Val-Pro-NH2 (SEQ ID NO: 168);
[3039] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-dVal-dPro-NH2 (SEQ ID NO: 169);
[3040] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO:
1 0);
[3041] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dVal-dPro-NH2 (SEQ ID NO:
171 );
[3042] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 172);
[3043] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dVal-NH2 (SEQ ID NO: 173);
[3044] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dTle-NH2 (SEQ ID NO: 174);
[3045] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO:
175);
[3046] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO:
176);
[3047] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-dTle-NH2 (SEQ ID NO: 177); [3048] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 178);
[3049] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Trp-NH2 (SEQ ID NO: 203); and
[3050] Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dPro-dl_ys-dAsp-NH2 (SEQ ID
NO: 263),
[3051] wherein c represents cyclization through R2 and R7 via a lactam bond.
[3052] 68. The method or the use of any one of embodiments 1 -48 and 57, wherein one or more of Y3-Y7 are present and are each independently dVal or dPro.
[3053] 69. The method or the use of any one of embodiments 1 -48, 57, and 68, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[3054] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO:
179);
[3055] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
180);
[3056] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 181 );
[3057] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID
NO: 182); and
[3058] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dVal-dVal-dVal-dVal-dVal-dPro-
NH2 (SEQ ID NO: 183),
[3059] wherein c represents cyclization through R2 and R7 via a lactam bond.
[3060] 70. The method or the use of any one of embodiments 1 -48 and 57, wherein one or more of X1-X3 are present and are Nle.
[3061] 71 . The method or the use of any one of embodiments 1 -48, 57, and 70, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[3062] Ac-Nle-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 184); [3063] Ac-Nle-Nle-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
185); and
[3064] Ac-Nle-Nle-Nle-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID
NO: 186),
[3065] wherein c represents cyclization through R2 and R7 via a lactam bond.
[3066] 72. The method or the use of any one of embodiments 1 -48, wherein the non-naturally occurring melanocortin analog comprises a sequence cyclized through a lactam bond between (i) Asp at R1 and Lys at R7, (ii) Asp at R2 and Lys at R8, or (ii) Asp at R1 and Lys at R8.
[3067] 73. The method or the use of any one of embodiments 1 -48 and 72, wherein
R2 is selected from Asp, Trp, Pro, and Glu, R3 is selected from Pro, Glu, and His, and R7 is selected from Lys, Pro, and Gly.
[3068] 74. The method or the use of any one of embodiments 1 -48, 72, and 73, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[3069] Ac-Nle-c[Asp-Pro-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 194);
[3070] Ac-Nle-c[Asp-Trp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 195);
[3071] Ac-Nle-c[Asp-Pro-Glu-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 257);
[3072] Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 245);
[3073] Ac-Nle-c[Asp-Glu-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 256);
[3074] Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 259);
[3075] Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys]-dPro-dPro-Lys-Asp-NH2 (SEQ ID
NO: 260);
[3076] Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys]-dPro-dPro-dLys-dAsp-NH2 (SEQ
ID NO: 261 );
[3077] Ac-Glu-c[Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys]-dPro-dPro-Lys-Asp-NH2 (SEQ ID
NO: 262); [3078] Ac-Nle-c[Asp-Glu-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 264); and
[3079] Ac-Nle-c[Asp-Glu-His-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO:
265),
[3080] wherein c represents cyclization through R1 or R2 and R7 or R8 via a lactam bond.
[3081] 75. The method or the use of any one of embodiments 1 -48, wherein one of R2 and R3 is Ala or dAla.
[3082] 76. The method or the use of any one of embodiments 1 -48, 72, and 75, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[3083] Ac-Nle-c[Asp-dAla-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
266);
[3084] Ac-Arg-c[Asp-dAla-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
267);
[3085] Ac-Arg-c[Cys-dAla-His-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO:
269);
[3086] Ac-dArg-c[Asp-dAla-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
270);
[3087] Ac-Arg-c[Asp-dAla-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 271 );
[3088] Ac-dArg-c[Asp-dAla-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 272);
[3089] Ac-Nle-c[Asp-Ala-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 273);
[3090] Ac-Arg-c[Asp-Ala-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 274);
[3091] Ac-dArg-c[Asp-Ala-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
275);
[3092] Ac-Arg-c[Cys-dAla-His-dNal(2’)-Arg-Trp-Cys]-NH2 (SEQ ID NO: 282); and [3093] Ac-Arg-c[Asp-dAla-His-dNal(2’)-Arg-Trp-Lys]-NH2 (SEQ ID NO: 283),
[3094] wherein c represents cyclization through R1 or R2 and R7 via a lactam bond or a disulfide bond.
[3095] 77. The method or the use of any one of embodiments 1 -48, wherein the non-naturally occurring melanocortin analog comprises a sequence cyclized through a disulfide bond between dPen at R2 and dPen at R7 or R8.
[3096] 78. The method or the use of any one of embodiments 1 -48 and 77, wherein
R1 is selected from the group consisting of Nle, dLeu, dNIe, dArg, Arg, dPhe, dTyr, Ala, dHis, His, dLys, and Lys.
[3097] 79. The method or the use of any one of embodiments 1 -48, 77, and 78, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[3098] Ac-dl_eu-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO:
327);
[3099] Ac-dNle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 328);
[3100] Ac-dArg-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 329);
[3101] Ac-Arg-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 330);
[3102] Ac-dPhe-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO:
331 );
[3103] Ac-dTyr-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 332);
[3104] Ac-Ala-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 333);
[3105] Ac-dHis-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 334);
[3106] Ac-His-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 335);
[3107] Ac-dl_ys-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 336);
[3108] Ac-Lys-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 337); [3109] Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dArg-dVal-dPro-NH2 (SEQ ID NO:
344);
[3110] Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dl_ys-dVal-dPro-NH2 (SEQ ID NO:
345);
[3111] Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dArg-dPro-NH2 (SEQ ID NO: 346);
[3112] Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dLys-dPro-NH2 (SEQ ID NO: 347);
[3113] Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dHyp-NH2 (SEQ ID NO: 348);
[3114] Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dTle-dPro-NH2 (SEQ ID NO: 349); and
[3115] Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-Gly-dPen]-dVal-dPro-NH2 (SEQ ID NO:
350),
[3116] wherein c represents cyclization through R1 or R2 and R7 or R8 via a disulfide bond.
[3117] 80. The method or the use of any one of embodiments 1 -47, wherein the non-naturally occurring melanocortin analog is linear.
[3118] 81 . The method or the use of any one of embodiments 1 -47 and 80, wherein the sequence of any one of Formulae (l)-(ID) is:
[3119] Ac-Nle-Asp-Pro-dNal(2')-Arg-Trp-Lys-dVal-dPro-NH2 (SEQ ID NO: 13); or
[3120] Ac-Nle-Pro-dNal(2’)-Arg-Trp-dVal-dPro-NH2 (SEQ ID NO: 14).
[3121] 82. The method or the use of any one of embodiments 1-46, wherein R4 is selected from the group consisting of dPhe, p(CI)dPhe p(l)dPhe, p(Br)dPhe, p(F)dPhe, or p(CF3)dPhe.
[3122] 83. The method or the use of any one of embodiments 1 -46 and 82, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:
[3123] Ac-Nle-c[Asp-Pro-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 215);
[3124] Ac-Nle-c[Asp-Pro-p(l)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 216); [3125] Ac-Nle-c[Asp-Pro-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 217);
[3126] Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 219);
[3127] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 220);
[3128] Ac-Nle-c[Asp-His-p(l)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 221 );
[3129] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 222);
[3130] Ac-Nle-c[Asp-His-p(CF3)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 224);
[3131] Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Aia-Lys]-dVal-dPro-NH2 (SEQ ID NO: 236);
[3132] Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Aba-Lys]-dVal-dPro-NH2 (SEQ ID NO: 237);
[3133] Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Ata-Lys]-dVal-dPro-NH2 (SEQ ID NO: 238);
[3134] Ac-Nle-c[Asp-dBip-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 369);
[3135] Ac-Nle-c[Asp-Pro-dPhe-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 426);
[3136] Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2’)-Lys]-dVal-dPro-NH2 (SEQ ID NO: 430);
[3137] Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 431 );
[3138] Ac-Nle-c[Cys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 432);
[3139] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
444);
[3140] Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Nal(2’)-Lys]-dVal-dPro-NH2 (SEQ ID NO:
445);
[3141] Ac-Nle-c[Asp-Phe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 487);
[3142] Ac-Nle-c[Asp-Bip-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 489);
[3143] Ac-Nle-c[Asp-Trp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 493);
[3144] Ac-Nle-c[Asp-Tyr-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 495);
[3145] Ac-Nle-c[Cys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 497);
[3146] Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 500); [3147] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
507);
[3148] Ac-Nle-c[Asp-His-p(CI)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 508);
[3149] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
509);
[3150] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Nal(2’)-Lys]-dVal-dPro-NH2 (SEQ ID NO:
510);
[3151] Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 514);
[3152] Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 516);
[3153] Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 517);
[3154] Ac-Nle-c[Asp-dHis-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 524);
[3155] Ac-Nle-c[Asp-Phe-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 525);
[3156] Ac-Nle-c[Asp-dPhe-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 526);
[3157] Ac-Nle-c[Asp-Bip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 527);
[3158] Ac-Nle-c[Asp-Gln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 529);
[3159] Ac-Nle-c[Asp-Trp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 531 );
[3160] Ac-Nle-c[Asp-Tyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 533);
[3161] Ac-Nle-c[Asp-dTyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 534);
[3162] Ac-Nle-c[Cys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 535);
[3163] Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 538);
[3164] Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 539);
[3165] Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 540);
[3166] Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 541 );
[3167] Ac-dl_ys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 542); [3168] Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 543);
[3169] Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-d al-dPro-NH2 (SEQ ID NO: 544);
[3170] Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO:
545);
[3171] Ac-Nle-c[Asp-His-p(Br)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 546);
[3172] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO:
547);
[3173] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Nal(2’)-Lys]-dVal-dPro-NH2 (SEQ ID NO:
548);
[3174] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO:
549);
[3175] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID
NO: 550);
[3176] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO:
551 );
[3177] Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 552);
[3178] Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO:
553);
[3179] Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID
NO: 554);
[3180] Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 555);
[3181] Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 556);
[3182] Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 557);
[3183] Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 558);
[3184] Ac-dl_ys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 559);
[3185] Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 560); [3186] Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 561 );
[3187] Ac-Nle-c[Asp-dHis-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 562);
[3188] Ac-Nle-c[Asp-Phe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 563);
[3189] Ac-Nle-c[Asp-dPhe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 564);
[3190] Ac-Nle-c[Asp-Bip-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 565);
[3191] Ac-Nle-c[Asp-dBip-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 566);
[3192] Ac-Nle-c[Asp-Gln-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 567);
[3193] Ac-Nle-c[Asp-dGln-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 568);
[3194] Ac-Nle-c[Asp-Trp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 569);
[3195] Ac-Nle-c[Asp-dTrp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 570);
[3196] Ac-Nle-c[Asp-Tyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 571 ); and
[3197] Ac-Nle-c[Asp-dTyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 572),
[3198] wherein c represents cyclization through R2 and R7 via a lactam bond or a disulfide bond.
[3199] 84. The method or the use of any one of embodiments 1 -83, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-7, 9-12, 13-23, 24-27, 28-30, 31 -43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-1 11 , 1 15-122, 123-138, 139-157, 158-164, 165-172, 173-182, 183- 186, 194-197, 199-201 , 203-206, 215-217, 219-222, 224, 236-242, 244-245, 247-248, 250- 251 , 253-257, 259-267, 269-275, 282-283, 327-337, 344-350, 369, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-510, 514, 516-517, 524-527, 529, 531 , 533-535, and 538- 572.
[3200] 85. The method or the use of embodiment 84, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-7, 9- 10, 12-23, 24-27, 28-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108- 1 11 , 115-138, 139-157, 158-162, 164-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219, 221 -222, 224, 236-242, 244-245, 247-248, 250-257, 259-267, 269-275, 282- 283, 327-337, 344-350, 509-510, 525-527, 531 , 533-535, 538, 545-549, 551 -553, 555, 562- 569, 571 -572.
[3201] 86. The method or the use of embodiment 84, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-4, 13, 15-23, 24-32, 35-43, 48-55, 59, 64-69, 71 -76, 77-82, 86-87, 90, 92-93, 96, 102, 104- 105, 108-111 , 115-138, 139-162, 164, 165-186, 195-197, 199-201 , 203, 215-217, 219, 221 - 222, 224, 240-242, 244, 255-256, 259-267, 269-275, 327-328, 331 , 344-350, 525-527, 531 , 533-535, 538, 545, 547-549, 551 -553, 555, 562-569, 571 -572.
[3202] 87. The method or the use of embodiment 84, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-7, 9- 10, 12-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-1 1 1 , 115- 138, 139-162, 164, 165-186, 194-197, 199-201 , 203-206, 239-242, 244-245, 247-248, 250- 251 , 253-257, 259-267, 269-275, 282-283, 327-337, 344-350.
[3203] 88. The method or the use of embodiment 84, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 215- 217, 219-222, 224, 236-238, 497, 500, 507-510, 514, 516-517, 535, 538-561 .
[3204] 89. The method or the use of embodiment 84, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 220, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-508, 514, 516-517, 524, 529, 539-544, 550, 554, 556-561 .
[3205] 90. The method or the use of embodiment 89, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.
[3206] 91 . The method or the use of any one of embodiments 1 -90, wherein the non-naturally occurring melanocortin analog is present in a pharmaceutical composition.
[3207] 92. The method or the use of embodiment 91 , wherein the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients and/or carriers. [3208] 93. The method or the use of embodiment 92, wherein the one or more pharmaceutically acceptable excipients and/or carriers of the pharmaceutical composition comprise water.
[3209] 94. The method or the use of any one of embodiments 1 -93, wherein the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg/kg to about 20 mg/kg administered once a day for about 5 days to about 10 days; (ii) at a second dose of about 10 mg/kg to about 40 mg/kg administered once a day after administration of the first dose for about 5 days to about 10 days; (iii) at a third dose of about 5 mg/kg to about 30 mg/kg administered twice a day after administration of the second dose for at least about 5 days to about 10 days.
[3210] 95. The method or the use of any one of embodiments 1 -93, wherein the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg/kg administered once a day for about 7 days; (ii) at a second dose of about 15 mg/kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 10 mg/kg administered twice a day after administration of the second dose for at least about 7 days.
[3211] 96. The method or the use of any one of embodiments 1 -93, wherein the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 10 mg/kg administered once a day for about 7 days; (ii) at a second dose of about 20 mg/kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 15 mg/kg administered twice a day after administration of the second dose for at least about 7 days.
[3212] 97. The method or the use of any one of embodiments 1 -93, wherein the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 15 mg/kg administered once a day for about 7 days; (ii) at a second dose of about 25 mg/kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 20 mg/kg administered twice a day after administration of the second dose for at least about 7 days. [3213] 98. The method or the use of any one of embodiments 1 -93, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 0.5 mg/kg to about 10 mg/kg per body weight of the subject once daily.
[3214] 99. The method or the use of embodiment 98, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 1 mg/kg or 3 mg/kg per body weight of the subject once daily.
[3215] 100. The method or the use of any one of embodiments 1 -93, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily.
[3216] 101. The method or the use of any one of embodiments 1 -95, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily.
[3217] 102. The method or the use of any one of embodiments 1 -101 , wherein the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.
[3218] 103. The method or the use of any one of embodiments 1 -102, wherein the non-naturally occurring melanocortin analog crosses a blood-brain-barrier of a subject.
[3219] 104. The method or the use of any one of embodiments 101 or 102, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3 and is administered at least once daily in an amount ranging from 0.001 mg/kg to 25 mg/kg per body weight of the subject.
[3220] 105. The method or the use of embodiment 104, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NOs: 3 and is administered at least once daily in an amount ranging from 0.5 mg/kg to 10 mg/kg per body weight of the subject. [3221] 106. The method or the use of any one of embodiments 1 -105, wherein the non-naturally occurring melanocortin analog is administered to a subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.
[3222] 107. The method or the use of any one of embodiments 1 -105, wherein the non-naturally occurring melanocortin analog is administered to a subject for 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 1 10 days, or 120 days.
[3223] 108. The method or the use of any one of embodiments 1 -107, wherein the method or the use further comprises maintaining muscle mass or promoting muscle mass gain in the subject.

Claims

CLAIMS I/We claim:
1 . A method of increasing body weight in a subject in need thereof, comprising administering to the subject a non-naturally occurring melanocortin analog comprising a sequence of Formula (I): X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4-Y5-Y6-Y7 (I), wherein:
X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
X2 is absent, phenylalanine (Phe), or Nle;
X3 is absent, Phe, or Nle;
R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D- valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), frans-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D- phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys);
R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/'s- CH=CH-CO, proline (Pro), and tryptophan (Trp);
R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), transPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and transPro(guan);
R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and T- naphthylalanine (Nal(1 ’));
R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
R9 is absent or Lys;
Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
Y5 is absent or dVal; Y6 is absent or dVal;
Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when R3 is dTrp or Phe, then R4 is not dNal(2’) and R6 is not dPhe; when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2’) or Nal(2’); when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent; when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
2. Use of a non-naturally occurring melanocortin analog for increasing body weight in a subject in need thereof, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I):
X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4-Y5-Y6-Y7 (I), wherein:
X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
X2 is absent, phenylalanine (Phe), or Nle;
X3 is absent, Phe, or Nle;
R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D- valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (czsPro(guan)), trans-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D- phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys);
R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/'s- CH=CH-CO, proline (Pro), and tryptophan (Trp);
R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), transPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), czsPro(guan), and transP ro (guan);
R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
R9 is absent or Lys;
Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
Y5 is absent or dVal;
Y6 is absent or dVal;
Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/'s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when R3 is dTrp or Phe, then R4 is not dNal(2’) and R6 is not dPhe; when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2’) or Nal(2’); when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent; when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
3. The method or the use of claim 1 or 2, wherein the method further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject.
4. The method of the use of claim 3, wherein the lean mass is lean muscle mass.
5. The method or the use of any one of claims 1 to 4, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 0.5 mg/kg to about 10 mg/kg per body weight of the subject once daily.
6. The method or the use of claim 5, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 1 mg/kg or 3 mg/kg per body weight of the subject once daily.
7. The method or the use of any one of claims 1 to 4, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily.
8. The method or the use of any one of claims 1 to 4, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily.
9. The method or the use of any one of claims 1 to 6, wherein the non-naturally occurring melanocortin analog is an antagonist of a melanocortin 4 receptor.
10. The method or the use of claim 9, wherein the non-naturally occurring melanocortin analog is a full antagonist of the melanocortin 4 receptor.
1 1 . The method or the use of claim 9, wherein the non-naturally occurring melanocortin analog is a partial antagonist of the melanocortin 4 receptor.
12. The method or the use of any one of claims 1 to 11 , wherein the non-naturally occurring melanocortin analog is an antagonist of a melanocortin 3 receptor.
13. The method or the use of claim 12, wherein the non-naturally occurring melanocortin analog is a full antagonist of the melanocortin 3 receptor.
14. The method or the use of claim 12, wherein the non-naturally occurring melanocortin analog is a partial antagonist of the melanocortin 3 receptor.
15. The method or the use of any one of claims 1 to 11 , wherein the non-naturally occurring melanocortin analog is an agonist of the melanocortin 3 receptor.
16. The method or the use of claim 15, wherein the non-naturally occurring melanocortin analog is a full agonist of the melanocortin 3 receptor.
17. The method or the use of claim 15, wherein the non-naturally occurring melanocortin analog is a partial agonist of the melanocortin 3 receptor.
18. The method or the use of claim 15, wherein the non-naturally occurring melanocortin analog has no melanocortin 3 receptor activity.
19. The method or the use of any one of claims 1 to 18, wherein the method or the use further comprises preventing or reducing one or more side effects associated with a metabolic disorder, relative to a control.
20. A method of preventing or reducing cachexia in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (I): X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4-Y5-Y6-Y7 (I), wherein:
X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
X2 is absent, phenylalanine (Phe), or Nle;
X3 is absent, Phe, or Nle;
R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D- valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), fra/?s-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D- phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys);
R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s- CH=CH-CO, proline (Pro), and tryptophan (Trp);
R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), transPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and transP ro (guan);
R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and T- naphthylalanine (Nal(1 ’));
R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
R9 is absent or Lys; Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
Y5 is absent or dVal;
Y6 is absent or dVal;
Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when R3 is dTrp or Phe, then R4 is not dNal(2’) and R6 is not dPhe; when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2’) or Nal(2’); when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent; when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
21. Use of a non-naturally occurring melanocortin analog for preventing or reducing cachexia in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I):
X1 -X2-X3- R1 - R2- R3- R4- R5- R6- R7- R8- R9- Y1 - Y2- Y3- Y4- Y5- Y6- Y7 ( I ) , wherein:
X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
X2 is absent, phenylalanine (Phe), or Nle;
X3 is absent, Phe, or Nle;
R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D- valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), frans-4-guanidinyl-proline (fransPro(guan)), cysteine (Cys), D-cysteine (dCys), D- phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys);
R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s- CH=CH-CO, proline (Pro), and tryptophan (Trp); R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), transPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and tra/?sPro(guan);
R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
R9 is absent or Lys;
Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn; Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dl_ys;
Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
Y5 is absent or dVal;
Y6 is absent or dVal;
Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/'s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when R3 is dTrp or Phe, then R4 is not dNal(2’) and R6 is not dPhe; when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2’) or Nal(2’); when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent; when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
22. A method of preventing or reducing anorexia in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (I): X1 -X2-X3- R1 - R2- R3- R4- R5- R6- R7- R8- R9- Y1 - Y2- Y3- Y4- Y5- Y6- Y7 ( | ) , wherein:
X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
X2 is absent, phenylalanine (Phe), or Nle;
X3 is absent, Phe, or Nle;
R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D- valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), fra/?s-4-guanidinyl-proline (f/'a/?sPro(guan)), cysteine (Cys), D-cysteine (dCys), D- phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys);
R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/'s- CH=CH-CO, proline (Pro), and tryptophan (Trp);
R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), fransPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2 ,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fransPro(guan);
R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and T- naphthylalanine (Nal(1 ’));
R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
R9 is absent or Lys;
Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
Y5 is absent or dVal;
Y6 is absent or dVal;
Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when R3 is dTrp or Phe, then R4 is not dNal(2’) and R6 is not dPhe; when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2’) or Nal(2’); when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent; when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
23. Use of a non-naturally occurring melanocortin analog for preventing or reducing anorexia in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I):
X1 -X2-X3- R1 - R2- R3- R4- R5- R6- R7- R8- R9- Y1 - Y2- Y3- Y4- Y5- Y6- Y7 ( I ) , wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
X2 is absent, phenylalanine (Phe), or Nle;
X3 is absent, Phe, or Nle;
R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D- valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), fra/?s-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D- phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys);
R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/'s- CH=CH-CO, proline (Pro), and tryptophan (Trp);
R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), fransPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2 ,3]triazolo-[ 1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe); R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fransPro(guan);
R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
R9 is absent or Lys;
Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
Y5 is absent or dVal;
Y6 is absent or dVal;
Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/'s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when R3 is dTrp or Phe, then R4 is not dNal(2’) and R6 is not dPhe; when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2’) or Nal(2’); when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent; when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
24. A method of increasing, maintaining, or reducing a loss in a body mass index (BMI) level in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (I): X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4-Y5-Y6-Y7 (I), wherein:
X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
X2 is absent, phenylalanine (Phe), or Nle;
X3 is absent, Phe, or Nle; R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D- valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), frans-4-guanidinyl-proline (fransPro(guan)), cysteine (Cys), D-cysteine (dOys), D- phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys);
R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s- CH=CH-CO, proline (Pro), and tryptophan (Trp);
R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), fransPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fransPro(guan); R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
R9 is absent or Lys;
Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
Y5 is absent or dVal;
Y6 is absent or dVal;
Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/'s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when R3 is dTrp or Phe, then R4 is not dNal(2’) and R6 is not dPhe; when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2’) or Nal(2’); when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent; when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
25. Use of a non-naturally occurring melanocortin analog for increasing, maintaining, or reducing a loss in a BMI level in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I):
X1 -X2-X3- R1 - R2- R3- R4- R5- R6- R7- R8- R9- Y1 - Y2- Y3- Y4- Y5- Y6- Y7 ( I ) , wherein:
X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
X2 is absent, phenylalanine (Phe), or Nle;
X3 is absent, Phe, or Nle;
R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D- valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), fra/?s-4-guanidinyl-proline (f/'a/?sPro(guan)), cysteine (Cys), D-cysteine (dCys), D- phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys);
R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/'s- CH=CH-CO, proline (Pro), and tryptophan (Trp);
R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), transPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fransPro(guan);
R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
R8 is absent or is selected from the group consisting of Trp, Lys, and dPen; R9 is absent or Lys;
Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
Y5 is absent or dVal;
Y6 is absent or dVal;
Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when R3 is dTrp or Phe, then R4 is not dNal(2’) and R6 is not dPhe; when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2’) or Nal(2’); when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent; when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
26. The method or the use of any one of claims 1-25, wherein the method or the use prevents fat mass gain after administration of the non-naturally occurring melanocortin analog, relative to a control.
27. The method or the use of any one of claims 1-26, wherein the method or the use reduces increases a fat mass level after administration of the non-naturally occurring melanocortin analog, relative to a control.
28. The method or the use of any one of claims 1-27, wherein the method or the use maintains or increases brain mass in the subject during or after administration of the non-naturally occurring melanocortin analog, relative to a control.
29. The method or the use of any one of claims 1-27, wherein the method or the use prevents or reduces brain mass loss in the subject during or after administration of the non-naturally occurring melanocortin analog, relative to a control.
30. The method or the use of any one of claims 1 -29, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I):
X1 -X2-X3- R1 - R2- R3- R4- R5- R6- R7- R8- R9- Y1 - Y2- Y3- Y4- Y5- Y6- Y7 ( I ) , wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
X2 is absent, phenylalanine (Phe), or Nle;
X3 is absent, Phe, or Nle;
R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D- valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), fra/?s-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D- phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys);
R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/'s- CH=CH-CO, proline (Pro), and tryptophan (Trp);
R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), fransPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2 ,3]triazolo-[ 1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe); R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fransPro(guan);
R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
R9 is absent or Lys;
Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
Y5 is absent or dVal;
Y6 is absent or dVal;
Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/'s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when R3 is dTrp or Phe, then R4 is not dNal(2’) and R6 is not dPhe; when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; when R4 is dPhe, then (i) R3 is dBip or (ii) R3 is Pro, R2 is not Trp, and either R5 is Lys or R6 is dNal(2’) or Nal(2’); when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, Phe, dPhe, Bip, Gin, Trp, Tyr, dTyr, and Pro, R2 is not Trp, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent; when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
31 . The method or the use of any one of claims 1 -29, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I), wherein:
X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
X2 is absent, phenylalanine (Phe), or Nle;
X3 is absent, Phe, or Nle;
R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D- valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), fra/?s-4-guanidinyl-proline (fransPro(guan)), cysteine (Cys), D-cysteine (dCys), D- phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys)
R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s- CH=CH-CO, proline (Pro), and tryptophan (Trp);
R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, D-tryptophan (dTrp), Tyr, dTyr, c/sPro(guan), transPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
R4 is selected from the group consisting of Pro, dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and transP ro (guan);
R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and T- naphthylalanine (Nal(1 ’));
R7 is absent or is selected from the group consisting of Arg, Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
R8 is absent or is selected from the group consisting of Trp, Lys, and dPen;
R9 is absent or Lys; Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
Y5 is absent or dVal;
Y6 is absent or dVal;
Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-dTrp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 83);
Ac-Nle-c[Asp-Phe-Phe-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 420); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 223);
Ac-Nle-c[dCys-His-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 460);
Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 464); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 465); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 466); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 467);
Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 468);
Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 469);
Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 470);
Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 474);
Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 475);
Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 476);
Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 477);
Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 478);
Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 481 );
Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 482);
Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 483);
Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 484);
Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 485);
Ac-Nle-c[Cys-His-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 459);
Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 472);
Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 471 );
Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 463);
Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 462);
Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 479);
Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 473);
Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 480);
Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 486);
Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 491 );
Ac-Nle-c[dCys-His-p(F)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 461 );
Ac-Nle-c[Asp-dGln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 492);
Ac-Nle-c[Asp-dTyr-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 496);
Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 218);
Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 442);
Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 449);
Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 455); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-d al-dPro-NH2 (SEQ ID NO: 447);
Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 438);
Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 450);
Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 435);
Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 439);
Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 441 );
Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 436);
Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 454);
Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 452);
Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 451 );
Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 456);
Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 437);
Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 440);
Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 448);
Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 457);
Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 453);
Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 458);
Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 446);
Ac-Nle-c[dCys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 433);
Ac-Nle-c[dCys-Pro-p(F)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 434);
Ac-Nle-c[Asp-dPhe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 488);
Ac-Nle-c[Asp-dBip-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 490);
Ac-Nle-c[Asp-dTrp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 494);
Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 443);
Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 268);
Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 363);
Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 365);
Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 370);
Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 378); Ac-dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 379);
Ac-Nle-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 380);
Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 418);
Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 621 );
Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 666);
Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 297);
Ac-Nle-c[Asp-His-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 228);
Ac-Nle-c[Asp-His-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 229);
Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 281 );
Ac-Nle-c[Asp-Leu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 355);
Ac-Nle-c[Asp-Tic-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 362);
Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 424);
Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 366);
Ac-Nle-c[Asp-Bip-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 368);
Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dLeu-dPro-NH2 (SEQ ID NO: 422);
Ac-Nle-c[Asp-Trp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 372);
Ac-Nle-c[Asp-Tyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 374);
Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 639);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dPro-dPro-Lys-Asp-NH2 (SEQ ID NO: 352);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 351 );
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Trp-NH2 (SEQ ID NO: 600);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 322);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dAsn-NH2 (SEQ ID NO: 605);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Gly-Gly-NH2 (SEQ ID NO: 610); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Arg-NH2 (SEQ ID NO: 581 );
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dPro-dPro-dLys-dAsp-NH2 (SEQ ID NO: 353);
Ac-Nle-c[dCys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 319);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asn-dPro-NH2 (SEQ ID NO: 607);
Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 638);
Ac-Nle-c[Asp-Pro-His-Phe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 295);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 575);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH2 (SEQ ID NO: 587);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-NH2 (SEQ ID NO: 582);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Arg-Pro-Val-NH2 (SEQ ID NO: 588);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAsn-dPro-NH2 (SEQ ID NO: 612);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-Pro-Val-NH2 (SEQ ID NO: 583);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Ala-Ala-NH2 (SEQ ID NO: 609);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 594);
Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 631 );
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Arg-Val-Pro-NH2 (SEQ ID NO: 589);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 597);
Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 628);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 591 );
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 590);
Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 311 );
Ac-Nle-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 629);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-Hyp-NH2 (SEQ ID NO: 574);
Ac-dPhe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 303); Ac-Nle-c[Asp-Oic-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 360);
Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 313);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 291 );
Ac-dAla-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 299);
Phe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 305);
His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 306);
Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 312);
Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 314);
Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 315);
Ac-Nle-c[dCys-Pro-dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 321 );
Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 423);
Ac-Nle-Phe-Phe-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 421 );
Ac-Nle-c[Cys-Trp-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 383);
Ac-Nle-c[dCys-Trp-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 384);
Ac-Lys-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 387);
Ac-Arg-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 389);
Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 403);
Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 407);
Ac-Nle-c[Asp-Trp-Leu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 395);
Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 633);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Val-Pro-NH2 (SEQ ID NO: 573);
Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 643);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Val-NH2 (SEQ ID NO: 576);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Pro-NH2 (SEQ ID NO: 577); dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 309);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 593);
Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dl_ys-dVal-dPro-NH2 (SEQ ID NO: 632);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asp-NH2 (SEQ ID NO: 603);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 617);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 620);
Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dl_ys-dPro-NH2 (SEQ ID NO: 634);
Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 635);
Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 644);
Ac-dTyr-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 304);
Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 642); dPhe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 308);
Ac-Nle-c[Asp-Atc-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 212);
Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 226);
Ac-Nle-c[dPen-Pro-dPhe-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 320);
Ac-Nle-c[Cys-dPhe-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 324);
Ac-Nle-c[Asp-Cpe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 358);
Ac-Nle-c[Asp-Che-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 359);
Ac-Nle-c[Asp-dPhe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 367);
Ac-Nle-c[Asp-dGln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 371 );
Ac-Nle-c[Asp-dTrp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 373);
Ac-Nle-c[Asp-dTyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 375);
Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 381 );
Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 382); Ac-Nle-c[dCys-Trp-Pro-dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 385);
Ac-Ala-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 386);
Ac-dLys-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 388);
Ac-dArg-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 390);
Ac-dHis-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 391 );
Ac-His-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 392);
Ac-Nle-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 393);
Ac-Nle-c[Asp-Trp-Ala-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 394);
Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 405);
Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH2 (SEQ ID NO: 406);
Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dLys-dPro-NH2 (SEQ ID NO: 408);
Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 409);
Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 410);
Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 41 1 );
Ac-Nle-c[Asp-Phe-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 412);
Ac-Nle-c[Asp-His-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 413);
Ac-Nle-c[Asp-Tyr-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 414);
Ac-Nle-c[Asp-dPhe-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 415);
Ac-Nle-c[Asp-dHis-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 416);
Ac-Nle-c[Asp-dTyr-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 417);
Ac-Nle-c[Asp-Hyp-dPhe-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 419);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 596);
Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dl_ys]-dPro-dVal-NH2 (SEQ ID NO: 622);
Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 645); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 646);
Ac-dLeu-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 298);
Ac-Nle-c[Asp-Ala-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 354);
Ac-Nle-c[Asp-Hyp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 364);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-Arg-NH2 (SEQ ID NO: 578);
Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 300);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dArg-NH2 (SEQ ID NO: 579);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 580);
Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 640);
Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 641 );
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dPro-NH2 (SEQ ID NO: 584);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-Val-Pro-NH2 (SEQ ID NO: 585);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-dVal-dPro-NH2 (SEQ ID NO: 586);
Ac-dNle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 301 );
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 595);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 598);
Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 302);
Ac-Nle-Nle-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 630);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-dPro-dVal-NH2 (SEQ ID NO: 601 );
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAla-dAla-NH2 (SEQ ID NO: 602);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dHyp-NH2 (SEQ ID NO: 604);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-Asp-NH2 (SEQ ID NO: 606);
Ac-Nle-c[Cys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 318);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Hyp-NH2 (SEQ ID NO: 608); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asp-dPro-NH2 (SEQ ID NO: 61 1 );
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asn-NH2 (SEQ ID NO: 613);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAsp-NH2 (SEQ ID NO: 614);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAsn-NH2 (SEQ ID NO: 615);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-dPro-NH2 (SEQ ID NO: 616);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 599);
Ac-Nle-c[Asp-Pro-His-Phe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 296);
Ac-Nle-c[Asp-Aba-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 198);
Ac-Nle-c[Asp-Aia-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 207);
Ac-Nle-c[Asp-Ata-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 208);
Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 225);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 592);
Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 425);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(1 ’)-Lys]-dVal-dPro-NH2 (SEQ ID NO: 427);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Phe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 429);
Ac-Nle-c[Pen-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 325);
Ac-Nle-c[dPen-dPhe-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 326);
Ac-Nle-c[Asp-dlle-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 356);
Ac-Nle-c[Asp-dVal-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 357);
Ac-Arg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 376);
Ac-dArg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 377);
Ac-Nle-c[Asp-Trp-dLeu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 396);
Ac-Nle-c[Asp-Trp-dVal-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 397); Ac-Nle-c[Asp-Trp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 398);
Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-dNal(1 ')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 400);
Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Phe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 401 );
Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-dPhe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 402);
Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Nal(1 ')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 399);
Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 404);
Ac-Nle-c[Asp-Pro-dPhe-Arg-dTrp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 187);
Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 231 );
Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 232);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Aia-Lys]-dVal-dPro-NH2 (SEQ ID NO: 233);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Aba-Lys]-dVal-dPro-NH2 (SEQ ID NO: 234);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Ata-Lys]-dVal-dPro-NH2 (SEQ ID NO: 235);
Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(1 ’)-Lys]-dVal-dPro-NH2 (SEQ ID NO: 428);
Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 520);
Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 522);
Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 523);
Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 518);
Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 503);
Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 505);
Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 502);
Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 519);
Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 506);
Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 501 );
Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 521 ); Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 504);
Ac-Nle-c[Asp-dBip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 528);
Ac-Nle-c[Asp-dGln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 530);
Ac-Nle-c[Asp-dTrp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 532);
Ac-Nle-c[Asp-Aba-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 209);
Ac-Nle-c[Asp-Aia-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 210);
Ac-Nle-c[Asp-Ata-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 211 );
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 512);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 513);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 51 1 );
Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 515);
Ac-Nle-c[dPen-Ala-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 338);
Ac-Nle-c[dPen-Leu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 339);
Ac-Nle-c[dPen-dLeu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 340);
Ac-Nle-c[dPen-dVal-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 341 );
Ac-Nle-c[dPen-Gly-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 342);
Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 536);
Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 498);
Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 499);
Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 537);
Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 44);
Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 45);
Ac-Nle-c[Cys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 46);
Ac-Nle-c[dCys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 47); Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 56);
Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 57);
Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 58);
Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 60);
Ac-Nle-c[dPen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 61 );
Ac-Nle-c[dPen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 62);
Ac-Nle-c[Pen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 63);
Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 8); and Ac-Nle-c[Asp-Pro-Glu-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 258).
32. The method or the use of any one of claims 1 -30, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IA):
X1 -X2-X3- R1 - R2- R3- R4- R5- R6- R7- R8- Y1 - Y2-Y3- Y4- Y5-Y6- Y7 ( I A) , wherein:
X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
X2 is absent, phenylalanine (Phe), or Nle;
X3 is absent, Phe, or Nle;
R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D- valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), trans-4-guanidinyl-proline (f/-a/?sPro(guan)), cysteine (Cys), D-cysteine (dCys), D- phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys) R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/'s- CH=CH-CO, proline (Pro), and tryptophan (Trp);
R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, Tyr, dTyr, c/sPro(guan), tra/?sPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2 ,3]triazolo-[1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
R4 is selected from the group consisting of 2’-D-naphthylalanine (dNal(2’)), para- chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D- phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe);
R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and transP ro (guan);
R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and T- naphthylalanine (Nal(1 ’));
R7 is absent or is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
R8 is Lys or dPen;
Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp; Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
Y5 is absent or dVal;
Y6 is absent or dVal;
Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; a lactam bridge between R1 and R7 or R8 when R1 is Asp and R7 or R8 is Lys; provided that: when R4 is p(Br)dPhe, then R1 is Nle or Ala, Y4-Y7 are absent, and at least one of X1 and Y3 is absent; when R4 is p(CI)dPhe, then (i) R3 is selected from Phe, dPhe, Bip, Trp, Tyr, dTyr, and Pro or (ii) R3 is His and R6 is not Trp; when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R2 is not Pro.
33. The method or the use of any one of claims 1 -29 and 31 , wherein the non- naturally occurring melanocortin analog comprises a sequence according to Formula (IA), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
X2 is absent, phenylalanine (Phe), or Nle;
X3 is absent, Phe, or Nle;
R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D- valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), fra/?s-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dCys), D- phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys)
R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/'s- CH=CH-CO, proline (Pro), and tryptophan (Trp);
R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, Tyr, dTyr, c/'sPro(guan), transPro(guan), 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 7- amino-7,8-dihydro-4H-[1 ,2 ,3]triazolo-[ 1 ,5-a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 - amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), D-biphenylalanine (dBip);
R4 is selected from the group consisting of 2’-D-naphthylalanine (dNal(2’)), para- chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D- phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe); R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fransPro(guan);
R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’- naphthylalanine (Nal(1 ’));
R7 is absent or is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
R8 is Lys or dPen;
Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
Y5 is absent or dVal;
Y6 is absent or dVal;
Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/'s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:
Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 539);
Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 540);
Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 541 );
Ac-dLys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 542);
Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 543);
Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 544);
Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 556);
Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 557);
Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 558);
Ac-dLys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 559);
Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 560);
Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 561 );
Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 550);
Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 554);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 220);
Ac-Nle-c[Cys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 497);
Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 500);
Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 507);
Ac-Nle-c[Asp-His-p(CI)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 508);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 514);
Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 516);
Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 517); Ac-Nle-c[Asp-dHis-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 524);
Ac-Nle-c[Asp-Gln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 529);
Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 520);
Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 522);
Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 523);
Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 518);
Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 503);
Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 505);
Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 502);
Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 519);
Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 506);
Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 501 );
Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 521 );
Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 504);
Ac-Nle-c[Asp-dBip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 528);
Ac-Nle-c[Asp-dGln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 530);
Ac-Nle-c[Asp-Aba-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 209);
Ac-Nle-c[Asp-Aia-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 210);
Ac-Nle-c[Asp-Ata-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 211 );
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 512);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 513);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 51 1 );
Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 515);
Ac-Nle-c[dPen-Ala-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 338); Ac-Nle-c[dPen-Leu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 339);
Ac-Nle-c[dPen-dLeu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 340);
Ac-Nle-c[dPen-dVal-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 341 );
Ac-Nle-c[dPen-Gly-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 342);
Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 536);
Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 498);
Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 499);
Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 537);
Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 44);
Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 45);
Ac-Nle-c[Cys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 46);
Ac-Nle-c[dCys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 47);
Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 56);
Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 57);
Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 58);
Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 60);
Ac-Nle-c[dPen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 61 );
Ac-Nle-c[dPen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 62);
Ac-Nle-c[Pen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 63);
Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 8); and Ac-Nle-c[Asp-Pro-Glu-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 258).
34. The method or the use of any one of claims 1 -30 and 32, wherein the non- naturally occurring melanocortin analog comprises a sequence according to Formula (IA), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
X2 is absent or Nle;
X3 is absent or Nle;
R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D- valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cysteine (Cys), D-cysteine (dCys), D- phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), and glutamic acid (Glu);
R2 is selected from the group consisting of dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s- CH=CH-CO, and tryptophan (Trp);
R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, p-alanine (P-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, Tyr, dTyr, 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), and D-biphenylalanine (dBip);
R4 is selected from the group consisting of 2’-D-naphthylalanine (dNal(2’)), para- chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D- phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe);
R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, and ornithine (Orn);
R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’-naphthylalanine (Nal(1 ’)); R7 is selected from the group consisting of Gly, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
R8 is Lys or dPen;
Y1 is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
Y5 is absent or dVal;
Y6 is absent or dVal;
Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/'s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when R4 is p(Br)dPhe, then R1 is Nle or Ala, R5 is Arg, Y4-Y7 are absent, and at least one of X1 and Y3 is absent; when R4 is p(CI)dPhe, then R3 is selected from Phe, dPhe, Bip, Trp, Tyr, dTyr, and Pro; and when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is Pro and R1 is not dArg, Arg, dTyr, or Ala, (ii) R3 is His and R2 and R7 are both Cys, or (iii) R3 is absent, R2 is Pen, and R7 is dCys.
35. The method or the use of any one of claims 1 -29 and 33, wherein the non- naturally occurring melanocortin analog comprises a sequence according to Formula (IA), wherein:
X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
X2 is absent or Nle;
X3 is absent or Nle;
R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D- valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), cysteine (Cys), D-cysteine (dCys), D- phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), and glutamic acid (Glu);
R2 is selected from the group consisting of dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/'s- CH=CH-CO, and tryptophan (Trp);
R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, glutamine (Gin), dGIn, leucine (Leu), dLeu, isoleucine (He), dlle, valine (Vai), dVal, Trp, Tyr, dTyr, 3- aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 1 -amino-1 -cyclopentane carboxylic (Cpe), biphenylalanine (Bip), and D-biphenylalanine (dBip); R4 is selected from the group consisting of 2’-D-naphthylalanine (dNal(2’)), para- chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D- phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);
R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, and ornithine (Orn);
R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, dNal(2’), 2’-naphthylalanine (Nal(2’)), 1 ’-D-naphthylalanine (dNal(1 ’)), and 1 ’-naphthylalanine (Nal(1 ’));
R7 is selected from the group consisting of Gly, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
R8 is Lys or dPen;
Y1 is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
Y5 is absent or dVal;
Y6 is absent or dVal;
Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/'s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-His-p(Br)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 546);
Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 539);
Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 540);
Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 556);
Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 557);
Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 550);
Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 554);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 509);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 510);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 220);
Ac-Nle-c[Cys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 497);
Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 500);
Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 507);
Ac-Nle-c[Asp-His-p(CI)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 508);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 514);
Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 516);
Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 517);
Ac-Nle-c[Asp-dHis-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 524);
Ac-Nle-c[Asp-Gln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 529); Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 518);
Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 502);
Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 519);
Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 501 );
Ac-Nle-c[Asp-dBip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 528);
Ac-Nle-c[Asp-dGln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 530);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 512);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 513);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 51 1 );
Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 515);
Ac-dArg-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 329);
Ac-Arg-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 330);
Ac-dTyr-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 332);
Ac-Ala-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 333);
Ac-Nle-c[dPen-Ala-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 338);
Ac-Nle-c[dPen-Leu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 339);
Ac-Nle-c[dPen-dLeu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 340);
Ac-Nle-c[dPen-dVal-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 341 );
Ac-Nle-c[dPen-Gly-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 342);
Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 536);
Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 498);
Ac-Nle-c[dCys-His-p(CI)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 499);
Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 537);
Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[dCys-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 45);
Ac-Nle-c[Cys-dNal(2’)-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 46);
Ac-Nle-c[dCys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 47);
Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 56);
Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 57);
Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 58);
Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 60);
Ac-Nle-c[dPen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 61 );
Ac-Nle-c[dPen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 62); and
Ac-Nle-c[Pen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 63).
36. The method or the use of any one of claims 1 -30, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IB):
X1 -X2-X3- R1 - R2- R3-d Nal (2’)- R5- R6- R7- R8-Y1 - Y2- Y3-Y4- Y5-Y6- Y7 (IB), wherein:
X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
X2 is absent, phenylalanine (Phe), or Nle;
X3 is absent, Phe, or Nle;
R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D- valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), fra/?s-4-guanidinyl-proline (f/'a/?sPro(guan)), cysteine (Cys), D-cysteine (dCys), D- phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys)
R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s- CH=CH-CO, proline (Pro), and tryptophan (Trp);
R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, c/sPro(guan), tra/?sPro(guan), 4-amino-1 ,2,4,5- tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclopropane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5- a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), and 1 -amino-1 -cyclopentane carboxylic (Cpe);
R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and fransPro(guan);
R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), T-D-naphthylalanine (dNal(1 ’)), and T-naphthylalanine (Nal(1 ’));
R7 is absent or is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
R8 is absent or is Lys or dPen;
Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp;
Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys; Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
Y5 is absent or dVal;
Y6 is absent or dVal;
Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/'s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that: when the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2 and R7, then (i) R3 is not Ala, Leu, dLeu, dVal, or Gly, and if R3 is absent, then R2 is Pen and R7 is dCys; and when R7 is Pro or Gly, then (i) R3 is not His or (ii) R3 is His and R2 is Glu.
37. The method or the use of any one of claims 1 -29 and 31 , wherein the non- naturally occurring melanocortin analog comprises a sequence according to Formula (IB), wherein:
X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg) and D-arginine (dArg);
X2 is absent, phenylalanine (Phe), or Nle;
X3 is absent, Phe, or Nle;
R1 is absent or is selected from the group consisting of Arg, dArg, Nle, D-norleucine (dNIe), aspartic acid (Asp), D-methionine (dMet), D-isoleucine (dlle), D-leucine (dLeu), D- valine (dVal), D-alanine (dAla), alanine (Ala), tert-leucine (Tie), D-tert-leucine (dTle), norvaline (Nva), glycine (Gly), D-proline (dPro), c/s-4-guanidinyl-proline (c/sPro(guan)), frans-4-guanidinyl-proline (transPro(guan)), cysteine (Cys), D-cysteine (dOys), D- phenylalanine (dPhe), D-tyrosine (dTyr), tyrosine (Tyr), dimethyl-tyrosine (Dmt), D- glutamine (dGIn), D-asparagine (dAsn), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys)
R2 is selected from the group consisting of Phe, dAla, Ala, Gly, Asp, D-aspartic acid (dAsp), Cys, dCys, penicillamine (Pen), D-penicillamine (dPen), glutamic acid (Glu), CO-c/s- CH=CH-CO, proline (Pro), and tryptophan (Trp);
R3 is absent or is selected from the group consisting of Phe, dPhe, His, dHis, Glu, Pro, hydroxyproline (Hyp), Ala, dAla, b-alanine (b-Ala), dMet, Gly, dGIn, leucine (Leu), dLeu, isoleucine (lie), dlle, valine (Vai), dVal, Trp, c/sPro(guan), transPro(guan), 4-amino-1 ,2,4,5- tetrahydro-2-benzazepin-3-one (Aba), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo- propane-1 -carboxylic acid (Acpc), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5- a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1 -amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), 2-aminoindone-2-carboxylic acid (Aic), and 1 -amino-1 -cyclopentane carboxylic (Cpe);
R5 is absent or is selected from the group consisting of Arg, His, Ala, Glu, Lys, ornithine (Orn), c/sPro(guan), and transP ro (guan);
R6 is selected from the group consisting of Trp, dTrp, Tyr, dTyr, Phe, dPhe, Aia, Aba, Ata, dNal(2’), T-D-naphthylalanine (dNal(1 ’)), and 1 ’-naphthylalanine (Nal(1 ’));
R7 is absent or is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, Orn, and D-ornithine (dOrn);
R8 is absent or is Lys or dPen;
Y1 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, D- hydroxyporline (dHyp), dTle, dLeu, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, dAsn, asparagine (Asn), Lys, dLys, and Trp; Y2 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Hyp, dHyp, dTle, Ala, dAla, Gly, Asp, dAsp, Arg, dArg, Asn, and dAsn;
Y3 is absent or is selected from the group consisting of Vai, dVal, Pro, dPro, Lys, and dLys;
Y4 is absent or is selected from the group consisting of dVal, dPro, Asp, and dAsp;
Y5 is absent or dVal;
Y6 is absent or dVal;
Y7 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or R8 when each of R1 or R2 and R7 or R8 are independently selected from the group consisting of Cys, dCys, Pen and dPen; a lactam bridge between R2 and R7 or R8 when R2 is selected from the group consisting of Asp, dAsp, Glu, and CO-c/'s-CH=CH-CO and R7 or R8 is selected from the group consisting of Lys, dLys, Orn, and dOrn; and a lactam bridge between R1 and any one of R7-R9 when R1 is Asp and any one of R7-R9 is Lys; provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[dPen-Ala-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 338); Ac-Nle-c[dPen-Leu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 339);
Ac-Nle-c[dPen-dLeu-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 340);
Ac-Nle-c[dPen-dVal-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 341 ); Ac-Nle-c[dPen-Gly-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 342); Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 44);
Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 45);
Ac-Nle-c[Cys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 46);
Ac-Nle-c[dCys-dNal(2')-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 47);
Ac-Nle-c[Cys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-Nle-c[dCys-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 57);
Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c[Pen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 60); Ac-Nle-c[dPen-dNal(2')-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 61 ); Ac-Nle-c[dPen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 62);
Ac-Nle-c[Pen-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 63);
Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 8); and Ac-Nle-c[Asp-Pro-Glu-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 258).
38. The method or the use of any one of claims 1 -30, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IC):
X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4 (IC), wherein:
X1 is absent or norleucine (Nle)
R1 is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys);
R2 is aspartic acid (Asp) or cysteine (Cys);
R3 is His or proline (Pro);
R4 is selected from the group consisting of para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para- trifluoromethyl-D-phenylalanine (p(CFs)dPhe);
R5 is Arg or His;
R6 is selected from the group consisting of tryptophan (Trp), 4-amino-1 ,2,4,5- tetrahydro-2-benzazepin-3-one (Aba), 3- 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5- a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), 2’-D-naphthylalanine dNal(2’), and 2’-naphthylalanine (Nal(2’));
R7 is Lys or Cys; Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle);
Y2 is selected from the group consisting of dVal, dPro, and dTle;
Y3 is absent or is dVal or dPro;
Y4 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between Cys at R2 and Cys R7; and a lactam bridge between Asp at R2 and Lys at R7; provided that: when R4 is p(CI)dPhe, then R1 is Nle or Ala, Y4-Y7 are absent, and either X1 and Y3 are both present or X1 and Y3 are both absent.
39. The method or the use of any one of claims 1 -29 and 31 , wherein the non- naturally occurring melanocortin analog comprises a sequence according to Formula (IC), wherein:
X1 - R1 - R2- R3- R4- R5- R6- R7-Y1 - Y2-Y3- Y4 ( IC) , wherein:
X1 is absent or norleucine (Nle)
R1 is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys);
R2 is aspartic acid (Asp) or cysteine (Cys);
R3 is His or proline (Pro);
R4 is selected from the group consisting of para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para- trifluoromethyl-D-phenylalanine (p(CFs)dPhe);
R5 is Arg or His; R6 is selected from the group consisting of tryptophan (Trp), 4-amino-1 ,2,4,5- tetrahydro-2-benzazepin-3-one (Aba), 3- 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5- a][1 ,4]diazepin-6(5H)-one (Ata), 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2/-/)-one (Aia), 2’-D-naphthylalanine dNal(2’), and 2’-naphthylalanine (Nal(2’))j
R7 is Lys or Cys;
Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle);
Y2 is selected from the group consisting of dVal, dPro, and dTle;
Y3 is absent or is dVal or dPro;
Y4 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between Cys at R2 and Cys R7; and a lactam bridge between Asp at R2 and Lys at R7; provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:
Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 520);
Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 522);
Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 523);
Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 518);
Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 503);
Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 505);
Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 502);
Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 519);
Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 506);
Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 501 ); Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 521 );
Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 504);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 512);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 513);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 51 1 ); and
Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 515).
40. The method or the use of any one of claims 1 -30, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (ID):
X1 - R1 - R2- R3- R4- R5- R6- R7-Y1 - Y2-Y3- Y4 (ID), wherein:
X1 is absent or norleucine (Nle);
R1 is absent or is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys)
R2 is aspartic acid (Asp) or cysteine (Cys);
R3 is selected from the group consisting of His, D-histidine (dHis), proline (Pro), phenylalanine (Phe), tryptophan (Trp), tyrosine (Tyr), glutamine (Gin), and biphenylalanine (Bip);
R4 is selected from the group consisting of dPhe, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
R5 is selected from the group consisting of Arg, Lys, and His;
R6 is selected from the group consisting of Trp, 2’-D-naphthylalanine (dNal(2’)), and 2’-naphthylalanine (Nal(2’));
R7 is Lys or Cys; Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle);
Y2 is dVal or dPro;
Y3 is absent, dVal, or dPro;
Y4 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between Cys at R2 and Cys at R7; and a lactam bridge between Asp at R2 and Lys at R7; provided that: when R4 is p(Br)dPhe and R1 is Nle or Ala, then the C-terminus is not dVal-dPro or dTle- dPro and if the C-terminus is dPro-dVal-dPro, then X1 is present. when R4 is p(F)dPhe, then (i) R3 is selected from Phe, Bip, Trp, and Tyr or (ii) R3 is Pro and R5 is Lys, R6 is dNal(2’) or Nal(2’), or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between Cys at R2 and Cys at R7; when R4 is dPhe, then R3 is Pro and either R5 is Lys or R6 is dNal(2’) or Nal(2’); and when R4 is p(CI)dPhe, then R1 is Nle or Ala, R3 is selected from His, dHis, and Gin, R6 is Trp, and either X1 and Y3 are both present or X1 and Y3 are both absent.
41. The method or the use of any one of claims 1 -29 and 31 , wherein the non- naturally occurring melanocortin analog comprises a sequence according to Formula (ID), wherein:
R1 is absent or is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), alanine (Ala), histidine (His), D-histidine (dHis), lysine (Lys), D-lysine (dLys)
R2 is aspartic acid (Asp) or cysteine (Cys);
R3 is selected from the group consisting of His, D-histidine (dHis), proline (Pro), phenylalanine (Phe), tryptophan (Trp), tyrosine (Tyr), glutamine (Gin), and biphenylalanine (Bip); R4 is selected from the group consisting of dPhe, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);
R5 is selected from the group consisting of Arg, Lys, and His;
R6 is selected from the group consisting of Trp, 2’-D-naphthylalanine (dNal(2’)), and 2’-naphthylalanine (Nal(2’»;
R7 is Lys or Cys;
Y1 is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle);
Y2 is dVal or dPro;
Y3 is absent, dVal, or dPro;
Y4 is absent or dPro; and the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between Cys at R2 and Cys at R7; and a lactam bridge between Asp at R2 and Lys at R7; provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:
Ac-Nle-c[Asp-Pro-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 217);
Ac-Nle-c[Asp-dHis-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 562);
Ac-Nle-c[Asp-Phe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 563);
Ac-Nle-c[Asp-Bip-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 565);
Ac-Nle-c[Asp-Gln-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 567);
Ac-Nle-c[Asp-Trp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 569);
Ac-Nle-c[Asp-Tyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 571 );
Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 222);
Ac-Nle-c[Cys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 535);
Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 538); Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 545);
Ac-Nle-c[Asp-His-p(Br)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 546);
Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 547);
Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 548);
Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 552);
Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 553);
Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 555);
Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 551 );
Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 223);
Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 464);
Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 465);
Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 466);
Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 467);
Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 468);
Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 469);
Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 470);
Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 474);
Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 475);
Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 476);
Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 477);
Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 478);
Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 481 );
Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 482);
Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 483);
Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 484);
Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 485);
Ac-Nle-c[Cys-His-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 459);
Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 472);
Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 471 );
Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 463);
Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 462); Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 479);
Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 473);
Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 480);
Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 486);
Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 491 );
Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 218);
Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 442);
Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 449);
Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 455);
Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 447);
Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 438);
Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 450);
Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 435);
Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 439);
Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 441 );
Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 436);
Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 454);
Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 452);
Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 451 );
Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 456);
Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 437);
Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 440);
Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 448);
Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 457);
Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 453);
Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 458);
Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 443);
Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 363);
Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 365);
Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 370);
Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 621 ); Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 297);
Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 366);
Ac-Nle-c[Asp-Bip-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 368);
Ac-Nle-c[Asp-Trp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 372);
Ac-Nle-c[Asp-Tyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 374);
Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 639);
Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 638);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 295);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 597);
Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 628);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 591 );
Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 311 );
Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 313);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 291 );
Ac-dAla-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 299);
His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 306);
Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 312);
Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 314);
Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 315);
Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 643); dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 309);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 617);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 620);
Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 644);
Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 642);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 596);
Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 645);
Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 646);
Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 300);
Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 640);
Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 641 ); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 595);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 598);
Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 302);
Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 425);
Ac-Nle-c[Cys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 318);
Ac-Nle-c[Asp-Pro-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 215);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 509);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 510);
Ac-Nle-c[Asp-Phe-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 525);
Ac-Nle-c[Asp-Bip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 527);
Ac-Nle-c[Asp-Trp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 531 );
Ac-Nle-c[Asp-Tyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 533);
Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 520);
Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 522);
Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 523);
Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 518);
Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 503);
Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 505);
Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 502);
Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 519);
Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 506);
Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 501 );
Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 521 );
Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 504);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 512); Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 513); and Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 515).
42. The method or the use of any one of claims 1 -41 , wherein an N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an acyl group.
43. The method or the use of claim 42, wherein the acyl group is an acetyl group.
44. The method or the use of any one of claims 1 -41 , wherein an N-terminus of the non-naturally occurring melanocortin analog, if present, is not modified.
45. The method or the use of any one of claims 1 -44, wherein a C-terminus of the non-naturally occurring melanocortin analog is modified by an amide group.
46. The method or the use of any one of claims 1 -44, wherein a C-terminus of the non-naturally occurring melanocortin analog is not modified.
47. The method or the use of any one of claims 1 -46, wherein R4 is dNal(2’).
48. The method or the use of any one of claims 1 -47, wherein the non-naturally occurring melanocortin analog comprises a sequence cyclized.
49. The method or the use of any one of claims 1 -48, wherein R3 is Pro, Hyp, or His.
50. The method or the use of any one of claims 1 -49, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro (SEQ ID NO: 2);
Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 3); Ac-Nle-c[Asp-Hyp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 4); Ac-Nle-c[Asp-Pro-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 5); Ac-Nle-c[Asp-Phe-His-dNal(2')-Arg-Trp-Lys]-dLeu-dPro-NH2 (SEQ ID NO: 6); Ac-Nle-c[Asp-Phe-His-dNal(2')-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 7);
Ac-Nle-c[Asp-Hyp-dNal(2')-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 9); and Ac-Nle-c[Asp-Pro-His-dNal(2’)-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 10), wherein c represents cyclization through R1 or R2 and R7via a lactam bond.
51 . The method or the use of any one of claims 1 -48, wherein R9 is present.
52. The method or the use of any one of claims 1 -48 and 51 , wherein the sequence of any one of Formulae (l)-(ID) is: Ac-Nle-c[Asp-Phe-Phe-Pro-His-dNal(2')-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 1 1 ), wherein c represents cyclization through R1 and R9 via a lactam bond.
53. The method or the use of any one of claims 1 -48, wherein R9 is absent and X1-X3 are present.
54. The method or the use of any one of claims 1 -48 and 53, wherein the sequence of any one of Formulae (l)-(ID) is: Ac-Nle-Phe-Phe-c[Asp-Phe-His-dNal(2')-Arg-Trp-l_ys]- dVal-dPro-NH2 (SEQ ID NO: 12), wherein c represents cyclization through R1 and R8 via a lactam bond.
55. The method or the use of any one of claims 1 -48, wherein the non-naturally occurring melanocortin analog comprises a sequence cyclized between R2 and R7 via a lactam bond or a disulfide bond.
56. The method or the use of any one of claims 1 -48 and 55, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[dAsp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 38); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-dLys]-dVal-dPro-NH2 (SEQ ID NO: 39);
Ac-Nle-c[Cys-Pro-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 40); Ac-Nle-c[dCys-Pro-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 41 ); Ac-Nle-c[Cys-Pro-dNal(2’)-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 42); Ac-Nle-c[dCys-Pro-dNal(2’)-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 43);
Ac-Nle-c[Cys-Pro-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Nle-c[dCys-Pro-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 49); Ac-Nle-c[Pen-Pro-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 50); Ac-Nle-c[Pen-Pro-dNal(2’)-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 51 ); Ac-Nle-c[Pen-Pro-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 52); Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 53); Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 54); Ac-Nle-c[Pen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 55);
Ac-Nle-c[Pen-dNal(2’)-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 59);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 64);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-dOrn]-dVal-dPro-NH2 (SEQ ID NO: 65);
Ac-Nle-c[Glu-Pro-dNal(2’)-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 66);
Ac-Nle-c[Glu-Pro-dNal(2’)-Arg-Trp-dOrn]-dVal-dPro-NH2 (SEQ ID NO: 67); and c[CO-cis-CH = CH-CO-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 197), wherein c represents cyclization through R1 or R2 and R7 via a lactam bond or a disulfide bond.
57. The method or the use of any one of claims 1 -48, wherein the non-naturally occurring melanocortin analog comprises a sequence cyclized through a lactam bond between Asp at R1 or R2 and Lys at R7.
58. The method or the use of any one of claims 1 -48 and 57, wherein R1 is selected from the group consisting of dArg, dMet, dlle, dLeu, dVal, dAla, Ala, Tie, dTle, dNIe, Nva, Gly, dPro, dCys, dPhe, dGIn, dAsn, transPro(guan), c/sPro(guan), dTyr, Tyr, and Dmt.
59. The method or the use of any one of claims 1 -48, 57, and 58, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-dArg-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 15); Ac-dMet-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 16);
Ac-dlle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 17);
Ac-dLeu-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 18);
Ac-dVal-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 19);
Ac-dAla-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 20);
Ac-Ala-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 21 );
Ac-Tle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 22); Ac-dTle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 23); Ac-dNle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 24); Ac-Nva-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 25); Ac-Gly-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 26);
Ac-dPro-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 27); Ac-dCys-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 28); Ac-dPhe-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 29); Ac-dTyr-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 30);
Ac-dGln-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 31 ); Ac-dAsn-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 32); Ac-f/'a/?sPro(guan)-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 33); Ac-c/sPro(guan)-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 34); dTyr-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 35);
Tyr-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 36); and Dmt-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 37), wherein c represents cyclization through R2 and R7 via a lactam bond.
60. The method or the use of any one of claims 1 -48 and 57, wherein R3 is absent or selected from the group consisting of Ala, dAla, dMet, Gly, Leu, He, Vai, dLeu, d He, dVal, Trp, transPro(guan), c/sPro(guan), £-Ala, Mamb, Acpc, Aba, Aia, Aic, Cpe, Che, Oic, Tic, and Glu.
61. The method or the use of any one of claims 1 -48, 57, and 60, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 68); Ac-Nle-c[Asp-Ala-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 69); Ac-Nle-c[Asp-dAla-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 71 );
Ac-Nle-c[Asp-dMet-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Nle-c[Asp-Pro-Gly-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 73); Ac-Nle-c[Asp-Gly-Gly-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 74);
Ac-Nle-c[Asp-Gly-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 75); Ac-Nle-c[Asp-Leu-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 76);
Ac-Nle-c[Asp-lle-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 77);
Ac-Nle-c[Asp-Val-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 78);
Ac-Nle-c[Asp-dl_eu-dNal(2')-Arg-Trp-l_ys]-dVal-dPro-NH2 (SEQ ID NO: 79);
Ac-Nle-c[Asp-dlle-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 80);
Ac-Nle-c[Asp-dVal-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 81 );
Ac-Nle-c[Asp-Trp-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 82);
Ac-Nle-c[Asp-fransPro(guan)-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 84);
Ac-Nle-c[Asp-c/sPro(guan)-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 85), Ac-Nle-c[Asp-[3-Ala-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 199); Ac-Nle-c[Asp-Mamb-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 200);
Ac-Nle-c[Asp-Acpc-dNal(2') Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 201 );
Ac-Nle-c[Asp-Aba-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 204);
Ac-Nle-c[Asp-Aia-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 205);
Ac-Nle-c[Asp-Aic-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 239);
Ac-Nle-c[Asp-Cpe-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 240);
Ac-Nle-c[Asp-Che-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 241 );
Ac-Nle-c[Asp-Oic-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 242);
Ac-Nle-c[Asp-Tic-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 244); and Ac-Nle-c[Asp-Glu-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 255), wherein c represents cyclization through R1 or R2 and R7 via a lactam bond.
62. The method or the use of any one of claims 1 -48 and 57, wherein R5 is absent or selected from the group consisting of Lys, Orn, His, Ala, transP ro (guan), c/sPro(guan), and Glu.
63. The method or the use of any one of claims 1 -48, 57, and 62, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-dNal(2’)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 86);
Ac-Nle-c[Asp-Pro-dNal(2’)-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 87);
Ac-Nle-c[Asp-Pro-dNal(2’)-Orn-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 90); Ac-Nle-c[Asp-Pro-dNal(2’)-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 92);
Ac-Nle-c[Asp-Pro-dNal(2’)-Ala-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 93);
Ac-Nle-c[Asp-Pro-dNal(2’)-Glu-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 96);
Ac-Nle-c[Asp-His-dNal(2’)-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 247);
Ac-Nle-c[Asp-His-dNal(2’)-c/sPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 248);
Ac-Nle-c[Asp-Pro-dNal(2’)-f/'a/?sPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 250); and Ac-Nle-c[Asp-Pro-dNal(2’)-c/sPro(guan)Pro-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 251 ), wherein c represents cyclization through R2 and R7 via a lactam bond.
64. The method or the use of any one of claims 1 -48 and 57, wherein R6 is selected from the group consisting of Nal( 1 ’), dNal(1 ’), Aia, Phe, dPhe, Tyr, dTyr, dNal(2’), dTrp, Aba, and Ata.
65. The method or the use of any one of claims 1 -48, 57, and 64, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Nal(1 ’)-Lys]-dVal-dPro-NH2 (SEQ ID NO: 102);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Aia-Lys]-dVal-dPro-NH2 (SEQ ID NO: 103);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Phe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 104);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Tyr-Lys]-dVal-dPro-NH2 (SEQ ID NO: 105);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dNal(1 ’)-Lys]-dVal-dPro-NH2 (SEQ ID NO: 108);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dPhe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 109);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dNal(2’]-Lys]-dVal-dPro-NH2 (SEQ ID NO: 1 10);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dTyr-Lys]-dVal-dPro-NH2 (SEQ ID NO: 1 11 );
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dTrp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 196);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Aba-Lys]-dVal-dPro-NH2 (SEQ ID NO: 253); and Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Ata-Lys]-dVal-dPro-NH2 (SEQ ID NO: 254), wherein c represents cyclization through R2 and R7 via a lactam bond.
66. The method or the use of any one of claims 1 -48 and 57, wherein: (i) Y1 is selected from dPro, Vai, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, Lys, dLys, Trp, and dTle and Y2 is absent or selected from dVal, Vai, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, and dTle; or
(ii) Y1 is dVal, Y2 is dPro, and the C-terminus of the non-naturally occurring melanocortin analog is not modified.
67. The method or the use of any one of claims 1 -48, 57, and 66, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Val-Pro-NH2 (SEQ ID NO: 115);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 116);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 117);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-Hyp-NH2 (SEQ ID NO: 118);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 119);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Val-Hyp-NH2 (SEQ ID NO: 120);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Val-dHyp-NH2 (SEQ ID NO: 121 );
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Hyp-dVal-NH2 (SEQ ID NO: 122);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dHyp-dVal-NH2 (SEQ ID NO: 123);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Hyp-Val-NH2 (SEQ ID NO: 124);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dHyp-Val-NH2 (SEQ ID NO: 125);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dVal-NH2 (SEQ ID NO: 126);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-dPro-NH2 (SEQ ID NO: 127);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-NH2 (SEQ ID NO: 128);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-NH2 (SEQ ID NO: 129);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Val-NH2 (SEQ ID NO: 130);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Pro-NH2 (SEQ ID NO: 131 );
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Ala-NH2 (SEQ ID NO: 132);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAla-NH2 (SEQ ID NO: 133);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dHyp-NH2 (SEQ ID NO: 134);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Hyp-NH2 (SEQ ID NO: 135);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAla-dAla-NH2 (SEQ ID NO: 136);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Ala-Ala-NH2 (SEQ ID NO: 137); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-l_ys]-Gly-Gly-NH2 (SEQ ID NO: 138);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-Asp-NH2 (SEQ ID NO: 139);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-Arg-NH2 (SEQ ID NO: 140);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-Asn-NH2 (SEQ ID NO: 141 );
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dAsp-NH2 (SEQ ID NO: 142);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dArg-NH2 (SEQ ID NO: 143);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dAsn-NH2 (SEQ ID NO: 144);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Asp-dPro-NH2 (SEQ ID NO: 145);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-dPro-NH2 (SEQ ID NO: 146);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Asn-dPro-NH2 (SEQ ID NO: 147);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAsp-dPro-NH2 (SEQ ID NO: 148);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 149);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAsn-dPro-NH2 (SEQ ID NO: 150);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Asp-NH2 (SEQ ID NO: 151 );
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-NH2 (SEQ ID NO: 152);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Asn-NH2 (SEQ ID NO: 153);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAsp-NH2 (SEQ ID NO: 154);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dArg-NH2 (SEQ ID NO: 155);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAsn-NH2 (SEQ ID NO: 156);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-Pro-Val-NH2 (SEQ ID NO: 157);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-dPro-dVal-NH2 (SEQ ID NO: 158);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dLys-dPro-dVal-NH2 (SEQ ID NO: 159);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-dPro-NH2 (SEQ ID NO: 160);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dLys-dPro-NH2 (SEQ ID NO: 161 );
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-Val-Pro-NH2 (SEQ ID NO: 162);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-dVal-dPro-NH2 (SEQ ID NO: 163);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dLys-dVal-dPro-NH2 (SEQ ID NO: 164);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-Pro-Val-NH2 (SEQ ID NO: 165);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-dPro-dVal-NH2 (SEQ ID NO: 166);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dArg-dPro-dVal-NH2 (SEQ ID NO: 167);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-Val-Pro-NH2 (SEQ ID NO: 168); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-dVal-dPro-NH2 (SEQ ID NO: 169);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 170);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dVal-dPro-NH2 (SEQ ID NO: 171 );
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 172);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dVal-NH2 (SEQ ID NO: 173);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dTle-NH2 (SEQ ID NO: 174);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 175);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 176);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-dTle-NH2 (SEQ ID NO: 177);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 178);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Trp-NH2 (SEQ ID NO: 203); and Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dPro-dLys-dAsp-NH2 (SEQ ID NO: 263), wherein c represents cyclization through R2 and R7 via a lactam bond.
68. The method or the use of any one of claims 1 -48 and 57, wherein one or more of Y3-Y7 are present and are each independently dVal or dPro.
69. The method or the use of any one of claims 1 -48, 57, and 68, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 179);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 180);
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 181 );
Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 182); and Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dVal-dVal-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 183), wherein c represents cyclization through R2 and R7 via a lactam bond.
70. The method or the use of any one of claims 1 -48 and 57, wherein one or more of X1-X3 are present and are Nle.
71. The method or the use of any one of claims 1 -48, 57, and 70, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 184); Ac-Nle-Nle-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 185); and Ac-Nle-Nle-Nle-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 186), wherein c represents cyclization through R2 and R7 via a lactam bond.
72. The method or the use of any one of claims 1 -48, wherein the non-naturally occurring melanocortin analog comprises a sequence cyclized through a lactam bond between (i) Asp at R1 and Lys at R7, (ii) Asp at R2 and Lys at R8, or (ii) Asp at R1 and Lys at R8.
73. The method or the use of any one of claims 1 -48 and 72, wherein R2 is selected from Asp, Trp, Pro, and Glu, R3 is selected from Pro, Glu, and His, and R7 is selected from Lys, Pro, and Gly.
74. The method or the use of any one of claims 1 -48, 72, and 73, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 194); Ac-Nle-c[Asp-Trp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 195);
Ac-Nle-c[Asp-Pro-Glu-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 257); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 245); Ac-Nle-c[Asp-Glu-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 256); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 259);
Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys]-dPro-dPro-Lys-Asp-NH2 (SEQ ID NO: 260); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys]-dPro-dPro-dLys-dAsp-NH2 (SEQ ID NO: 261 ); Ac-Glu-c[Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys]-dPro-dPro-Lys-Asp-NH2 (SEQ ID NO: 262);
Ac-Nle-c[Asp-Glu-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 264); and Ac-Nle-c[Asp-Glu-His-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 265), wherein c represents cyclization through R1 or R2 and R7 or R8via a lactam bond.
75. The method or the use of any one of claims 1 -48, wherein one of R2 and R3 is Ala or dAla.
76. The method or the use of any one of claims 1 -48, 72, and 75, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-dAla-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 266); Ac-Arg-c[Asp-dAla-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 267);
Ac-Arg-c[Cys-dAla-His-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 269); Ac-dArg-c[Asp-dAla-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 270); Ac-Arg-c[Asp-dAla-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 271 ); Ac-dArg-c[Asp-dAla-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 272);
Ac-Nle-c[Asp-Ala-His-dNal(2’)-Arg-Trp-Lys]-d al-dPro-NH2 (SEQ ID NO: 273); Ac-Arg-c[Asp-Ala-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 274); Ac-dArg-c[Asp-Ala-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 275); Ac-Arg-c[Cys-dAla-His-dNal(2’)-Arg-Trp-Cys]-NH2 (SEQ ID NO: 282); and Ac-Arg-c[Asp-dAla-His-dNal(2’)-Arg-Trp-Lys]-NH2 (SEQ ID NO: 283), wherein c represents cyclization through R1 or R2 and R7 via a lactam bond or a disulfide bond.
77. The method or the use of any one of claims 1 -48, wherein the non-naturally occurring melanocortin analog comprises a sequence cyclized through a disulfide bond between dPen at R2 and dPen at R7 or R8.
78. The method or the use of any one of claims 1 -48 and 77, wherein R1 is selected from the group consisting of Nle, dLeu, dNIe, dArg, Arg, dPhe, dTyr, Ala, dHis, His, dLys, and Lys.
79. The method or the use of any one of claims 1 -48, 77, and 78, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-dLeu-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 327); Ac-dNle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 328); Ac-dArg-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 329);
Ac-Arg-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 330);
Ac-dPhe-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 331 );
Ac-dTyr-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 332);
Ac-Ala-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 333);
Ac-dHis-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 334);
Ac-His-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 335);
Ac-dLys-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 336);
Ac-Lys-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 337);
Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dArg-dVal-dPro-NH2 (SEQ ID NO: 344);
Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dLys-dVal-dPro-NH2 (SEQ ID NO: 345);
Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dArg-dPro-NH2 (SEQ ID NO: 346);
Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dLys-dPro-NH2 (SEQ ID NO: 347);
Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dHyp-NH2 (SEQ ID NO: 348);
Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dTle-dPro-NH2 (SEQ ID NO: 349); and Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-Gly-dPen]-dVal-dPro-NH2 (SEQ ID NO: 350), wherein c represents cyclization through R1 or R2 and R7 or R8 via a disulfide bond.
80. The method or the use of any one of claims 1 -47, wherein the non-naturally occurring melanocortin analog is linear.
81 . The method or the use of any one of claims 1 -47 and 80, wherein the sequence of any one of Formulae (l)-(ID) is:
Ac-Nle-Asp-Pro-dNal(2')-Arg-Trp-Lys-dVal-dPro-NH2 (SEQ ID NO: 13); or Ac-Nle-Pro-dNal(2’)-Arg-Trp-dVal-dPro-NH2 (SEQ ID NO: 14).
82. The method or the use of any one of claims 1 -46, wherein R4 is selected from the group consisting of dPhe, p(CI)dPhe p(l)dPhe, p(Br)dPhe, p(F)dPhe, or p(CFs)dPhe.
83. The method or the use of any one of claims 1 -46 and 82, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 215);
Ac-Nle-c[Asp-Pro-p(l)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 216);
Ac-Nle-c[Asp-Pro-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 217);
Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 219);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 220);
Ac-Nle-c[Asp-His-p(l)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 221 );
Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 222);
Ac-Nle-c[Asp-His-p(OF3)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 224);
Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Aia-Lys]-dVal-dPro-NH2 (SEQ ID NO: 236);
Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Aba-Lys]-dVal-dPro-NH2 (SEQ ID NO: 237);
Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Ata-Lys]-dVal-dPro-NH2 (SEQ ID NO: 238);
Ac-Nle-c[Asp-dBip-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 369);
Ac-Nle-c[Asp-Pro-dPhe-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 426);
Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2’)-Lys]-dVal-dPro-NH2 (SEQ ID NO: 430);
Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 431 );
Ac-Nle-c[Cys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 432);
Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 444);
Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Nal(2’)-Lys]-dVal-dPro-NH2 (SEQ ID NO: 445);
Ac-Nle-c[Asp-Phe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 487);
Ac-Nle-c[Asp-Bip-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 489);
Ac-Nle-c[Asp-Trp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 493);
Ac-Nle-c[Asp-Tyr-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 495);
Ac-Nle-c[Cys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 497);
Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 500);
Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 507);
Ac-Nle-c[Asp-His-p(CI)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 508);
Ac-Nle-c[Asp-His-p(OI)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 509);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Nal(2’)-Lys]-dVal-dPro-NH2 (SEQ ID NO: 510);
Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 514);
Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 516);
Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 517); Ac-Nle-c[Asp-dHis-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 524);
Ac-Nle-c[Asp-Phe-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 525);
Ac-Nle-c[Asp-dPhe-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 526);
Ac-Nle-c[Asp-Bip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 527);
Ac-Nle-c[Asp-Gln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 529);
Ac-Nle-c[Asp-Trp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 531 );
Ac-Nle-c[Asp-Tyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 533);
Ac-Nle-c[Asp-dTyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 534);
Ac-Nle-c[Cys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 535);
Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 538);
Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 539);
Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 540);
Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 541 );
Ac-dLys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 542);
Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 543);
Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 544);
Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 545);
Ac-Nle-c[Asp-His-p(Br)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 546);
Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 547);
Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Nal(2’)-Lys]-dVal-dPro-NH2 (SEQ ID NO: 548);
Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 549);
Ac-Nle-c[Asp-His-p(Br)dP e-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 550);
Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 551 );
Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 552);
Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 553);
Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 554);
Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 555);
Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 556);
Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 557);
Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 558);
Ac-dLys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 559); Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 560); Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 561 ); Ac-Nle-c[Asp-dHis-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 562); Ac-Nle-c[Asp-Phe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 563); Ac-Nle-c[Asp-dPhe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 564); Ac-Nle-c[Asp-Bip-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 565); Ac-Nle-c[Asp-dBip-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 566);
Ac-Nle-c[Asp-Gln-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 567); Ac-Nle-c[Asp-dGln-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 568); Ac-Nle-c[Asp-Trp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 569); Ac-Nle-c[Asp-dTrp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 570); Ac-Nle-c[Asp-Tyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 571 ); and Ac-Nle-c[Asp-dTyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 572), wherein c represents cyclization through R2 and R7 via a lactam bond or a disulfide bond.
84. The method or the use of any one of claims 1 -83, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-7, 9- 12, 13-23, 24-27, 28-30, 31 -43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102- 105, 108-111 , 1 15-122, 123-138, 139-157, 158-164, 165-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219-222, 224, 236-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, 344-350, 369, 426, 430-432, 444-445, 487, 489, 493, 495, 497, 500, 507-510, 514, 516-517, 524-527, 529, 531 , 533-535, and 538-572.
85. The method or the use of claim 84, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-7, 9-10, 12-23, 24-27, 28-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-111 , 115- 138, 139-157, 158-162, 164-172, 173-182, 183-186, 194-197, 199-201 , 203-206, 215-217, 219, 221 -222, 224, 236-242, 244-245, 247-248, 250-257, 259-267, 269-275, 282-283, 327- 337, 344-350, 509-510, 525-527, 531 , 533-535, 538, 545-549, 551 -553, 555, 562-569, 571 - 572.
86. The method or the use of claim 84, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-4, 13, 15-23, 24-32, 35-43, 48-55, 59, 64-69, 71 -76, 77-82, 86-87, 90, 92-93, 96, 102, 104-105, 108-111 , 1 15-138, 139-162, 164, 165-186, 195-197, 199-201 , 203, 215-217, 219, 221 -222, 224, 240- 242, 244, 255-256, 259-267, 269-275, 327-328, 331 , 344-350, 525-527, 531 , 533-535, 538, 545, 547-549, 551 -553, 555, 562-569, 571 -572.
87. The method or the use of claim 84, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-7, 9-10, 12-43, 48-55, 59, 64-69, 71 -76, 77-82, 84-87, 90, 92-93, 96, 102-105, 108-1 11 , 1 15-138, 139-162, 164, 165-186, 194-197, 199-201 , 203-206, 239-242, 244-245, 247-248, 250-251 , 253-257, 259-267, 269-275, 282-283, 327-337, 344-350.
88. The method or the use of claim 84, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 215-217, 219- 222, 224, 236-238, 497, 500, 507-510, 514, 516-517, 535, 538-561.
89. The method or the use of claim 84, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 220, 426, 430- 432, 444-445, 487, 489, 493, 495, 497, 500, 507-508, 514, 516-517, 524, 529, 539-544, 550, 554, 556-561 .
90. The method or the use of claim 89, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.
91. The method or the use of any one of claims 1 -90, wherein the non-naturally occurring melanocortin analog is present in a pharmaceutical composition.
92. The method or the use of claim 91 , wherein the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients and/or carriers.
93. The method or the use of claim 92, wherein the one or more pharmaceutically acceptable excipients and/or carriers of the pharmaceutical composition comprise water.
94. The method or the use of any one of claims 1 -93, wherein the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg/kg to about 20 mg/kg administered once a day for about 5 days to about 10 days; (ii) at a second dose of about 10 mg/kg to about 40 mg/kg administered once a day after administration of the first dose for about 5 days to about 10 days; (iii) at a third dose of about 5 mg/kg to about 30 mg/kg administered twice a day after administration of the second dose for at least about 5 days to about 10 days.
95. The method or the use of any one of claims 1 -93, wherein the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg/kg administered once a day for about 7 days; (ii) at a second dose of about 15 mg/kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 10 mg/kg administered twice a day after administration of the second dose for at least about 7 days.
96. The method or the use of any one of claims 1 -93, wherein the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 10 mg/kg administered once a day for about 7 days; (ii) at a second dose of about 20 mg/kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 15 mg/kg administered twice a day after administration of the second dose for at least about 7 days.
97. The method or the use of any one of claims 1 -93, wherein the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 15 mg/kg administered once a day for about 7 days; (ii) at a second dose of about 25 mg/kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 20 mg/kg administered twice a day after administration of the second dose for at least about 7 days.
98. The method or the use of any one of claims 1 -93, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 0.5 mg/kg to about 10 mg/kg per body weight of the subject once daily.
99. The method or the use of claim 98, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 1 mg/kg or 3 mg/kg per body weight of the subject once daily.
100. The method or the use of any one of claims 1 -93, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily.
101. The method or the use of any one of claims 1 -93, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily.
102. The method or the use of any one of claims 1 -101 , wherein the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.
103. The method or the use of any one of claims 1 -102, wherein the non-naturally occurring melanocortin analog crosses a blood-brain-barrier of a subject.
104. The method or the use of any one of claims 101 or 102, wherein the non- naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3 and is administered at least once daily in an amount ranging from 0.001 mg/kg to 25 mg/kg per body weight of the subject.
105. The method or the use of claim 104, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NOs: 3 and is administered at least once daily in an amount ranging from 0.5 mg/kg to 10 mg/kg per body weight of the subject.
106. The method or the use of any one of claims 1 -105, wherein the non-naturally occurring melanocortin analog is administered to a subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.
107. The method or the use of any one of claims 1 -105, wherein the non-naturally occurring melanocortin analog is administered to a subject for 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.
108. The method or the use of any one of claims 1 -107, wherein the method or the use further comprises maintaining muscle mass or promoting muscle mass gain in the subject.
PCT/US2024/059247 2023-12-07 2024-12-09 Non-naturally occurring melanocortin analogs and associated methods for modulating weight gain Pending WO2025123055A1 (en)

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