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WO2025245292A1 - Non-naturally occurring melanocortin receptor agonists and uses thereof for modulating weight loss - Google Patents

Non-naturally occurring melanocortin receptor agonists and uses thereof for modulating weight loss

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Publication number
WO2025245292A1
WO2025245292A1 PCT/US2025/030464 US2025030464W WO2025245292A1 WO 2025245292 A1 WO2025245292 A1 WO 2025245292A1 US 2025030464 W US2025030464 W US 2025030464W WO 2025245292 A1 WO2025245292 A1 WO 2025245292A1
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WO
WIPO (PCT)
Prior art keywords
arg
dphe
seq
trp
dpro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
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PCT/US2025/030464
Other languages
French (fr)
Inventor
Russell Potterfield
Daniel Marks
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Endevica Bio Inc
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Endevica Bio Inc
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Publication of WO2025245292A1 publication Critical patent/WO2025245292A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • 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
    • 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
    • A61K38/34—Melanocyte stimulating hormone [MSH], e.g. alpha- or beta-melanotropin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring

Definitions

  • the present technology comprises methods of reducing body weight and/or fat mass in a subject in need thereof, the methods comprising orally administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I): X 1 -R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -R 8 -R 9 -Y 1 -Y 2 -Y 3 -Y 4 (I), wherein: X 1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R 1 is selected from the group consisting of Nle, Arg, dArg, aspartic acid (Asp), alanine (Ala), lysine (
  • the present technology comprises a method of reducing body weight and/or fat mass in an obese subject, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • the present technology comprises a method of treating, preventing, or reducing hyperplasia in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • the present technology comprises a method of treating, preventing, or reducing hypothalamic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • the present technology comprises a method of treating, preventing, or reducing a proopiomelanocortin (POMC) deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • POMC proopiomelanocortin
  • the present technology comprises a method of treating, preventing, or reducing a leptin deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • the present technology comprises a method of treating, preventing, or reducing a syndromic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • the present technology comprises a method of treating, preventing, or reducing hyperinsulinism in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • the present technology comprises a method of treating, preventing, or reducing a cardiovascular disease in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • the present technology comprises a method of treating, preventing, or reducing osteoarthritis in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • the present technology comprises a method of treating, preventing, or reducing body weight gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • the present technology comprises a method of maintaining body weight after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • the present technology comprises a method of treating, preventing, or reducing fat mass gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • the present technology comprises a method of treating, preventing, or reducing glucose intolerance and/or diabetes mellitus in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • a non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • FIGS. 1 illustrates 24-hour plasma concentrations of non-naturally occurring melanocortin analogs of the present technology following oral administration of Compound Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (C2) (SEQ ID NO: 14) to Cynomolgus Monkeys at 30.0 mg/kg. [0023] FIGS.
  • 2A-2F illustrates 24-hour plasma concentrations of non-naturally occurring melanocortin analogs of the present technology following PO administration of Compound E (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (O10) (SEQ ID NO: 43)) to Cynomolgus Monkeys at 3 mg/kg, 10.0 mg/kg, 30.0 mg/kg, or 60 mg/kg. [0024] FIGS.
  • FIGS. 4A-4G illustrate plasma and CSF concentrations of non-naturally occurring melanocortin analogs of the present technology.
  • FIGS. 4A-4G illustrate 24-hour plasma and CSF concentrations of non-naturally occurring melanocortin analogs following IP administration of Compound E (SEQ ID NO: 43) to Rats at 1.0 mg/kg, 3.0 mg/kg, and 10.0 mg/kg.
  • FIGS. 5A-5C illustrates 24-hour plasma and CSF concentrations of non- naturally occurring melanocortin analogs of the present technology following PO administration of Compound E (SEQ ID NO: 43) to Rats at 10.0 mg/kg and 30.0 mg/kg.
  • FIGS.6A and 6B show preliminary weight loss and daily food intake results in animals administered 3 mg/kg of O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro- NH2) (SEQ ID NO: 43).
  • FIG.7A shows net weight of food intake among individual monkeys.
  • FIG.7B shows net weight of food intake for each group average.
  • FIG.7C shows cumulative food intake among individual monkeys.
  • FIG.7D shows cumulative food intake for each group average.
  • FIGS. 8A-8H show food intake (g) in the same monkeys as FIGS. 7A-7D administered 1 mg/kg or 3 mg/kg of O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2) (SEQ ID NO: 43) on day 8 (D8).
  • FIG.8A shows net weight of food intake among individual monkeys at day 8 (D8).
  • FIG.8B shows net weight of food intake for each group average of monkeys administered the same compound at D8.
  • FIG. 8C shows cumulative food intake among individual monkeys of FIG. 8A at D8.
  • FIG. 8D shows cumulative food intake for each group average of monkeys of FIG.8C administered the same compound at D8.
  • FIGS. 9A and 9B show food intake patterns in diet-induced obese monkeys administered saline, compared to the same monkeys administered 1mg/kg or 3 mg/kg of O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2) (SEQ ID NO: 43) in FIGS. 8A-8H.
  • FIGS. 10A-10C show changes in daily caloric intake (FIG. 10A), cumulative caloric intake (FIG.10B), percent change in caloric consumption from baseline through day -7- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 6 (FIG.10C) for diet-induced obese monkeys orally administered 10 mg/kg of or O10 (Ac- Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2) (SEQ ID NO: 43) (QD: once daily). [0032] FIGS.
  • 11A-11P show changes in cumulative caloric intake, percent change in caloric consumption from baseline, food intake of a normal diet, food intake of a high fat diet, food intake in calories, and food preference for diet-induced obese monkeys orally administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2) (SEQ ID NO: 43), saline, or semaglutide (sema) (PO: oral administration; SC: subcutaneous administration; QD: once daily; BID: twice daily; BIW: twice weekly). [0033] FIG.
  • FIG. 11R shows an average percent change in caloric consumption from baseline in moneys orally administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]- dVal-dPro-NH2) (SEQ ID NO: 43) at a starting dose of 10 mg/kg and increased to 20 mg/kg and 30 mg/kg.
  • FIGS.12A-12K show changes in body weight for diet included obese monkeys administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2) (SEQ ID NO: 43) orally and/or subcutaneously.
  • FIGS. 12A and 12B Shown are changes in daily body weight and percent change in body weight from baseline (FIGS. 12A and 12B) for the diet-induced obese monkeys of FIGS.11A-11P through day 8.
  • FIGS 12C shows percent change in body weight as a percentage of initial weight for the monkeys of FIGS. 12A and 12B through day 15 compared to those administered semaglutide (sema) alone.
  • FIG. 12D shows body weight change as a percentage of initial weight in diet induced obese monkeys orally administered O10 at increasing dosages or administered semaglutide.
  • FIG. 12E shows body weight change in the monkeys of FIG.12D.
  • FIG.12F shows body weight change as a percentage of initial weight in diet included obese monkeys administered O10 at changing doses and -8- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 administration frequencies.
  • FIG.12G shows body weight changes as a percentage of initial in monkeys orally administered O10 (PO) with dose changes or semaglutide.
  • FIG. 12H shows body weight change after removal of O10 administration for the monkeys of FIG. 12G.
  • FIG.12I shows percent change in body weight as a percentage of initial weight for diet induced obese monkeys orally administered O10 followed by subcutaneous administration.
  • FIG. 12J shows body weight percent change after removal of O10 treatment in monkeys.
  • FIG.12K shows body weight percent change at an oral O10 dosing regimen in accordance with the embodiments of the present technology.
  • PO oral administration
  • SC subcutaneous administration
  • QD once daily
  • BID twice daily
  • BIW twice weekly
  • 12L shows changes in body weight as a percentage of day 1 in rats administered saline, a melanocortin 4 receptor (MC4R) selective agonist (A07D (Ac-Nle- c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2) (SEQ ID NO: 48), O7 (Ac-Nle-c[Glu-Pro- p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2) (SEQ ID NO: 106), or O11 (Ac-Nle-c[Glu-Pro-dPhe- Arg-Trp-Orn]-dVal-dPro-NH2) (SEQ ID NO: 62), or an equal dose of a melanocortin 3 receptor (MC3R)/MC4R coagonist ((O10)(Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal
  • FIG. 12M shows an average percent change in normalized body weight from baseline in moneys orally administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]- dVal-dPro-NH2) at a starting dose of 10 mg/kg and increased to 20 mg/kg and 30 mg/kg.
  • FIGS.13A-13N show changes in body composition for the diet-induced obese monkeys of FIGS.10A-10C.
  • FIGS. 15A-15C show measurements of systolic blood pressure (FIG. 15A), diastolic blood pressure (FIG. 15B), and heart rate (FIG.
  • FIGS.16A-16D show measurements of diastolic blood pressure (DBP), systolic blood pressure (SBP), heart rate, and heart rate corrected QT interval (QTc) in rats administered setmelanotide at 0.5 mg/kg, 1.0 mg/kg, 3.0 mg/kg, or 6.0 mg/kg, relative to control rats administered saline.
  • FIGS.17A-17H show measurements of normalized heart rate (FIG.17A), QTc (FIG. 17B), systolic blood pressure (FIG. 17C), diastolic blood pressure (FIG.
  • SC subcutaneously
  • N 3 to 5 animals per group.
  • FIG. 18 shows results of O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2) (SEQ ID NO: 43) screened for binding against a panel of 87 targets at 10 ⁇ M.
  • X- axis represents the percent inhibition of control at 10 ⁇ M.
  • M1R melanocortin 1 receptor
  • MC4R melanocortin 4 receptor
  • FIG. 19 shows exemplary adipose tissue staining in diet-induced obese monkeys orally administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro- NH2) (SEQ ID NO: 43) at 10 mg/kg.
  • FIG. 20 shows plasma concentration of O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg- Trp-Orn]-dVal-dPro-NH2) (SEQ ID NO: 43) in monkeys orally (PO) administered 3mg/kg, 10 mg/kg, 30 mg/kg, or 60 mg/kg O10.
  • FIG.21 shows results of an in vitro pharmacology assessment of O10. Results showing an inhibition or stimulation higher than 50% are considered to represent significant effects of O10.
  • FIGS. 22A and 22B show the results of an in vitro binding assay for O10 on selected targets (SEQ ID NO: 43). Results showing an inhibition or stimulation higher than 50% are considered to represent significant effects of O10.
  • FIG. 23 shows effects of O10 on enzyme inhibition (SEQ ID NO: 43). Results are shown as percent inhibition of control values.
  • the present technology comprises methods of treating, preventing, or reducing one or more symptoms or conditions associated with metabolic dysfunction in a subject in need thereof using a non-naturally occurring melanocortin analog.
  • the non-naturally occurring melanocortin analog is administered orally.
  • the method comprises suppressing appetite in a subject in need thereof using a non-naturally occurring melanocortin analog in accordance with the present technology.
  • the method comprises promoting fat loss in a subject in need thereof using a non-naturally occurring melanocortin analog in accordance with the present technology. In some embodiments, the method comprises reducing body weight and/or fat mass in a subject in need thereof using a non-naturally occurring melanocortin analog, or a pharmaceutical composition thereof, of the present technology.
  • steps or functions recited in any description, method, system, or process may be executed in any -11- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 order and are not limited to the order presented. Moreover, any of the steps or functions thereof may be outsourced to or performed by one or more third parties. Definitions [0052] 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.
  • 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.
  • an element means one element or more than one element.
  • 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.
  • administering include delivery of non-naturally occurring melanocortin analogs (also referred to herein as peptides and synthetic 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.
  • melanocortin analogs also referred to herein as peptides and synthetic peptides
  • 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.
  • active compound 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.
  • -12- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 This can 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 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 pharmaceutical 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.
  • a carrier for use in a composition will depend upon the intended route of administration for the pharmaceutical composition.
  • the preparation of pharmaceutically acceptable carriers and formulations containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 21st Edition, ed. University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia Pa., 2005, which is incorporated herein by reference in its entirety).
  • 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 immuno
  • excipient of the 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. -13- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 [0059]
  • pharmaceutically acceptable salt refers to derivatives of the disclosed synthetic peptides wherein the parent peptide is modified by making acid or base salts thereof.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non- toxic, inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, trifluoroacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric
  • organic acids such as acetic, trifluoroacetic, propionic, succinic
  • salts can be prepared in situ during the final isolation and purification of the synthetic peptide of the present technology, or by separately reacting a purified peptide of the present technology in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed.
  • the terms “treat,” “treatment,” and “treating” may also refer to the reduction or inhibition of the progression and/or duration of a disease (e.g., metabolic dysfunction), the reduction or amelioration of the severity of the disease, 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 or reduction (e.g.
  • circulating glucose levels (2) inhibiting or reducing rate of fat mass gain, (3) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with a pathology related to or caused in part by metabolic dysfunction, (4) an increase in disease-free, relapse-free, progression-free, and/or overall survival, duration, or rate, (5) a decrease in hospitalization rate, (6) a decrease in hospitalization length, (7) an increase in the oxidation of lipids or carbohydrates by at least by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or at least 80% relative to the initial oxidation rate, (8) a stabilization or reduction -14- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 (e.g.
  • treat 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 shortening the length or frequency of the disease.
  • prevent means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.
  • 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 being treated. The result can be a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • An appropriate “effective amount” can differ from one individual to another.
  • An appropriate “effective amount” in any individual case can be determined using techniques, such as a dose escalation study.
  • the term “after administration” refers to any duration of time after the non- naturally occurring melanocortin analog or pharmaceutical composition thereof, and/or the weight loss agent has been administered to a subject.
  • After administration can 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.
  • “after administration” refers to completion of dosing regimen that includes one -15- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 or more doses.
  • the term “prior to administration” refers to any duration of time before the non-naturally occurring melanocortin analog or pharmaceutical composition thereof, and/or the weight loss agent has been administered to a subject.
  • durations of time encompassed by “after administration” or “prior to administration” can include seconds, minutes, hours, days, weeks, months, and years.
  • subject and patient refer to anyone being evaluated for disease 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 metabolic dysfunction.
  • 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
  • a placebo 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 melan
  • Melanocortin analogs include non-naturally occurring melanocortin peptides and truncated and/or modified versions of melanocortin full-length protein or peptides.
  • the full-length pro-opiomelanocortin 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 may be activating (e.g., agonist activity).
  • the non-naturally occurring melanocortin analogs include small molecule analogs of melanocortin or portions thereof -16- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 comprised of organic compounds, inorganic compounds, or combinations of peptide and small molecule—i.e., peptide mimetics, or various combinations thereof.
  • “Melanocortin peptides” can be structurally similar and/or functionally similar to biological melanocortin proteins in their ability to bind melanocortin receptors.
  • the non-naturally occurring 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.
  • His-Phe-Arg-Trp (SEQ ID NO: 1) and their analogs are the pharmacophore of melanocortin for the regulated physiological effect.
  • non-naturally occurring melanocortin pharmacophore analogs can 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” or “melanocortin agonist” is a naturally occurring substance or manufactured drug substance (e.g., non-naturally occurring) or composition that can interact with a melanocortin receptor and initiate a pharmacological response characteristic of the melanocortin receptor.
  • an “opioid receptor agonist” refers to a ligand that, upon binding an opioid receptor, increases the receptor's signaling activity.
  • a “delta opioid receptor agonist” refers to any compound or peptide that activates the delta opioid receptor (DOR) upon binding to the active site of the DOR.
  • a “mu opioid receptor agonist” refers to any compound or peptide that activates the mu opioid receptor (MOR) upon binding to the active site of the MOR.
  • the terms “bind,” “binding,” “complex,” and “complexing,” refer to all types of physical and chemical binding, reactions, complexing, attraction, chelating and the like.
  • the “peptides” of the present technology can 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 -17- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 methods resulting from a combination of methods (a) through (d) listed above, or (f) produced by any other means for producing peptides.
  • the term “peptide” as used herein includes any structure comprised of two or more amino acids, including chemical modifications and derivatives of amino acids.
  • 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.
  • peptide includes peptides containing a variable number of amino acid residues, optionally with non- amino 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.
  • amino acids 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.
  • R represents a side chain group.
  • the various ⁇ -amino acids differ in the side-chain moiety that is attached to the ⁇ -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.
  • amino acid also includes -18- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 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. 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.
  • 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.
  • the side chain moiety of any amino acid disclosed herein 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 or “lPhe” is L-phenylalanine
  • D-Phe or “dPhe” is D-phenylalanine
  • dVal is D-valine
  • dPro is D-proline
  • D-/L-Phe or “d/lPhe” is D-phenylalanine, L-phenylalanine, or combinations thereof
  • Phe is also D- phenylalanine, L-phenylalanine, or combinations thereof, and so on.
  • An alpha ( ⁇ )-amino acid has the generic formula H2N—C ⁇ HR—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 ⁇ -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 ⁇ -carbon).
  • Other types of amino acids exist when the amino group is attached to a different carbon atom.
  • beta ( ⁇ )-amino acids the carbon atom to which the amino group is attached is separated from the carboxylate group by one carbon atom, C ⁇ .
  • ⁇ -amino acids When ⁇ -amino acids are incorporated into peptides, two main types of ⁇ - 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 ⁇ 2 amino acids. Further, ⁇ -amino acids may adopt L- or D- stereochemistry. Unless otherwise indicated, all ⁇ -amino acid abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or combinations thereof.
  • Gamma ( ⁇ )-amino acids are amino acids where the carbon atom to which the amino group attaches is separated from the carboxylate moiety by two carbon atoms.
  • For additional modified and unusual amino acids see ⁇ 2422 of the MPEP, particularly Table 4 at 2400-24. Additionally, “Ac” indicates N-acetyl; “cyclo” and “c” refers to a cyclic structure; and “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 amidated C-terminus, i.e., —CO—NH2.
  • Nle is norleucine
  • Nal(2’) is 2′-naphthylalanine
  • Nal(1') is 1′-naphthylalanine
  • Tle is tert-leucine
  • Orn is ornithine
  • cisPro(guan) is cis-4-guanidyl-proline
  • transPro(guan) is trans-4-guanidyl-proline
  • p(Cl)dPhe is para-chloro-phenylalanine
  • p(F)dPhe is para-fluoro-phenylalanine.
  • acyl includes a group RCO—, where R is an organic group.
  • R is an organic group.
  • An example is the acetyl group CH3CO—, referred to herein as “Ac.”
  • 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.
  • 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 melanocortin peptide by physiological enzymes and other factors, in such a manner or to a degree that side effects appear.
  • a 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 melanocortin analog that lacks a C-terminal extension.
  • a “composition” refers to a mixture of the active ingredient with other chemical components.
  • 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 (MC1R), the melanocortin 2 receptor (MC2R), and the melanocortin 5 receptor (MC5R).
  • M1R melanocortin 1 receptor
  • M2R melanocortin 2 receptor
  • M5R melanocortin 5 receptor
  • Some of the non-naturally occurring melanocortin analogs may bind the MC4R with greater affinity than the MC3R.
  • some 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 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%.
  • the non-naturally occurring melanocortin analogs of the present technology may be partial agonists.
  • a partial agonist may comprise a non-naturally occurring melanocortin analog having a maximum effect Emax agonist value of less than 85%.
  • the non-naturally occurring melanocortin analog may be classified as an agonist (e.g., a full agonist or a partial agonist).
  • the non-naturally occurring melanocortin analogs of the present technology may be one or more of (i) a full MC4R agonist (ii) a full MC3R agonist; and (iii) a partial MC3R agonist with no MC3R antagonist activity.
  • the non-naturally occurring melanocortin is a full MC4R agonist.
  • the non-naturally occurring melanocortin agonist is a full MC3R agonist and a full MC3R agonist.
  • the non-naturally occurring melanocortin analog is a full MC4R agonist and -22- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 partial MC3R agonist with no MC3R antagonist activity.
  • the non- naturally occurring melanocortin analogs of the present technology have an MC3R Emax agonist value of 50-84%.
  • the non-naturally occurring melanocortin analogs of the present technology have a MC3R:MC4R half maximal effective concentration (EC50) selectivity ratio of less than or equal to 49.
  • the non-naturally occurring melanocortin analogs of the present technology comprise non-naturally occurring MC4R agonists or non-naturally occurring MC3R agonists.
  • the non-naturally occurring melanocortin analogs in accordance with the present technology may have 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 MC4R and/or MC3R.
  • the non-naturally occurring melanocortin analogs comprise one or more of (i) blood brain barrier passage capabilities, (ii) one or more pharmaceutical- like pharmacokinetic measurements (e.g., a pharmacokinetic measurement of a weight loss agent pharmaceutical composition or an oral non-naturally occurring melanocortin analog pharmaceutical), (iii) degradation resistance; (iv) equipotency on MC3R and MC4R activity, or (v) oral potency.
  • the oral potency is greater than a subcutaneous administration potency for an equivalent dose.
  • the non-naturally occurring melanocortin analogs comprise two or more of (i)-(v).
  • the non-naturally occurring melanocortin analogs comprise each of (i)-(v). Accordingly, in some embodiments, the non-naturally occurring melanocortin analogs have one or more beta hairpin ( ⁇ -hairpin) and/or beta turn ( ⁇ -turn) structures.
  • ⁇ -hairpin beta hairpin
  • ⁇ -turn beta turn
  • amino acids that are structurally rigid such as, for example, Pro, dPro, transPro(guan), and cisPro(guan)
  • disulfide bridges may induce and/or stabilize beta-turn structures of the non-naturally occurring melanocortin analogs.
  • cyclization and D-amino acids may induce and/or stabilize beta-turns.
  • melanocortin analogs include a D-valine-D-proline (dVal- dPro) chain as their C-terminus, which may provide enhanced transport and resistance to degradation.
  • melanocortin analogs of the present technology may impart the non-naturally occurring melanocortin analogs of the present technology with specific binding properties. For example, inclusion of p(F)dPhe or dPhe at the R 4 position may result in enhanced binding and activation of the melanocortin 4 receptor. Accordingly, melanocortin analogs having p(F)dPhe or dPhe at the R 4 position may be full agonists on MC4R. Further, inclusion of His at the R 3 position may result in full agonism on MC3R as well.
  • Non-naturally occurring melanocortin analogs in accordance with the present technology may induce or increase body weight and/or fat mass loss in a subject in need thereof while reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject. Additionally, the non-naturally occurring melanocortin analogs of the present technology may avoid cardiac activation typically seen in conventional melanocortin peptide and small molecule agonists.
  • the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I): X 1 -R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -R 8 -R 9 -Y 1 -Y 2 -Y 3 -Y 4 (I), wherein: X 1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R 1 is selected from the group consisting of Nle, Arg, dArg, aspartic acid (Asp), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (d
  • 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); R 1 is selected from the group consisting of Nle, Arg, dArg, aspartic acid (Asp), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R 2 is selected from the group consisting of Asp, 2,3-diaminopropionic acid (Dap), 2,4- diaminobutyric acid (Dab), Lys, ornithine (Orn), D-cysteine (dCys), Ala, D-alanine (dAla), proline (Pro), glutamic acid (Glu), and phenylalanine (Phe); R
  • R 4 is dPhe or p(F)dPhe.
  • the sequence of Formula (I) is a sequence of Formula (IA): X 1 -R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -R 8 -Y 1 -Y 2 -Y 3 -Y 4 (IA), wherein: X 1 is absent or is selected from the group consisting of Nle, Arg, and dArg; R 1 is selected from the group consisting of Nle, Arg, dArg, Asp, Ala, Lys, dLys, His, and dHis; R 2 is selected from the group consisting of Asp, Ala, dAla, Dab, Dap, Lys, Orn, Pro, and Glu R 3 is absent or selected from the group consisting of His, dHis, Asn, Pro, and Gln; R 4 is dPhe or
  • the sequence of Formula (I) is a sequence of Formula (IA(i)): X 1 -R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -Y 1 -Y 2 -Y 3 -Y 4 (IA(i)), wherein: X 1 is absent or Nle; R 1 is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; R 2 is selected from the group consisting of Dab, Dap, Lys, Orn, Asp and Glu; R 3 is absent or selected from the group consisting of His, dHis, Pro, and Gln; R 4 is dPhe or p(F)dPhe
  • R 4 is p(F)dPhe. In further embodiments, R 3 is His.
  • the sequence of Formula (I) is a sequence of Formula (IB): X 1 -R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -Y 1 -Y 2 -Y 3 -Y 4 (IB), wherein: X 1 is absent or Nle; R 1 is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; R 2 is selected from the group consisting of Asp, Dap, Dab, Lys, Orn, and Glu; R 3 is His; R 4 is p(F)dPhe; R 5 is Arg; R 6 is Trp; R 7 is selected from the group consisting of Orn, Glu, Asp, and Lys; Y 1 is selected from the group consisting of dVal, dPro, and dTle; Y 2 is selected from the group consisting of dVal, dPro, and dT
  • R 4 is dPhe.
  • the non-naturally occurring melanocortin analog is cyclized between R2 and R 7 or R 8 .
  • the sequence of Formula (I) is a sequence of Formula (IC): X 1 -R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -R 8 -Y 1 -Y 2 -Y 3 (IC), wherein: -37- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 X 1 is absent or norleucine (Nle); R 1 is Nle or Asp; R 2 is selected from the group consisting of Asp, Dap, Dab, Lys, Orn, Glu, and Pro; R 3 is selected from the group consisting of His, dHis, Pro, and Gln; R 4 is dPhe; R 5 is
  • the non-naturally occurring melanocortin analog is cyclized between a lactam bond between R 2 and R 7 .
  • the sequence of Formula (I) is a sequence of Formula (ID): R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -Y 1 -Y 2 (ID), wherein: R 1 is selected from Nle, Arg, and dArg; -38- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 R 2 is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R 3 is absent or selected from the group consisting of Pro, Asn, and His; R 4 is selected from dPhe, p(F)dPhe, and p(Cl)dPhe; R 5 is Arg; R 6 is Trp; R 7 is selected from the group consisting of Glu
  • the sequence of Formula (I) is a sequence of Formula (IE): R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -Y 1 -Y 2 (IE), wherein: R 1 is Nle or Arg; R 2 is selected from the group consisting of Dab, Lys, Orn, and Glu; R 3 is Asn or His; R 4 is p(Cl)dPhe; R 5 is Arg; R 6 is Trp; -39- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 R 7 is selected from the group consisting of Glu, Asp, Lys, and Orn; Y 1 is absent or dVal; Y 2 is absent
  • the sequence of Formula (I) is a sequence of Formula (IF): R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -Y 1 -Y 2 (IF), wherein: R 1 is selected from Nle, Arg, and dArg; R 2 is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R 3 is absent, Asn, or His; R 4 is p(F)dPhe; R 5 is Arg; R 6 is Trp; R 7 is selected from the group consisting of Glu, Asp, Lys, and Orn; Y 1 is absent or dVal; Y 2 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between Glu or Asp at R 2 and Orn at R 7 ; a lactam bridge between Glu at R 2 and Lys at R
  • the sequence of Formula (IG) is a sequence of Formula (IG): R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -Y 1 -Y 2 (IG), wherein: R 1 is Nle or Arg; R 2 is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R 3 is selected from the group consisting of Pro, Asn, and His; R 4 is dPhe; R 5 is Arg; R 6 is Trp; R 7 is selected from the group consisting of Glu, Asp, Lys, and Orn; Y 1 is absent, dVal, or dArg; Y 2 is absent, dPro, or dVal; and the non-naturally occurring melanocortin analog is
  • the non-naturally occurring melanocortin analog of any one of Formulae (I)-(IG) has one or more beta hairpin ( ⁇ -hairpin) and/or beta turn ( ⁇ -turn) structures.
  • the presence of Pro, dPro, transPro(guan), and/or cisPro(guan) provides the ⁇ -hairpin and/or ⁇ -turn structures of the non-naturally occurring melanocortin analog.
  • the disulfide bond of the sequence according -41- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 to Formula (I), if present, provides the ⁇ -hairpin and/or ⁇ -turn structures of the non-naturally occurring melanocortin analog.
  • non-naturally occurring melanocortin analogs comprising a sequence of any one of Formulae (I)-(IG), 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.
  • the N-terminus of a non-naturally melanocortin analog comprising a sequence of any one of Formulae (I)-(IG) may be at X 1 or R 1 .
  • the C-terminus of a non-naturally occurring melanocortin analog comprising a sequence of any one of Formulae (I)-(IG) may be at any of R 7 , R 8 , R 9 , Y 1 , Y 2 , Y 3 , and Y 4 .
  • the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an acyl group.
  • the acyl group is acetyl ).
  • Y 1 Y 2 Y 3 Y 4 or a fragment thereof represents a C-terminus of the non-naturally occurring melanocortin analog.
  • Y 1 and Y 2 are present and Y 3 -Y 4 are absent.
  • Y 3 -Y 4 are absent, and Y 1 is D-valine and Y 2 is D-proline.
  • Y 3 -Y 4 are absent, and Y 1 is D-proline and Y 2 is D-valine.
  • Y 3 -Y 4 are absent, and Y 1 is D-tert-leucine and Y 2 is D-proline.
  • Y 1 -Y 3 are present and Y 4 is absent.
  • Y 4 is absent and Y 1 is D-proline, Y 2 is D-valine, and Y 3 is D-proline.
  • Y 4 is absent, and Y 1 is D-tert-leucine, Y 2 is D-tert-leucine, and Y 3 is D-valine.
  • Y 1 -Y 4 are present.
  • a non-naturally occurring melanocortin analog with an unmodified C-terminus may be represented by -OH.
  • Non-naturally occurring melanocortin analogs comprising a sequence of any one of Formulae (I)-(IG) are cyclized.
  • the non-naturally occurring melanocortin analog may be cyclized through a moiety selected from the group consisting of: a disulfide bond between R 2 and R 7 when R 2 is dCys, R 4 is p(Cl)dPhe, and R 7 is Cys; a lactam bridge between R 1 or R 2 and any one of R 7 -R 9 when R 1 or R 2 is Asp, R 4 is dPhe, or p(F)dPhe, and any one of R 7 -R 9 is Lys; a lactam bridge between R 2 and R 7 when R 1 is Dap, Dab, Orn, or Lys, and R 7 is Glu or Asp; and a lactam bridge between R 2 and R 7 when R 2 is Asp or Glu and R 7 is Orn.
  • R 3 is His. In further embodiments, R 3 is His and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between the Asp at R 2 and the Lys at R 7 . In still further embodiments, R 4 is p(F)dPhe or dPhe. [0121] In some embodiments, X 1 , Y 3 , and Y 4 are all absent. In further embodiments, R 1 is selected from Nle, Ala, Arg, dArg, Lys, dLys, His, and dHis and R 4 is p(F)dPhe.
  • Y 1 is dVal and Y 2 is dPro.
  • the sequence of any one of Formulae (I)-(IG) is selected from the group consisting of: Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 3); Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 4); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 14); -43- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Arg-
  • Y 1 is dTle
  • Y 2 is dPro.
  • the sequence of any one of Formulae (I)-(IG) is selected from the group consisting of: Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 7); Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 8); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 24); Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 27);
  • R 1 is Nle and R 4 is dPhe.
  • Y 1 is dVal or dPro
  • Y 2 is dPro or dVal.
  • the sequence of any one of Formulae (I)-(IG) is: Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 33); or Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 42), wherein c represents cyclization through R 2 and R 7 via a lactam bond.
  • X 1 , Y 3 and Y 4 are present.
  • R 1 is Nle
  • R 4 is p(F)dPhe.
  • sequence of any one of Formulae (I)-(IG) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 6); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 20); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 22); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 23); Ac-Nle-Nle-c[Asp-His-p
  • R 5 is an amino acid other than Arg.
  • R 5 is selected from His, transPro(guan), cisPro(guan).
  • the sequence of any one of Formulae (I)-(IG) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 21); Ac-Nle-c[Asp-His-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 46); and Ac-Nle-c[Asp-His-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 47), wherein c represents cyclization through R 2 and R 7 via a lactam bond.
  • R 6 when R 3 is His, R 4 is p(F)dPhe or dPhe, and the non- naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R 2 and Lys at R 7 , then R 6 is Trp. Alternatively, in some embodiments, R 6 is an amino acid other than Trp. In further embodiments, R 6 is dNal(2’).
  • the sequence of any one of Formulae (I)-(IG) is: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro- NH2 (SEQ ID NO: 5), wherein c represents cyclization through R 2 and R 7 via a lactam bond.
  • R 3 is His and the non-naturally occurring melanocortin analog is cyclized through a bond other than a lactam bond between Asp at R 2 and Lys at R 7 .
  • the non-naturally occurring melanocortin analog is cyclized through R 2 and R 7 via a bond other than a lactam bond between Asp at and Lys.
  • the non-naturally occurring melanocortin analog may be cyclized through R 2 and R 7 via a disulfide bond or a lactam formed between amino acids other than Asp and Lys.
  • the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp or Glu at R 2 and Orn at R 7 or Glu at R 2 and Lys at R 7 .
  • R 4 is selected from dPhe, p(Cl)dPhe, and p(F)dPhe.
  • the sequence of any one of Formulae (I)-(IG) is selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 11); Ac-Nle-c[Glu-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO
  • the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Dab, Dap, Orn, or Lys at R 2 and Asp or Glu at R 7 .
  • R 4 is selected from dPhe, p(Cl)dPhe, and p(F)dPhe.
  • the sequence of any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Nle-c[Dap-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 172); Ac—Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 173); Ac—Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 174); Ac—Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 172); Ac—Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Asp]-d
  • the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between dCys at R 2 and Cys at R 7 .
  • R 4 is p(Cl)dPhe.
  • the sequence of any one of Formulae (I)-(IG) is Ac-Nle-c[dCys-His-p(Cl)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 2), wherein c represents cyclization through R 2 and R 7 via a disulfide bond.
  • the non-naturally occurring melanocortin analog is cyclized through Asp at a residue position other than R 2 and/or Lys at a residue position other than R 7 .
  • the non-naturally occurring melanocortin analog may be cyclized through Asp at R 1 and Lys at R 7 or through Asp at R 2 and Lys at R 8 .
  • the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R 2 and Lys at R 8 .
  • the sequence of any one of Formulae (I)-(IG) is: Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Pro-Lys]- dVal-dPro-NH2 (SEQ ID NO: 35), wherein c represents cyclization through R 2 and R 8 via a lactam bond.
  • the non-naturally occurring melanocortin analog is cyclized between a lactam bond between Asp at R 1 and Lys at R 7 .
  • R 2 is Ala or dAla and R 4 is dPhe.
  • the sequence of any one of Formulae (I)-(IG) is selected from the group consisting of: Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 38); Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 40); and Ac-Nle-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 41), wherein c represents cyclization through R 1 and R 7 via a lactam bond.
  • R 2 is Pro
  • R 4 is Phe.
  • the sequence of any one of Formulae (I)-(IG) is: Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 13), wherein c represents cyclization through R 1 and R 7 via a lactam bond. -48- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 [0135]
  • R 3 is an amino acid other than His.
  • R 3 is Asn.
  • R 2 is Asp or Glu
  • R 7 is Lys or Orn.
  • Y 1 is dVal
  • Y 2 is dPro
  • Y 3 -Y 4 are absent.
  • sequence of any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Nle-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 184); Ac—Nle-c[Asp-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 185); Ac—Nle-c[Glu-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 186); Ac—Nle-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 187); Ac—Nle-c[Asp-Asn-dPhe-Arg-Trp-Orn]-dVal-d
  • Y 1 -Y 4 are absent.
  • the sequence of any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]—NH2 (SEQ ID NO: 213); Ac—Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Orn]—NH2 (SEQ ID NO: 214); -49- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 Ac—Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Lys]—NH2 (SEQ ID NO: 215); Ac—Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]—NH2 (SEQ ID NO: 216); Ac—
  • R 3 when R 3 is Asn, then R 2 is Dap, Dab, Lys, or Orn and R 7 is Asp or Glu.
  • R 1 is dArg or dVal
  • Y 2 is dVal or dPro and Y 3 -Y 4 are absent.
  • sequence of any one of Formulae (I)-(IG) is selected form the group consisting of: Ac—Nle-c[Dab-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 178); Ac—Nle-c[Lys-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 179); Ac—Nle-c[Lys-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 180); Ac—Nle-c[Orn-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 181); Ac—Nle-c[Orn-Asn-p(F)dPhe-Arg-Trp-Asp
  • Y 1 -Y 4 are absent.
  • the sequence of any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 207); Ac—Arg-c[Dap-Asn-p(F)dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 208); Ac—Arg-c[Dab-Asn-p(F)dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 209); Ac—Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 210); Ac—Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 207); Ac—Arg-c
  • R 3 is absent or selected from dHis, Gln and Pro.
  • R 2 is Asp or Lys
  • R 4 is dPhe or p(F)dPhe
  • R 5 is Arg
  • R 6 is Trp
  • R 7 is Lys or Glu.
  • sequence of any one of Formulae (I)- (IG) is selected from the group consisting of: Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 9); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 10); Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 32); Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 36); Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro
  • R 3 is an amino acid other than His and R 9 is absent. Alternatively, in some embodiments, R 9 is present.
  • the sequence of any one of Formulae (I)-(IG) is: Ac-Nle-c[Asp-Phe-Phe-Pro- His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 34), wherein c represents cyclization through R 1 and R 9 via a lactam bond.
  • the non-naturally occurring melanocortin analog comprises a sequence of Formula (I).
  • the non-naturally occurring -52- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-47 and 172- 263. [0142] 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: 3-10, 14-33, 35- 47, 172-187, 190-247, 254, 255, 257, 258, and 260-263.
  • the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(i)). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: SEQ ID NOs: 3- 10, 14-33, 36, 37, 42-47, 172-187, 190-247, 254, 255, 257, 258, and 260-263. [0144] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB).
  • the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 3-8, 14-31, 43, 44, 172-187, 207-216, 227-234, 242-247, 257, 258, and 263. [0145] 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: 10, 13, 33, 35- 37, 42, 45-47, 190-206, 217-226, 235-241, 254, 255, and 260-262.
  • the non-naturally occurring melanocortin analog comprises a sequence of Formula (ID). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 172-263. [0147] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IE). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 188, 189, 248- 250, 252, 253, 256, and 259. [0148] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IF).
  • the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 172-187, 207- 216, 227-234, 242-247, 257, 258, and 263. -53- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 [0149]
  • the non-naturally occurring melanocortin analog comprises a sequence of Formula (IG).
  • the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 190-206, 217- 226, 235-241, 254, 255, and 260-262.
  • Non-naturally occurring melanocortin analogs of any one of Formulae (I)-(IG) may be an agonist of the melanocortin 4 receptor and an agonist of the melanocortin 3 receptor.
  • non-naturally occurring melanocortin analogs of any one of Formulae (I)-(IG) are full agonists of the melanocortin 4 receptor and full agonists of the melanocortin 3 receptor.
  • non-naturally occurring melanocortin analogs of any one of Formulae (I)-(IG) are full agonists of the melanocortin 4 receptor and partial agonists of the melanocortin 3 receptor.
  • Non-Naturally Occurring Melanocortin Analog Synthesis 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.
  • the non-naturally occurring melanocortin analogs of the present technology may be synthesized by solid-phase synthesis and purified according to methods known in the art.
  • the process for synthesizing the non-naturally occurring melanocortin analogs 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.
  • Solid phase peptide synthesis methods are well known and practiced in the art. In such methods, the synthesis of peptides can 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).
  • 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.
  • a suitable protecting group including a urethane-type protecting group, such as benzyloxycarbonyl (Z) and substituted benzyloxycarbonyl, such as
  • Fmoc is useful for alpha amino protection.
  • 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.
  • 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 -55- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 between an Fmoc-Linker, such as p-[(R,S)- ⁇ -[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 such as p-[(R,S)- ⁇ -[1-(9H-fluor-en-9-yl)-methoxyformamido]-2,4- dimethyloxybenzyl]
  • 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. [0158] 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 non-naturally occurring melanocortin analogs are well known in the art.
  • the orthogonally protected side chain protecting groups may be removed using methods well known in the art for further derivatization of the peptide.
  • Reactive groups in a peptide may be selectively modified, either during solid phase synthesis or after removal from the resin.
  • 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.
  • the peptide may be cyclized prior to cleavage from the peptide resin.
  • 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 (DCM) or 1-methyl-2-pyrrolidone (NMP).
  • Suitable cyclic coupling reagents include, for example, 2-(1H-benzotriazol-1-yl)- 1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate (HBTU), benzotriazole-1-yl-oxy- -56- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole-1-yl-oxy- tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP), 2-(7-aza-1H-benzotriazol-1- yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TATU), 2-(2-
  • Coupling is convention initiated by use of a suitable base, such as N,N-diispropylethylamine (DIPEA), sym-collidine or N-methylmorpholine (NMM).
  • DIPEA N,N-diispropylethylamine
  • NMM N-methylmorpholine
  • the peptide can 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, can also be employed.
  • the peptide can 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 may be in the form of any salt.
  • 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 non-toxic 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
  • 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 non- naturally occurring melanocortin analogs of the present technology are prepared in a suitable solvent for the non-naturally occurring melanocortin analogs and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, citric, tartaric, maleic, succinic or methanesulfonic acid.
  • an acid such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, citric, tartaric, maleic, succinic or methanesulfonic acid.
  • suitable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts.
  • the present technology also provides methods of treating, preventing, reducing, or otherwise ameliorating one or more symptoms or conditions associated with metabolic dysfunction comprising administering a non-naturally occurring melanocortin analog to a subject in need thereof.
  • the methods of the present technology may promote fat loss, prevent muscle loss, decrease body weight, accelerate weight loss, decrease fat mass to lean mass ratio, improve body composition and/or BMI, reduce waist circumference, or any combination thereof.
  • the present technology comprises methods of reducing body weight and/or fat mass in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog of the present technology to the subject.
  • the present technology comprises methods of reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject.
  • the lean mass is lean muscle mass. -58- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00
  • the present technology comprises methods of treating, preventing, reducing, or otherwise ameliorating glucose intolerance and/or diabetes mellitus in the subject.
  • the present technology comprises a method of reducing body weight and/or fat mass in an obese subject (e.g., an obese subject without diabetes mellitus or an obese subject having diabetes mellitus), comprising administering a non- naturally occurring melanocortin analog to the subject.
  • the methods of the present technology (i) reduce a lipid droplets size (e.g., an average lipid droplet size); (ii) increase an adipose tissue mitochondrial number or adipose tissue mitochondrial concentration; (iii) increase an adipose tissue vascularization level; (iv) increase, maintain, or prevent reduction of a beige or brown adipocyte level; (v) increase a metabolic rate; (vi) increase a calorie burn level; and/or (vii) increase, maintain, or prevent reduction of an insulin sensitivity level, relative to a control.
  • a lipid droplets size e.g., an average lipid droplet size
  • the methods of the present technology comprise reducing a lipid droplet, or an average lipid droplet, size by about 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, or 95%, relative to a control.
  • the methods of the present technology comprise reducing a lipid droplet, or an average lipid droplet, size by at least 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, or 95%, relative to a control.
  • the methods of the present technology comprise reducing a lipid droplet, or an average lipid droplet, size by at least about 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, or 95%, relative to a control.
  • the methods of the present technology comprise one or more of (i) increasing an adipose tissue mitochondrial number; (ii) increasing an adipose tissue mitochondrial concentration; (iii) increasing an adipose tissue vascularization level; increasing a beige adipocyte level; (iv) increasing a brown adipocyte level; (v) increasing a metabolic rate; (vi) increasing a calorie burn level; or (vii) increasing an insulin sensitivity -59- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 level, by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% or more, relative to a control.
  • the methods of the present technology comprise one or more of (i) increasing an adipose tissue mitochondrial number; (ii) increasing an adipose tissue mitochondrial concentration; (iii) increasing an adipose tissue vascularization level; increasing a beige adipocyte level; (iv) increasing a brown adipocyte level; (v) increasing a metabolic rate; (vi) increasing a calorie burn level; or (vii) increasing an insulin sensitivity level, by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% or more, relative to a control.
  • the methods of the present technology comprise one or more of (i) increasing an adipose tissue mitochondrial number; (ii) increasing an adipose tissue mitochondrial concentration; (iii) increasing an adipose tissue vascularization level; increasing a beige adipocyte level; (iv) increasing a brown adipocyte level; (v) increasing a metabolic rate; (vi) increasing a calorie burn level; or (vii) increasing an insulin sensitivity level, by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% or more, relative to a control.
  • the present technology comprises a method of preventing, reducing, or otherwise ameliorating hyperplasia in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.
  • the present technology comprises a method of preventing, reducing, or otherwise ameliorating hypothalamic obesity (e.g., congenital hypothalamic damage and/or or damage from tumors or trauma) in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.
  • hypothalamic obesity e.g., congenital hypothalamic damage and/or or damage from tumors or trauma
  • the present technology comprises a method of preventing, reducing, or otherwise ameliorating a proopiomelanocortin (POMC) deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.
  • POMC proopiomelanocortin
  • the present technology comprises a method of preventing, reducing, or otherwise ameliorating a leptin deficiency in a subject in need -60- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.
  • the present technology comprises a method of preventing, reducing, or otherwise ameliorating a syndromic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.
  • syndromic obesity include Prader–Willi syndrome, Wilms tumor, Aniridia, Genitourinary, Range of Developmental Delays (WAGR) syndrome, Bardet- Biedl syndrome, Fragile X syndrome, Cohen syndrome, Proprotein Convertase Subtilisin/Kexin Type 1 (PCSK1) deficiency, Alstrom syndrome, MC4 haploinsufficiency, 17p11.2 deletion syndrome, and 2q37 deletion syndrome.
  • the present technology comprises a method of preventing, reducing, or otherwise ameliorating non-alcoholic steatohepatitis (NASH) (i.e., metabolic dysfunction-associated steatohepatitis (MASH)), in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.
  • NASH non-alcoholic steatohepatitis
  • MASH metabolic dysfunction-associated steatohepatitis
  • the present technology comprises a method of preventing, reducing, or otherwise ameliorating hyperinsulinism in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.
  • the present technology comprises a method of preventing, reducing, or otherwise ameliorating Type 2 Diabetes in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.
  • the present technology comprises a method of preventing, reducing, or otherwise ameliorating a cardiovascular disease (e.g., stroke and/or heart attack) in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.
  • a cardiovascular disease e.g., stroke and/or heart attack
  • the present technology comprises a method of preventing, reducing, or otherwise ameliorating osteoarthritis in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.
  • the present technology comprises a method of preventing, reducing, or otherwise ameliorating a cancer (e.g., decreasing a risk of cancer) -61- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.
  • the present technology comprises a method of preventing, reducing, or otherwise ameliorating erectile dysfunction in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.
  • the method further comprises reducing obesity-related inflammation in the subject.
  • method further comprises preserving or improving kidney function in the subject.
  • the present technology also provides methods of reducing obesity-related inflammation in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject.
  • the present technology further provides methods of preserving or improving kidney function in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject.
  • the method comprises orally administering a non-naturally occurring melanocortin analog comprising a sequence of any one of Formulae (I)- (IG) to the subject. Any of the sequences of Formulae (I)-(IG) listed above may be used in the methods of the present technology.
  • the method comprises orally administering a non-naturally occurring melanocortin analog comprising a sequence of any one of Formulae (I)-(IG)to the subject.
  • the present technology also provides methods of reducing body weight and/or fat mass in a subject in need thereof, comprising orally administering about 15 mg/kg to about 100 mg/kg of a non-naturally occurring melanocortin analog to the subject.
  • the non-naturally occurring melanocortin analog comprises a sequence of any one of Formulae (I)-(IG).
  • the present technology also provides methods of treating, preventing, or reducing glucose intolerance and/or diabetes mellitus in a subject in need thereof, comprising orally administering about 15 mg/kg to about 100 mg/kg of a non-naturally occurring melanocortin analog to the subject.
  • the non-naturally occurring melanocortin analog comprises a sequence of any one of Formulae (I)-(IG).
  • the present technology also provides methods of reducing obesity-related inflammation in a subject in need thereof, comprising orally administering about 15 mg/kg to about 100 mg/kg of a non-naturally occurring melanocortin analog to the subject.
  • the non-naturally occurring melanocortin analog comprises a sequence of any one of Formulae (I)-(IG).
  • the present technology also provides methods of preserving or improving kidney function in a subject in need thereof, comprising orally administering about 15 mg/kg to about 100 mg/kg of a non-naturally occurring melanocortin analog to the subject.
  • the non-naturally occurring melanocortin analog comprises a sequence of any one of Formulae (I)-(IG).
  • the present technology also provides methods of reducing body weight and/or fat mass in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog having a sequence selected from the group consisting of SEQ ID NOs: 11, 12, and 43-45 to the subject.
  • the method further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject.
  • the lean mass is lean muscle mass.
  • the method further comprises treating, preventing, or reducing glucose intolerance and/or diabetes mellitus in the subject.
  • the present technology also provides methods of treating, preventing, or reducing glucose intolerance and/or diabetes mellitus in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog having a sequence selected from the group consisting of SEQ ID NOs: 11, 12, and 43-45 to the subject. -63- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 [0201]
  • the method further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject.
  • the lean mass is lean muscle mass.
  • the method further comprises reducing body weight and/or fat mass in the subject. [0202] In some embodiments, the method further comprises reducing obesity-related inflammation in the subject. In some embodiments, the method further comprises preserving or improving kidney function in the subject. [0203] The present technology also provides methods of reducing obesity-related inflammation in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject. [0204] The present technology also provides methods of preserving or improving kidney function in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject.
  • the subject’s body weight is more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.
  • the subject’s fat mass is more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.
  • the subject exhibits about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, or about a 10% reduction in body weight about 10 days, about 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.
  • the subject exhibits at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, or at least a 10% reduction in body weight at least 10 days, at least 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.
  • the subject exhibits at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, or at least about a 10% reduction in body weight at least about 10 days, at least about 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.
  • the subject exhibits at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, at least a 10%, at least a 12.5%, at least a 15%, at least a 17.5%, at least a 20%, at least a 25%, or at least a 30% reduction in fat mass at least 10 days, at least 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.
  • the subject exhibits at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, at least about a 10%, at least about a 12.5%, at least about a 15%, at least about a 17.5%, at least about a 20%, at least about a 25%, or at least about a 30% reduction in fat mass at least about 10 days, at least about 20 days, or at least about 30 days after -65- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.
  • the subject exhibits no change, about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, or about a 10% reduction in lean mass loss about 10 days, about 20 days, or about 30 days after administration of a first dose of a non- naturally occurring melanocortin analog of the present technology.
  • the subject exhibits no change, at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, or at least a 10% reduction in lean mass loss at least 10 days, at least 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.
  • the subject exhibits no change, at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, or at least about a 10% reduction in lean mass loss at least about 10 days, at least about 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.
  • the subject exhibits no change, about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, or about a 10% increase in lean mass about 10 days, about 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.
  • the subject exhibits no change, at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, or at least a 10% increase in lean mass at least 10 days, at least 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.
  • the subject exhibits no change, at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, or at least about a 10% increase in lean mass at least about 10 days, at least about 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.
  • the subject exhibits about a 5%, about a 10%, about a 12.5%, about a 15%, about a 17.5%, about a 20%, about a 25%, about a 30%, about a 35%, about a 40%, about a 45%, about a 50%, about a 60%, or about a 70% reduction in food intake per day about 10 days, about 20 days, or about 30 days after administration of a first dose of the combination therapy.
  • the reduction in food intake occurs about 0.5 hours, about 1 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 10 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 4 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, or about 6 weeks after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.
  • Food intake may reflect cumulative food intake, net food intake, or both. Cumulative food intake may represent total food intake. Net food intake may represent the difference between total food intake and energy expenditure.
  • Cumulative and net food intake may represent a food intake measurement from start to end of dosing, from start to an intermediate time point of dosing (i.e., a time point after the start of dosing but prior to the end of dosing), from an intermediate time point to end of dosing, or between two or more intermediate time points.
  • the methods of the present technology alter a subject’s preference for food having high-fat content or low-fat content or is otherwise calorically dense or less calorically dense.
  • the methods of the present technology increase a subject’s preference for one or more of a lower-fat food or a less calorically dense food relative to the food preference of the subject at baseline or of a control.
  • the methods of the present technology decrease the subject’s preference for one or more of a higher-fat -67- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 food or a more calorically dense food relative to the food preference of the subject at baseline or of a control.
  • the blood glucose level of the subject is decreased following administration of the combination therapy. In some embodiments, the blood glucose level of the subject is decreased following administration of a first dose of the combination therapy.
  • the subject exhibits at least about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, about a 10%, about a 15%, about a 20%, about a 25%, or about a 30% reduction in a blood glucose level about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog, relative to a control.
  • the subject exhibits at least at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, or at least a 30% reduction in a blood glucose level at least 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog, relative to a control.
  • the subject exhibits at least about at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, at least about a 10%, at least about a 15%, at least about a 20%, at least about a 25%, or at least about a 30% reduction in a blood glucose level at least about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog, relative to a control.
  • the subject of the methods of the present technology may experience no change in or a reduction in one or more of an alkaline phosphatase level, a total protein level, an albumin level, a globulin level, a gamma-glutamyl transferase (GGT), a glucose level, a urea nitrogen level, a creatine level, a urea acid level, or a C-reactive -68- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 protein level in a biological sample from the subject.
  • GTT gamma-glutamyl transferase
  • Nonlimiting examples of biological samples include a circulatory fluid sample (e.g., blood, serum, lymphatic fluid), a urine sample, or a tissue sample.
  • the subject exhibits at least about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, about a 10%, about a 15%, about a 20%, about a 25%, or about a 30% reduction in an alkaline phosphatase level, a total protein level, an albumin level, a globulin level, a GGT, a glucose level, a urea nitrogen level, a creatine level, a urea acid level, or a C-reactive protein level in the biological sample about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or about 30 days after administration of a first dose of a non-naturally occurring
  • the subject exhibits at least at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, or at least a 30% reduction in an alkaline phosphatase level, a total protein level, an albumin level, a globulin level, a GGT, a glucose level, a urea nitrogen level, a creatine level, a urea acid level, or a C-reactive protein level in the biological sample at least 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology, relative to a control.
  • the subject exhibits at least about at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, at least about a 10%, at least about a 15%, at least about a 20%, at least about a 25%, or at least about a 30% reduction in an alkaline phosphatase level, a total protein level, an albumin level, a globulin level, a GGT, a glucose level, a urea nitrogen level, a creatine level, a urea acid level, or a C-reactive protein level in the biological sample at least about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocort
  • the subject of the methods of the present technology experiences no change or a reduction in one or more of a total white blood cell count level, a neutrophil level, a lymphocyte level, a monocyte level, an eosinophil level, a basophil level, a red cell distribution width level, a platelet count level, a mean platelet volume in a biological sample from the subject.
  • the subject exhibits at least about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, about a 10%, about a 15%, about a 20%, about a 25%, or about a 30% reduction in a total white blood cell count level, a neutrophil level, a lymphocyte level, a monocyte level, an eosinophil level, a basophil level, a red cell distribution width level, a platelet count level, a mean platelet volume in a biological sample from the subject.
  • the reduction occurs about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology, relative to a control.
  • the subject exhibits at least at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, or at least a 30% reduction in a total white blood cell count level, a neutrophil level, a lymphocyte level, a monocyte level, an eosinophil level, a basophil level, a red cell distribution width level, a platelet count level, a mean platelet volume in a biological sample from the subject.
  • the reduction occurs at least 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least 30 days after administration of a first dose of a non- naturally occurring melanocortin analog of the present technology, relative to a control.
  • the subject exhibits at least about at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, at least about a 10%, at least about a 15%, at least about a 20%, at least about a 25%, or at least about a 30% reduction in a total white blood cell count level, a neutrophil level, a lymphocyte level, a monocyte level, an eosinophil level, a basophil level, a red cell distribution width level, a platelet count level, a mean platelet volume in a biological sample from the subject.
  • the reduction occurs at least about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology, relative to a control.
  • the subject of the methods of the present technology experiences no change or an increase in one or more of a red blood cell count, a hemoglobin level, a hematocrit level, a mean corpuscular volume level, a mean corpuscular hemoglobin level, or a mean corpuscular hemoglobin concentration level in a biological sample from the subject, relative to a control.
  • the red blood cell count, a hemoglobin level, the hematocrit level, the mean corpuscular volume level, the mean corpuscular hemoglobin level, or the mean corpuscular hemoglobin concentration level is increased in the biological sample by at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or 300%, after administration of a first dose of a non- naturally occurring melanocortin analog, relative to a control.
  • the subject of the methods of the present technology may experience no change in or an increase in an albumin to globulin ratio in a biological sample from the subject, relative to a control.
  • the albumin to globulin ratio is increased in the biological sample by at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or 300%, after administration of a first dose of a non-naturally occurring melanocortin analog, relative to a control.
  • the subject administered a non-naturally occurring melanocortin analog of the present technology exhibits one or more of: (a) a reduction in fat mass by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (b) a reduction in epididymal fat mass at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; -71- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 (c) a reduction in perirenal fat mass at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%
  • any one of (a)-(nn) is maintained for at about 2 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after administration of the non-naturally occurring melanocortin analog.
  • any one of (a)-(nn) is maintained for at least 2 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after administration of the non-naturally occurring melanocortin analog.
  • any one of (a)-(nn) is maintained for at least about 2 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after administration of the non-naturally occurring melanocortin analog.
  • any one of (a)-(nn) occurs during or after administration of a first, a second, and/or a third dose of the non-naturally occurring melanocortin analog.
  • any one of (a)-(nn) is greater during or after administration the second dose relative to during or after administration of the first dose.
  • any one of (a)-(nn) is greater during or after administration the third dose relative to during or after administration of the first dose or the second dose.
  • 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.
  • the muscle mass changes may be assessed by using magnetic resonance imaging (MRI) and/or or nuclear magnetic resonance (NMR).
  • Administration of the non-naturally occurring melanocortin analogs of the present technology may comprise rebound-resistant weight loss (i.e., prevention of weight gain after treatment completion) and/or increased muscle retention, relative to a control (e.g., administration of a conventional weight loss agent alone).
  • the rebound resistant weight loss may comprise a prevention or a reduction in fat mass gain and/or BMI increase, relative to the control.
  • the non-naturally occurring melanocortin analog is administered as a combination therapy with a weight loss agent, where the combination therapy achieves the same weight loss as administration of the weight loss agent alone, but at a reduced dose or dosing frequency relative to the weight loss agent.
  • the rebound-resistant weight loss is maintained for about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration of the non-naturally occurring melanocortin analog is complete and/or discontinued.
  • the rebound-resistant weight loss is maintained for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration of the non-naturally occurring melanocortin analog is complete and/or discontinued. [0245] In some embodiments, the rebound-resistant weight loss is maintained for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration of the non-naturally occurring melanocortin analog is complete and/or discontinued.
  • the subject’s weight increases no more than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, or less than about 1%.
  • the present technology comprises a method of suppressing appetite in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and/or after administration of the weight loss agent.
  • Administration of the non-naturally occurring melanocortin analog prior to, during, and/or after administration of the weight loss agent may produce an additive -77- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 or synergistic effect on suppressing the subject’s appetite.
  • the weight loss agent is a GLP-1 receptor agonist and the non-naturally occurring melanocortin analog is a melanocortin agonist and administration of the combination therapy produces an additive effect on suppressing the subject’s appetite.
  • the weight loss agent is a dual GLP-1/GIP receptor agonist and the non-naturally occurring melanocortin analog is a melanocortin agonist and administration of the combination therapy produces a synergistic effect on suppressing the subject’s appetite.
  • the method reduces food intake of the subject. Administration of the non-naturally occurring melanocortin analog prior to, during, and/or after administration of the weight loss agent may produce an additive or synergistic effect on reducing the subject’s food intake.
  • the method reduces fat body mass and/or body weight of the subject.
  • the reduction in food intake is a reduction in caloric intake.
  • the subject’s weight increases no more than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, or less than about 1% at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration of the non-naturally occurring melanocortin analog is complete and/or discontinued.
  • the present technology comprises a method of preventing, reducing, or otherwise ameliorating body weight gain a during or after use of a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.
  • the present technology comprises a method of maintaining body weight after use of a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.
  • the present technology comprises a method of preventing, reducing, or otherwise ameliorating a fat mass gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.
  • the methods of the present technology may decrease the risk and/or incidence of adverse cardiovascular events associated with the use of a weight loss agent including, but not limited to, cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, angina, sinus tachycardia, sinus bradycardia, coronary artery bypass grafting, percutaneous coronary intervention, heart failure, carotid endarterectomy, peripheral vascular disease, or any combination thereof.
  • a weight loss agent including, but not limited to, cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, angina, sinus tachycardia, sinus bradycardia, coronary artery bypass grafting, percutaneous coronary intervention, heart failure, carotid endarterectomy, peripheral vascular disease, or any combination thereof.
  • the methods of the present technology may prevent or decrease the risk and/or incidence of adverse cardiac effects associated with the use of conventional melanocortin analogs, melanocortin peptides, and/or melanocortin receptor agonists.
  • the subject of the present technology experiences no or substantially no adverse cardiac effects and/or no change in cardiac outcomes during or after administration of a non-naturally occurring melanocortin analog of the present technology, relative to a control (e.g., a subject administered conventional melanocortin analogs, melanocortin peptides, and/or melanocortin receptor agonists).
  • the adverse cardiac effect and/or change in cardiac outcomes comprises one or more of a change in blood pressure (e.g., systolic blood pressure, diastolic blood pressure, mean arterial blood pressure), heart rate, QT interval, QRS interval, RR interval, or QTc, relative to a control.
  • a change in blood pressure e.g., systolic blood pressure, diastolic blood pressure, mean arterial blood pressure
  • heart rate e.g., systolic blood pressure, diastolic blood pressure, mean arterial blood pressure
  • heart rate, QT interval, QRS interval, RR interval, or QTc e.g., systolic blood pressure, diastolic blood pressure, mean arterial blood pressure
  • the transient change in blood pressure comprises an increase in blood pressure in the evening, at night, during a sleep cycle, or during a dark cycle after administration of the conventional melanocortin analogs, melanocortin peptides, and/or melanocortin receptor agonists.
  • Tanning and Hyperpigmentation [0255] The present technology comprises a method of inducing a tanning effect in a subject during or after administration of a non-naturally occurring melanocortin analog.
  • the tanning effect comprises skin darkening without hyperpigmentation (e.g., an uneven distribution of melanin) compared to subjects who have not received the -79- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 non-naturally occurring melanocortin analog or compared to the same subject at baseline (e.g., prior to receiving a dose of the non-naturally occurring melanocortin analog).
  • the tanning effect is not clinically significant, occurs in response to UV or sun exposure, and/or is not substantially ectopic. The tanning effect may occur in combination with weight loss.
  • the weight loss may comprise a retention in muscle mass (e.g., lean muscle mass) and a loss of fat mass.
  • the tanning effect is observed about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20 days after administration of a non- naturally occurring melanocortin analog.
  • the tanning effect occurs at a dose of greater than 100 mg or at least about 200 mg. [0256]
  • the tanning effect is reduced after completion and/or discontinuation of the non-naturally occurring melanocortin analog dosing.
  • the tanning effect is reduced at least about 1 day, 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks, 3 week, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks, 15 weeks, or 20 weeks after completion and/or discontinuation of the non-naturally occurring melanocortin analog dosing.
  • the reduced tanning effect comprises reversal of about 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80% 90%, 95%, 99%, or 100% of the total area of skin darkening.
  • the tanning effect does not comprise ectopic skin hyperpigmentation and/or tanning effects (e.g., of the palms or gums).
  • the reduced tanning effect comprises reversal of at least 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80% 90%, 95%, 99%, or 100% of the total area of skin darkening.
  • the tanning effect does not comprise ectopic skin hyperpigmentation and/or tanning effects (e.g., of the palms or gums).
  • the reduced tanning effect comprises reversal of at least about 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80% 90%, 95%, 99%, or 100% of the total area of skin darkening.
  • the tanning effect does not comprise ectopic skin hyperpigmentation and/or tanning effects (e.g., of the palms or gums).
  • the non-naturally occurring melanocortin analog may be useful in treating, preventing, or otherwise ameliorating one or more hypopigmentation diseases.
  • Nonlimiting -80- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 examples of hypopigmentation disease include albinism (e.g., oculocutaneous albinism), vitiligo, piebaldism, nevus depigmentosus, hypomelanosis of Ito, phenylketonuria, tuberous sclerosis, dyschromatosis symmetrica hereditaria, Waardenburg syndrome, Hermansky- Pudlak syndrome, Chediak-Higashi syndrome, Griscelli syndrome, and Tietz syndrome, and acquired hypopigmentary diseases such as leukoderma Sutton, Vogt-Koyanagi Harada syndrome, leukoderma senile, leukoderma after sea bathing, and leukoderma syphiliticum.
  • albinism e.g., oculocutaneous albinism
  • vitiligo e.g., piebaldism
  • the methods of the present technology may prevent or decrease the risk and/or incidence of hyperpigmentation associated with the use of conventional melanocortin analogs, melanocortin peptides, and/or melanocortin receptor agonists.
  • the subject of the present technology experiences no or substantially no hyperpigmentation during or after administration of a non-naturally occurring melanocortin analog of the present technology, relative to a control (e.g., a subject administered conventional melanocortin analogs, melanocortin peptides, and/or melanocortin receptor agonists).
  • the hyperpigmentation comprises one or more of hyperpigmentation of the skin, nose, cheeks, or site of administration of the non-naturally occurring melanocortin analog.
  • Subjects [0262] InIn some embodiments, the subject of the present technology has an addiction or is susceptible to an addiction. In some embodiments, the subject of the present technology has used or is using one or more addictive substances. [0263] In some embodiments, the subject of the present technology has pain or is susceptible to pain. [0264] In some embodiments, the subject has or had an alcohol use disorder (AUD) or an opioid use disorder (OUD). In some embodiments, the subject is at risk of developing an AUD or an OUD. [0265] In some embodiments, the subject has used or is using an addictive substance.
  • the subject has used or is using a medication to treat an addiction.
  • the frequency or amount of the addictive substance and/or rescue medication is reduced during or after administration of the non-naturally occurring -81- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 melanocortin analog.
  • the frequency or amount of the addictive substance and/or rescue medication is reduced as the dose or dosage of the non-naturally occurring melanocortin analog increases.
  • the frequency or amount of the addictive substance and/or rescue medication comprises a downward titration during or after administration of a non-naturally occurring melanocortin analog.
  • Nonlimiting examples of rescue medications include opioid agonists (e.g., partial or full opioid agonists), opioid antagonists, and non-opioid medications.
  • the addictive substances of the present technology may comprise a substance in a prescription medication, a substance in an over-the-counter medication, a recreational substance, or an illegal substance.
  • Nonlimiting examples of addictive substances include opioids (e.g., morphine, heroin, codeine, oxycodone, hydrocodone, fentanyl), painkillers, stimulants (e.g., caffeine, nicotine, methamphetamines, cocaine, amphetamines), narcotics, alcohol, barbiturates (e.g., phenobarbital, methohexital, butalbital, pentobarbital, primidone, and amobarbital), sedatives (e.g., tranquilizers, xylazine, eszopiclone, zaleplon, zolpidem, zopiclone), marijuana, cannabis, tetrahydrocannabinol (THC), and cannabidiol (CBD), or inhalants (e.g., aerosols, butanes, freon, helium, nitrous oxide, propane, nitrites).
  • stimulants e.g.
  • the sedative comprises barbiturates (e.g., phenobarbital, methohexital, butalbital, pentobarbital, primidone, and amobarbital) or benzodiazepines (e.g., alprazolam, lorazepam, clonazepam, diazepam, temazepam).
  • the nicotine comprises nicotine in a tobacco chew, a nicotine pouch, or a smoking device (e.g., cigarettes, electronic cigarettes, cigars, vape products).
  • the subject has received or is receiving a conventional medication used to treat an addiction.
  • the conventional medication used to treat an addiction comprises one or more of buprenorphine, naltrexone, acamprosate, methadone, naloxone, nalmefene, xycodone, levo ⁇ alpha ⁇ acetylmethadol (LAAM), codeine, or a slow-release morphine (e.g., a slow-release oral morphine).
  • LAAM levo ⁇ alpha ⁇ acetylmethadol
  • codeine or a slow-release morphine (e.g., a slow-release oral morphine).
  • the subject has a body mass index (BMI) of about 18.5 kg/m 2 to about 35 kg/m 2 .
  • the subject has a BMI of about 20 kg/m 2 or greater. In some embodiments, the subject has a BMI of about 18.5 kg/m 2 or greater. [0272] In some embodiments, the subject has a BMI of greater than 24.9 kg/m 2 . In some embodiments, the subject has a BMI of 25 kg/m 2 to 29.9 kg/m 2 . In some embodiments, the subject has a BMI of greater than or equal to 30 kg/m 2 . [0273] In some embodiments, the subject is an overweight subject.
  • Overweight subjects include those having a body weight about 3% or more, 5% or more, 10% or more, 20% or more, or 30% or less, than the upper end of "normal" BMI (e.g., 24.9 kg/m 2 ).
  • the subject is an obese subject.
  • Obese subjects include those having a BMI of greater than or equal to 30 kg/m 2 .
  • the subject has a metabolic dysfunction.
  • the metabolic dysfunction is selected from the group consisting of obesity, diabetes mellitus, metabolic syndrome, insulin resistance, non-alcoholic fatty liver disease, polycystic ovarian syndrome, metabolic acidosis, hypothyroidism, hyperlipidemia, Cushing Syndrome, and metabolic myopathies.
  • the subject has another condition which is not metabolic dysfunction, but administration of the weight loss agent provides therapeutic benefit to the non-metabolic dysfunction condition.
  • the subject with a metabolic dysfunction has previously received treatment with the weight loss agent. A subject who has previously received treatment with the weight loss agent has completed at least one full treatment cycle with the weight loss agent.
  • the subject with a metabolic dysfunction is currently receiving treatment with the weight loss agent. A subject who is currently receiving treatment with the weight loss has received at least one dose of the weight loss agent.
  • the subject with a metabolic dysfunction has not received any treatment with the weight loss agent. A subject who has not received any treatment with the weight loss agent has not received even a single dose of the weight loss agent.
  • a subject who has been treated with a weight loss agent has received a weight loss agent in an amount sufficient to induce at -83- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 least minimum weight loss.
  • a subject how is currently undergoing treatment with a weight loss agent is receiving a weight loss agent in an amount sufficient to induce at least minimum weight loss.
  • the subject has previously received treatment with the weight loss agent and has not lost body weight and/or fat mass.
  • the subject has previously received treatment with the weight loss agent and has lost body weight and/or fat mass. In such embodiments, the subject may still be overweight or obese.
  • the subject may have stopped treatment with the weight loss agent because they were unable to continue losing body weight and/or fat mass with the weight loss agent.
  • the subject’s body weight may be more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.
  • the subject in which the subject has previously received treatment with the weight loss agent, the subject’s fat mass may be more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.
  • the subject is currently receiving treatment with the weight loss agent and has not lost any body weight.
  • the subject is currently receiving treatment with the weight loss agent and has lost body weight and/or fat mass.
  • the subject is currently receiving treatment with the weight loss agent, has lost body weight and/or fat mass, and has failed to lose sufficient body weight and/or fat mass following administration of the weight loss agent.
  • the subject who is currently receiving treatment with the weight loss agent may still be overweight or obese.
  • the subject’s body weight may be more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.
  • the subject in which the subject is currently receiving treatment with the weight loss agent, the subject’s fat mass may be more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.
  • the subject has not received any treatment with the weight loss agent and has failed to lose sufficient or any weight using other weight loss methods.
  • the subject has not received any treatment with the weight loss agent and has not attempted to lose weight using any other methods.
  • the subject may begin treatment with non-naturally occurring melanocortin analog and the weight loss agent at the same time.
  • a subject who begins administration of the weight loss agent and the non-naturally occurring melanocortin analog at the same time, and continues with concurrent administration of the two therapies, may experience greater body weight and/or fat mass loss compared to a subject who is administered only one of the therapies, e.g., only the weight loss agent or only the non-naturally occurring melanocortin analog.
  • the subject’s body weight may be more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, or more than 55% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.
  • the subject may be more than 10%, more than 15%, more than 20%, more than 25%, more than -85- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 30%, more than 35%, more than 40%, more than 45%, more than 50%, or more than 55% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.
  • the method prevents or reduces muscle mass loss (e.g., involuntary muscle mass loss) in the subject.
  • the subject’s muscle mass is not more than 5%, not more than 10%, not more than 15%, not more than 20%, not more than 25%, or not more than 30% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and/or the weight loss agent.
  • the weight loss agent is administered to the subject for treating or preventing one of one or more metabolic dysfunctions.
  • metabolic dysfunctions include obesity, diabetes mellitus, metabolic syndrome, insulin resistance, non-alcoholic fatty liver disease, polycystic ovarian syndrome, metabolic acidosis, hypothyroidism, hyperlipidemia, Cushing Syndrome, and metabolic myopathies.
  • the subject of the present technology may be 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.
  • the subject is a human.
  • the subject is an animal such as a rat or a dog.
  • the non-naturally occurring melanocortin analogs of the present technology comprise an increased distribution relative to a control.
  • the increased distribution may be an increase in distribution of the non-naturally occurring melanocortin analogs at a given time point relative to a control administered at the same dose and measured at the same time point.
  • the distribution may be measured at an intermediate time point or a final time point.
  • the measurement of distribution comprises measuring a volume of distribution at the terminal phase (Vd or Vdß), a central volume of distribution (V), -86- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 a peripheral volume of distribution (V2), an apparent volume of distribution (Vz), or a measurement of distribution comprises measuring a volume of distribution at steady state (Vss).
  • Vd or Vdß a volume of distribution at the terminal phase
  • V central volume of distribution
  • Vz an apparent volume of distribution
  • Vss a measurement of distribution comprises measuring a volume of distribution at steady state (Vss).
  • Vss steady state
  • a high or increased Vd, Vdß, Vz, and/or Vss may suggest large distribution beyond the tissue, plasma, and/or serum compartment, relative to the control.
  • the increase in distribution comprises a measurement about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.
  • the increase in distribution comprises a measurement at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.
  • the increase in distribution comprises a measurement at least about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.
  • the increase in distribution comprises a measurement during administration of the non-naturally occurring melanocortin analogs.
  • the increase in distribution comprises a measurement at the completion of administration of the non-naturally occurring melanocortin analogs.
  • the non-naturally occurring melanocortin analog of the present technology exhibits one or more of the following: (a) an increase in half-life relative to a control; (b) a reduction in clearance relative to a control; (c) an increase in tissue concentration relative to a control; (d) an increase in plasma concentration relative to a control; -87- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 (e) an increase in serum concentration relative to a control; (f) an increase in distribution relative to a control; (g) an increase in an AUC measurement relative to a control; (h) an increase in a DNAUC measurement relative to a control; (i) an increase in Tfinal relative to a control; (j) an increase in Cmax relative to a control; (k) an increase in Cmin relative to a control; (l) an increase in DNCmin relative to a control;
  • the non-naturally occurring melanocortin analog of the present technology exhibits one or more of the following, relative to a control: (a) an increase in half-life by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (b) a reduction in clearance by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to a control; (c) an increase in tissue concentration by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; -88- 146316.80
  • 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.
  • the non-naturally occurring melanocortin analog is administered every morning, every evening, or every afternoon.
  • the non-naturally occurring melanocortin analog is administered before a meal, after a meal, or with a meal.
  • the non-naturally occurring melanocortin analog or pharmaceutical composition thereof can 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.
  • 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).
  • 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 can 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.
  • 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.
  • the dosage regimen may be decreased or increased from an initial dosing regimen for days, weeks, months, or years.
  • the dosing regimen is repeated at other intervals. -91- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 [0302]
  • the methods comprise administering a non-naturally occurring melanocortin analog at a first dose and a second to a subject in need thereof, wherein the second dose is greater than the first dose.
  • the subject is administered a third dose that is greater than the first and the second dose.
  • the methods comprise administered the non-naturally occurring melanocortin analog to the subject in increase doses or increased dosages, relative to the first dose.
  • the 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 30 mg/kg or 60 mg/kg per body weight of the subject once daily.
  • the 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.
  • 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. [0306] In some embodiments, the 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 30 mg/kg or 60 mg/kg per body weight of the subject once daily. [0307] 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.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily. [0308] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 0.1 mg to at least 100 mg once daily. In some -92- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 10 mg or at least 50 mg once daily.
  • the 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 30 mg/kg or 60 mg/kg per body weight of the subject once daily. [0310] In some embodiments, the 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 30 mg/kg or 60 mg/kg per body weight of the subject once daily.
  • the 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 30 mg/kg or 60 mg/kg per body weight of the subject once daily. [0312] In some embodiments, the non-naturally occurring melanocortin analog is MC4- NN2-0453 and is administered at a dose of about 0.03, 0.06, 0.15, 0.30, 0.60, 1.00, or 1.50 mg/kg. In some embodiments, the MC4-NN2-0453 is administered as a single dose.
  • the non-naturally occurring melanocortin analog is MC4- NN2-0453 and is administered at a dose of at least 0.03, 0.06, 0.15, 0.30, 0.60, 1.00, or 1.50 mg/kg. In some embodiments, the MC4-NN2-0453 is administered as a single dose. [0314] In some embodiments, the non-naturally occurring melanocortin analog is MC4- NN2-0453 and is administered at a dose of at least about 0.03, 0.06, 0.15, 0.30, 0.60, 1.00, or 1.50 mg/kg. In some embodiments, the MC4-NN2-0453 is administered as a single dose.
  • the non-naturally occurring melanocortin analog is MC4- NN2-0453 and is administered at a dose of about 0.75, 1.5, 3.0, or 5.0 mg/day.
  • the subject is administered two or more doses of the MC4-NN2-0453. -93- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 [0316]
  • the non-naturally occurring melanocortin analog is MC4- NN2-0453 and is administered at a dose of at least 0.75, 1.5, 3.0, or 5.0 mg/day.
  • the subject is administered two or more doses of the MC4-NN2-0453.
  • the non-naturally occurring melanocortin analog is MC4- NN2-0453 and is administered at a dose of at least about 0.75, 1.5, 3.0, or 5.0 mg/day.
  • the subject is administered two or more doses of the MC4-NN2-0453.
  • the doses comprise two or more different doses selected from the group consisting of 0.75, 1.5, 3.0, and 5.0 mg/day.
  • the two or more doses are administered as ascending doses.
  • the MC4-NN2-0453 is administered once daily.
  • the non-naturally occurring melanocortin analog is LY2112688 and is administered at a dose of about 0.45 mg or 1.0 mg. In some embodiments, the LY2112688 is administered at a first dose of about 0.45 mg and a second dose of 1.0 mg.
  • the non-naturally occurring melanocortin analog is LY2112688 and is administered at a dose of about 0.5 mg/kg/day.
  • the non-naturally occurring melanocortin analog is LY2112688 and is administered at a dose of at least 0.45 mg or 1.0 mg.
  • the LY2112688 is administered at a first dose of at least 0.45 mg and a second dose of 1.0 mg.
  • the non-naturally occurring melanocortin analog is LY2112688 and is administered at a dose of at least 0.5 mg/kg/day.
  • the non-naturally occurring melanocortin analog is LY2112688 and is administered at a dose of at least about 0.45 mg or 1.0 mg.
  • the LY2112688 is administered at a first dose of at least about 0.45 mg and a second dose of 1.0 mg.
  • the non-naturally occurring melanocortin analog is LY2112688 and is administered at a dose of at least about 0.5 mg/kg/day.
  • the non-naturally occurring melanocortin analog is Melanotan-II and is administered at a dose of about 0.01 mg/kg.
  • the dose is a first dose. The first dose may be escalated by 0.005 mg/kg increments to 0.03 mg/kg or to 0.025 mg/kg.
  • the non-naturally occurring melanocortin analog is Melanotan-II and is administered at a dose of about 0.01 mg/kg, about 0.025 mg/kg, or about 0.03 mg/kg.
  • the non-naturally occurring melanocortin analog is Melanotan-II and is administered at a dose of at least 0.01 mg/kg.
  • the dose is a first dose. The first dose may be escalated by 0.005 mg/kg increments to 0.03 mg/kg or to 0.025 mg/kg.
  • the non-naturally occurring melanocortin analog is Melanotan-II and is administered at a dose of at least 0.01 mg/kg, at least 0.025 mg/kg, or at least 0.03 mg/kg.
  • the non-naturally occurring melanocortin analog is Melanotan-II and is administered at a dose of at least about 0.01 mg/kg.
  • the dose is a first dose. The first dose may be escalated by 0.005 mg/kg increments to 0.03 mg/kg or to 0.025 mg/kg.
  • the non-naturally occurring melanocortin analog is Melanotan-II and is administered at a dose of at least about 0.01 mg/kg, at least about 0.025 mg/kg, or at least about 0.03 mg/kg.
  • the non-naturally occurring melanocortin analog is Afamelanotide and is administered at a dose of about 0.08 mg/kg to about 0.21 mg/kg.
  • the Afamelanotide is administered as a daily dose. The subject may be administered about ten daily doses.
  • the non-naturally occurring melanocortin analog is Afamelanotide and is administered at a dose of at least 0.08 mg/kg to at least 0.21 mg/kg. In some embodiments, the Afamelanotide is administered as a daily dose. The subject may be administered at least ten daily doses.
  • the non-naturally occurring melanocortin analog is Afamelanotide and is administered at a dose of at least about 0.08 mg/kg to at least about 0.21 mg/kg.
  • the Afamelanotide is administered as a daily dose.
  • the subject may be administered at least about ten daily doses.
  • the non-naturally occurring melanocortin analog is Afamelanotide and is administered at a dose of about 16 mg.
  • the Afamelanotide may be administered about once every 60 days.
  • the Afamelanotide is administered using a subcutaneous implant.
  • the non-naturally occurring melanocortin analog is Afamelanotide and is administered at a dose of at least 16 mg.
  • the Afamelanotide may be administered at least once every 60 days.
  • the Afamelanotide is administered using a subcutaneous implant.
  • the non-naturally occurring melanocortin analog is Afamelanotide and is administered at a dose of at least about 16 mg. In some embodiments, the Afamelanotide may be administered at least about once every 60 days. In some embodiments, the Afamelanotide is administered using a subcutaneous implant.
  • the non-naturally occurring melanocortin analog is Bremelanotide and is administered at a dose of about 1.75 mg, 4.0 mg, or 6.0 mg.
  • the non-naturally occurring melanocortin analog is Bremelanotide and is administered at a dose of at least about 7.0 mg or at least about 10 mg. In some embodiments, the dose is administered intranasally. [0339] In some embodiments, the non-naturally occurring melanocortin analog is Bremelanotide and is administered at a dose of at least 1.75 mg, 4.0 mg, or 6.0 mg.
  • the non-naturally occurring melanocortin analog is Bremelanotide and is administered at a dose of at least at least 7.0 mg or at least at least 10 mg. In some embodiments, the dose is administered intranasally.
  • the non-naturally occurring melanocortin analog is Bremelanotide and is administered at a dose of at least about 1.75 mg, 4.0 mg, or 6.0 mg.
  • the non-naturally occurring melanocortin analog is Bremelanotide and is administered at a dose of at least at least about 7.0 mg or at least at least about 10 mg. In some embodiments, the dose is administered intranasally [0343] In some embodiments, the non-naturally occurring melanocortin analog is MK- 0493 and is administered at a dose of about 10 mg or about 30 mg. [0344] In some embodiments, the non-naturally occurring melanocortin analog is MK- 0493 and is administered at a dose of about 1 mg/kg to about 4 mg/kg.
  • the non-naturally occurring melanocortin analog is MK- 0493 and is administered at a dose of about 2 mg/kg, about 6 mg/kg, or about 20 mg/kg. [0346] In some embodiments, the non-naturally occurring melanocortin analog is MK- 0493 and is administered at a dose of at least 10 mg or at least 30 mg. [0347] In some embodiments, the non-naturally occurring melanocortin analog is MK- 0493 and is administered at a dose of at least 1 mg/kg to at least 4 mg/kg.
  • the non-naturally occurring melanocortin analog is MK- 0493 and is administered at a dose of at least 2 mg/kg, at least 6 mg/kg, or at least 20 mg/kg. [0349] In some embodiments, the non-naturally occurring melanocortin analog is MK- 0493 and is administered at a dose of at least about 10 mg or at least about 30 mg. [0350] In some embodiments, the non-naturally occurring melanocortin analog is MK- 0493 and is administered at a dose of at least about 1 mg/kg to at least about 4 mg//kg.
  • the non-naturally occurring melanocortin analog is MK- 0493 and is administered at a dose of at least about 2 mg/kg, at least about 6 mg/kg, or at least about 20 mg/kg. -97- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 [0352] In some embodiments, the non-naturally occurring melanocortin analog is PF- 00446687 and is administered at a dose of about 200 mg, 175 mg, 125 mg, 100 mg, or 20 mg.
  • the subject is administered one dose of PF-00446687 comprising about 200 mg, 175 mg, 125 mg, 100 mg, or 20 mg. In some embodiments, the subject is administered two doses of PF-00446687, each dose comprising about 200 mg, 175 mg, 125 mg, 100 mg, or 20 mg.
  • the non-naturally occurring melanocortin analog is PF- 00446687 and is administered at a dose of at least 200 mg, 175 mg, 125 mg, 100 mg, or 20 mg. In some embodiments, the subject is administered one dose of PF-00446687 comprising at least 200 mg, 175 mg, 125 mg, 100 mg, or 20 mg.
  • the subject is administered two doses of PF-00446687, each dose comprising at least 200 mg, 175 mg, 125 mg, 100 mg, or 20 mg.
  • the non-naturally occurring melanocortin analog is PF- 00446687 and is administered at a dose of at least about 200 mg, 175 mg, 125 mg, 100 mg, or 20 mg.
  • the subject is administered one dose of PF-00446687 comprising at least about 200 mg, 175 mg, 125 mg, 100 mg, or 20 mg.
  • the subject is administered two doses of PF-00446687, each dose comprising at least about 200 mg, 175 mg, 125 mg, 100 mg, or 20 mg.
  • the non-naturally occurring melanocortin analog is setmelanotide and is administered at a dose of about 0.5 mg, 1.0 mg, 2.0 mg, or 3.0 mg.
  • the non-naturally occurring melanocortin analog is setmelanotide and is administered at a dose of at least 0.5 mg, 1.0 mg, 2.0 mg, or 3.0 mg.
  • the non-naturally occurring melanocortin analog is setmelanotide and is administered at a dose of at least about 0.5 mg, 1.0 mg, 2.0 mg, or 3.0 mg. In some embodiments, the dose is administered once daily. [0358] In some embodiments, the dose is administered once daily. In some embodiments, the setmelanotide is administered at two or more doses. When the setmelanotide is administered at two or more doses, the second dose may be greater than the first dose.
  • the non-naturally occurring melanocortin analog is administered about 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.
  • 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.
  • 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.
  • the non-naturally occurring melanocortin analog is administered at least about once daily in an amount ranging from at least about 0.5 mg/kg to at least about 10 mg/kg, at least about 1 mg/kg to at least about 7.5 mg/kg, or at least about 2.5 mg/kg to at least about 5 mg/kg per body weight of the subject.
  • 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.
  • the non-naturally occurring melanocortin analog (i.e., pharmaceutical combination) 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.
  • 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.
  • the non-naturally occurring melanocortin analog (i.e., pharmaceutical combination) 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 -99- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 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.
  • 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.
  • the non-naturally occurring melanocortin analog i.e., pharmaceutical combination
  • a method disclosed herein is performed on the subject for about a period of 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. [0367] In some embodiments, a method disclosed herein is performed on the subject for at least a period of 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.
  • a method disclosed herein is performed on the subject for at least about a period of 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.
  • Concentrations after Administration [0369] In some embodiments, the concentration of the non-naturally occurring melanocortin analog in the plasma or a tissue of the subject is about 5 ng/mL to about 2000 ng/mL about 24 hours after administration of the non-naturally occurring melanocortin analog.
  • the concentration of the non-naturally occurring melanocortin analog in the plasma or a tissue of the subject is at least 5 ng/mL to at least 2000 ng/mL about 24 hours after administration of the non-naturally occurring melanocortin analog.
  • concentration of the non-naturally occurring melanocortin analog in the plasma or a tissue of the subject is at least about 5 ng/mL to at least about 2000 ng/mL about 24 hours after administration of the non-naturally occurring melanocortin analog.
  • the non-naturally occurring melanocortin analog is administered to the subject until the concentration of the non-naturally occurring melanocortin analog in the plasma or a tissue of the subject is at least about 5 ng/mL to at least about 2000 ng/mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 5 ng/mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 10 ng/mL after administration of the non-naturally occurring melanocortin analog.
  • the concentration is at least about 50 ng/mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 100 ng/mL after administration of the non- naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 200 ng/mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 300 ng/mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 400 ng/mL after administration of the non-naturally occurring melanocortin analog.
  • the concentration is at least about 500 ng/mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the wherein concentration is at least about 750 ng/mL after administration of the non- naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 1000 ng/mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 1500 ng/mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 2000 ng/mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is a maximum concentration (Cmax).
  • the non-naturally occurring melanocortin analogs of the present technology may be administered using any means known in the art, including orally, ocularly, intranasally, topically, parenterally, by injection, rectally, or vaginally. If administered by injection, the non-naturally occurring melanocortin analog injection may be intravenous (IV), subcutaneous (SC), intramuscular (IM), intraperitoneal (IP), intracerebroventricular (ICV), or other means known in the art.
  • IV intravenous
  • SC subcutaneous
  • IM intramuscular
  • IP intraperitoneal
  • ICV intracerebroventricular
  • the non-naturally occurring melanocortin analog 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, anti-oxidants and other agents known in the art.
  • Administration includes topical delivery.
  • 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.
  • administration of the non-naturally occurring melanocortin analog comprises delivery across the blood brain barrier.
  • administration of the non-naturally occurring melanocortin analog comprises delivery across the epithelium.
  • administration of the non-naturally occurring melanocortin analog comprises delivery across the epithelium and the blood brain barrier.
  • administration of the non-naturally occurring melanocortin analog comprises delivery through the gastrointestinal tract.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg/mL to about 500 mg/mL.
  • the non-naturally occurring melanocortin analog is administered at a dose of at least 0.1 mg/mL to at least 500 mg/mL.
  • the non-naturally occurring melanocortin analog is administered at a dose of at least about 0.1 mg/mL to at least about 500 mg/mL.
  • 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.
  • 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.
  • the methods disclosed herein may be performed on the subject for about 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.
  • the combination therapy i.e., pharmaceutical combination
  • the methods disclosed herein may be performed on the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.
  • the combination therapy (i.e., pharmaceutical combination) 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.
  • the methods disclosed herein 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.
  • the combination therapy (i.e., pharmaceutical combination) 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, -103- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 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.
  • a method disclosed herein is performed on the subject for 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.
  • at least one active ingredient of the combination therapy is administered to a subject in a continuous doing schedule.
  • a “continuous dosing schedule” is an administration or dosing regimen without dose interruptions, e.g., without days off treatment. Repetition of 21-day or 28-day treatment cycles without dose interruptions is an exemplary continuous dosing schedule.
  • the 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 30 mg/kg or 60 mg/kg per body weight of the subject once daily. [0385] 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. In some embodiments, 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 at a dose of about 5 mg/kg to about 1000 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 550 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.
  • the non-naturally occurring melanocortin analog is -104- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 administered at a dose of about 30 mg/kg or 60 mg/kg per body weight of the subject once daily.
  • the non-naturally occurring melanocortin analog is administered at a dose of at least 5 mg/kg to at least 1000 mg/kg per body weight of the subject once daily.
  • the non-naturally occurring melanocortin analog is administered at a dose of at least 10 mg/kg to at least 550 mg/kg per body weight of the subject once daily.
  • 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. [0388] 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 1000 mg/kg per body weight of the subject once daily.
  • the non-naturally occurring melanocortin analog is administered at a dose of at least about 10 mg/kg to at least about 550 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.
  • 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. [0389] 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 -105- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.
  • 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, at least 550 mg/kg, at least 600 mg/kg, at least 650 mg/kg, at least 700 mg/kg, at least
  • 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, at least about 550 mg
  • the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg/kg per body weight of the subject once daily.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg/kg per body weight of the subject once daily.
  • -106- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 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.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 20 mg/kg per body weight of the subject once daily.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 25 mg/kg per body weight of the subject once daily.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 30 mg/kg per body weight of the subject once daily.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 35 mg/kg per body weight of the subject once daily.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 40 mg/kg per body weight of the subject once daily.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 50 mg/kg per body weight of the subject once daily.
  • 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.
  • 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.
  • 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. [0404] 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. [0405] 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. [0406] 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.
  • 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.
  • 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.
  • 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.
  • 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. [0411] 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. [0412] 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. [0413] 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.
  • 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. [0415] 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. [0416] 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. [0417] 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.
  • 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.
  • 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 -108- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 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
  • the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg/kg per body weight of the subject twice daily. [0421] 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. [0422] 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. [0423] 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.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 25 mg/kg per body weight of the subject twice daily. [0425] 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. [0426] 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. [0427] 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.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 50 mg/kg per body weight of the subject twice daily.
  • 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 -109- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 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,
  • the non-naturally occurring melanocortin analog is administered at a dose of at least 5 mg/kg per body weight of the subject twice daily. [0431] 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 twice daily. [0432] 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 twice daily. [0433] 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 twice daily.
  • the non-naturally occurring melanocortin analog is administered at a dose of at least 25 mg/kg per body weight of the subject twice daily. [0435] 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 twice daily. [0436] 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 twice daily. [0437] 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 twice daily.
  • the non-naturally occurring melanocortin analog is administered at a dose of at least 50 mg/kg per body weight of the subject twice daily. [0439] 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, -110- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 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
  • 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. [0441] 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. [0442] 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. [0443] 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.
  • 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. [0445] 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. [0446] 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. [0447] 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.
  • 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. -111- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 [0449] 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. [0450] In some embodiments, the non-naturally occurring melanocortin analog is administered at a first dose once daily or twice daily.
  • the non- naturally occurring melanocortin analog is administered at a second dose once daily or twice daily.
  • the non-naturally occurring melanocortin analog is administered at a dose that is a projected human equivalent dose (HED) based on a nonhuman primate dose.
  • HED human equivalent dose
  • the HED based on a 10 mg/kg nonhuman primate dose ranges from about 300 mg to about 550 mg.
  • the HED based on a 10 mg/kg nonhuman primate dose ranges from at least 300 mg to at least 550 mg.
  • the HED based on a 10 mg/kg nonhuman primate dose ranges from at least about 300 mg to at least about 550 mg.
  • the non-naturally occurring melanocortin analog is administered at a first dose once daily for about 5 days to about 10 days.
  • 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.
  • 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.
  • the second dose is greater than the first dose.
  • the third dose comprises a cumulative dose that is greater than the second dose.
  • the non-naturally occurring melanocortin analog is administered at a first dose once daily for at least 5 days to at least 10 days. In some embodiments, the non-naturally occurring melanocortin analog is administered at a second dose once daily for at least 5 days to at least 10 days, after administration of the first dose. -112- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 In some embodiments, the non-naturally occurring melanocortin analog is administered at a third dose twice daily for at least 7 days to at least 21 days, after administration of the second dose.
  • the second dose is greater than the first dose.
  • the third dose comprises a cumulative dose that is greater than the second dose.
  • the non-naturally occurring melanocortin analog is administered at a first dose once daily for at least about 5 days to at least about 10 days.
  • the non-naturally occurring melanocortin analog is administered at a second dose once daily for at least about 5 days to at least about 10 days, after administration of the first dose.
  • the non-naturally occurring melanocortin analog is administered at a third dose twice daily for at least about 7 days to at least about 21 days, after administration of the second dose.
  • the second dose is greater than the first dose.
  • the third dose comprises a cumulative dose that is greater than the second dose.
  • the non-naturally occurring melanocortin analogs or a pharmaceutical composition thereof is administered at a second dose that is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% greater than the first dose.
  • the non-naturally occurring melanocortin analogs or a pharmaceutical composition thereof is administered at a second dose that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% greater than the first dose.
  • the non-naturally occurring melanocortin analogs or a pharmaceutical composition thereof is administered at a second dose that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% greater than the first dose.
  • the non-naturally occurring melanocortin analogs or a pharmaceutical composition thereof is administered at a third dose that about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% greater than the first dose and/or the second dose.
  • the non-naturally occurring melanocortin analogs or a pharmaceutical composition thereof is administered at a third dose that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% greater than the first dose and/or the second dose.
  • the non-naturally occurring melanocortin analogs or a pharmaceutical composition thereof is administered at a third dose that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% greater than the first dose and/or the second dose.
  • the dosage of the second dose is greater than the dosage of the first dose.
  • the first dose is administered about once a day and the second dose is administered about twice a day.
  • the dosage of the second dose is greater than the dosage of the first dose.
  • the first dose is administered at least once a day and the second dose is administered at least twice a day.
  • the dosage of the second dose is greater than the dosage of the first dose.
  • the first dose is administered at least about once a day and the second dose is administered at least about twice a day.
  • the dosage of the third dose is greater than the dosage of the first dose and/or the second dose.
  • the first dose and/or the second dose is administered about once a day, and the third dose is administered about twice a day.
  • the dosage of the third dose is greater than the dosage of the first dose and/or the second dose. In some embodiments, the first dose and/or the second dose is administered at least once a day, and the third dose is administered at least twice a day. [0469] In some embodiments, the dosage of the third dose is greater than the dosage of the first dose and/or the second dose. In some embodiments, the first dose and/or the second dose is administered at least about once a day, and the third dose is administered at least about twice a day.
  • the non-naturally occurring melanocortin analog is administered using two or more different administration routes.
  • the two or more different administration routes may comprise an oral administration and a subcutaneous administration.
  • the oral administration may occur before, during, or after the subcutaneous administration.
  • the first dose and the second dose comprise different routes of administration.
  • the first dose comprises an oral dose and the second dose comprises a subcutaneous dose.
  • the first dose and/or second dose and the third dose comprise different routes of administration.
  • the first dose and/or the second dose comprises an oral dose and the third dose comprises a subcutaneous dose.
  • the second dose is administered at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks after the first dose.
  • the third dose is administered at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks after the first dose and/or the second dose.
  • the second dose is administered at least at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 -115- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks after the first dose.
  • the third dose is administered at least at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks after the first dose and/or the second dose.
  • the second dose is administered at least about at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, or at least about 6 weeks after the first dose.
  • the third dose is administered at least about at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, or at least about 6 weeks after the first dose and/or the second dose.
  • the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof is administered at two or more dosage amounts, each dosage amount differing from the other.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 0.5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day. In some embodiments, the non-naturally occurring melanocortin analog is administered 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, twice, 3 times, 4 times, 5 times, or 10 times per day.
  • the non-naturally occurring melanocortin analog is administered at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day. In some embodiments, the administration is performed once per day.
  • the non-naturally occurring melanocortin analog is administered at a dose of at least 0.5 mg to at least 500 mg in a dose volume of at least 1 mL to 20 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.
  • the non-naturally occurring melanocortin analog is administered at a dose of at least 50 mg to at least 100 mg in a dose volume of at least 2 mL to 10 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 75 mg in a dose volume of at least 5 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day. In some embodiments, the administration is performed once per day.
  • the non-naturally occurring melanocortin analog is administered at a dose of at least about 0.5 mg to at least about 500 mg in a dose volume of at least about 1 mL to 20 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.
  • the non-naturally occurring melanocortin analog is administered at a dose of at least about 50 mg to at least about 100 mg in a dose volume of at least about 2 mL to 10 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.
  • the non-naturally occurring melanocortin analog is administered at a dose of at least about 75 mg in a dose volume of at least about 5 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day. In some embodiments, the administration is performed once per day. [0482] In some embodiments, the non-naturally occurring melanocortin analog is administered as a single dosage unit. In some embodiments, the non-naturally occurring melanocortin analog dose is administered as multiple dosage units. In some embodiments, the multiple dosage units individually comprise about 2.5 mg/mL to about 100 mg/mL of the non-naturally occurring melanocortin analog.
  • the multiple dosage units individually comprise about 2.5 mg/mL to about 10 mg/mL of the non-naturally occurring melanocortin analog. In some embodiments, the multiple dosage units individually comprise about 6 mg/mL of the non-naturally occurring melanocortin analog. In some embodiments, the non-naturally occurring melanocortin analog is administered as about 5 -117- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 dosage units to about 10 dosage units. In some embodiments, the non-naturally occurring melanocortin analog is administered as 5 dosage units. In some embodiments, the non- naturally occurring melanocortin analog is administered as 10 dosage units.
  • the non-naturally occurring melanocortin analog is administered as a single dosage unit. In some embodiments, the non-naturally occurring melanocortin analog dose is administered as multiple dosage units. In some embodiments, the multiple dosage units individually comprise at least 2.5 mg/mL to at least 100 mg/mL of the non-naturally occurring melanocortin analog. In some embodiments, the multiple dosage units individually comprise at least 2.5 mg/mL to at least 10 mg/mL of the non-naturally occurring melanocortin analog. In some embodiments, the multiple dosage units individually comprise at least 6 mg/mL of the non-naturally occurring melanocortin analog.
  • the non-naturally occurring melanocortin analog is administered as at least 5 dosage units to at least 10 dosage units. In some embodiments, the non-naturally occurring melanocortin analog is administered as 5 dosage units. In some embodiments, the non- naturally occurring melanocortin analog is administered as 10 dosage units. [0484] In some embodiments, the non-naturally occurring melanocortin analog is administered as a single dosage unit. In some embodiments, the non-naturally occurring melanocortin analog dose is administered as multiple dosage units. In some embodiments, the multiple dosage units individually comprise at least about 2.5 mg/mL to at least about 100 mg/mL of the non-naturally occurring melanocortin analog.
  • the multiple dosage units individually comprise at least about 2.5 mg/mL to at least about 10 mg/mL of the non-naturally occurring melanocortin analog. In some embodiments, the multiple dosage units individually comprise at least about 6 mg/mL of the non-naturally occurring melanocortin analog. In some embodiments, the non-naturally occurring melanocortin analog is administered as at least about 5 dosage units to at least about 10 dosage units. In some embodiments, the non-naturally occurring melanocortin analog is administered as 5 dosage units. In some embodiments, the non-naturally occurring melanocortin analog is administered as 10 dosage units.
  • the non-naturally occurring melanocortin analogs of the present technology may be present in a pharmaceutical composition.
  • the non-naturally occurring melanocortin analog is present in a pharmaceutical composition in a concentration of about 0.1 mg/mL to about 500 mg/mL.
  • the non-naturally occurring melanocortin analog is present in a pharmaceutical composition in a concentration of at least 0.1 mg/mL to at least 500 mg/mL.
  • the non-naturally occurring melanocortin analog is present in a pharmaceutical composition in a concentration of at least about 0.1 mg/mL to at least about 500 mg/mL.
  • the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 0.1 mg/mL to 500 mg/mL, relative to a total volume of the pharmaceutical composition.
  • the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 0.1 mg/mL to 500 mg/mL, 0.5 mg/mL to 250 mg/mL, 1 mg/mL to 100 mg/mL, 2.5 mg/mL to 50 mg/mL, or 5 mg/mL to 25 mg/mL, relative to a total volume of the pharmaceutical composition.
  • the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 50 mg/mL, relative to a total volume of the pharmaceutical composition.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and/or excipient.
  • the pharmaceutical composition contains about 0.1 to about 99.9999 wt.%, about 1 to 99.999 wt.%, preferably 5 to 99.99 wt.%, preferably 10 to 99.9 wt.%, preferably 15 to 99 wt.%, preferably 20 to 90 wt.%, preferably 30 to 85 wt.%, preferably 40 to 80 wt.%, preferably 50 to 75 wt.%, preferably 60 to 70 wt.% of the pharmaceutically acceptable carrier and/or excipient relative to a total weight of the pharmaceutical composition.
  • the pharmaceutically acceptable carrier and/or excipient of the pharmaceutical composition is at least one selected from the group consisting of -119- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 water, a buffer, an inorganic salt, a fatty acid, a vegetable oil, a synthetic fatty ester, a surfactant, and a polymer.
  • the pharmaceutically acceptable carrier and/or excipient is water.
  • the pharmaceutically acceptable carrier and/or excipient is a buffer.
  • the non-naturally occurring melanocortin analog comprises a sequence of any one of Formulae(I)-(IG) and the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 5 mg/mL to 100 mg/mL, relative to a total volume of the pharmaceutical composition.
  • the non-naturally occurring melanocortin analog comprising a sequence of any one of Formulae (I)-(IG) is present in the pharmaceutical composition in a concentration of 5 mg/mL to 100 mg/mL, 10 mg/mL to 75 mg/mL, 15 mg/mL to 50 mg/mL, 20 mg/mL to 40 mg/mL, or 25 mg/mL to 30 mg/mL, relative to a total volume of the pharmaceutical composition.
  • the non-naturally occurring melanocortin analog comprising a sequence of any one of Formulae (I)-(IG) is present in the pharmaceutical composition in a concentration of about 50 mg/mL, relative to a total volume of the pharmaceutical composition.
  • the pharmaceutical composition formulated for parenteral administration comprises the non-naturally occurring melanocortin analog of any one of Formulae (I)-(IG) at a concentration at 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 more, depending on the specific non-naturally occurring melanocortin analog selected, the desired response, the route of administration, the formulation and other factors known to those of skill in the art.
  • the non-naturally occurring melanocortin analog comprises any one of SEQ ID NOs: 299, 302, and 405.
  • the non-naturally occurring melanocortin analog crosses blood-brain-barrier (BBB) of the subject. -120- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00
  • the pharmaceutical compositions comprising the carriers and/or excipients of the present technology facilitate delivery (e.g., parenteral administration, in particular subcutaneous injection) of the non-naturally occurring melanocortin analogs to a subject.
  • the carriers and/or excipients of the pharmaceutical composition may generally include one or more of the following components: a pH buffered aqueous solution comprising (a) sodium acetate, (b) Tris, and (c) water.
  • a pH buffered aqueous solution comprising (a) sodium acetate, (b) Tris, and (c) water.
  • 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 pharmaceutical composition.
  • the carrier and/or excipient is isotonic.
  • the pharmaceutical composition of the present technology may further include a salt such as sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride.
  • 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 pharmaceutical composition.
  • 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.
  • 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.
  • 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, -121- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 deionized distilled water, and reverse osmosis water.
  • WFI water for injection
  • BWFI bacteriostatic water for injection
  • distilled water bidistilled water
  • deionized water -121- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 deionized distilled water, and reverse osmosis water.
  • the water present in the pH buffered aqueous solution is water for injection.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. -123- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 [0512]
  • 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.
  • 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. [0514] In some embodiments, a weight ratio of sodium acetate to Tris is at least 1:4 to at least 4:1, at least 2:7 to at least 7:2, at least 1:3 to at least 3:1, at least 2:5 to at least 5:2, at least 1:2 to at least 2:1, at least 2:3 to at least 3:2, or at least 1:1.
  • the weight ratio of sodium acetate to Tris is at least 1:1.
  • a weight ratio of sodium acetate to Tris is at least about 1:4 to at least about 4:1, at least about 2:7 to at least about 7:2, at least about 1:3 to at least about 3:1, at least about 2:5 to at least about 5:2, at least about 1:2 to at least about 2:1, at least about 2:3 to at least about 3:2, or at least about 1:1.
  • the weight ratio of sodium acetate to Tris is at least about 1:1.
  • 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.
  • a weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is at least 1:1 to at least 20:1, at least 3:2 to at least 15:1, at least 2:1 to at least 12:1, at least 3:1 to at least 10:1, at least 4:1 to at least 9:1, at least 5:1 to at least 8:1, or at least 6:1 to at least 7:1.
  • the weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is at least 7:1.
  • a weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is at least about 1:1 to at least about 20:1, at least about 3:2 to at least about 15:1, at least about 2:1 to at least about 12:1, at least about 3:1 to at least about 10:1, at least about 4:1 to at least about 9:1, at least about 5:1 to at least about 8:1, or at least about 6:1 to at least about 7:1.
  • the weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is at least about 7:1.
  • 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.
  • a weight ratio of the non-naturally occurring melanocortin analog to Tris is at least 1:1 to at least 20:1, at least 3:2 to at least 15:1, at least 2:1 to at least 12:1, at least 3:1 to at least 10:1, at least 4:1 to at least 9:1, at least 5:1 to at least 8:1, or at least 6:1 to at least 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to Tris is at least 7:1.
  • a weight ratio of the non-naturally occurring melanocortin analog to Tris is at least about 1:1 to at least about 20:1, at least about 3:2 to at least about 15:1, at least about 2:1 to at least about 12:1, at least about 3:1 to at least about 10:1, at least about 4:1 to at least about 9:1, at least about 5:1 to at least about 8:1, or at least about 6:1 to at least about 7:1.
  • the weight ratio of the non- naturally occurring melanocortin analog to Tris is at least about 7:1.
  • the pharmaceutical composition may include other buffering agents.
  • additional buffering agents include saline, phosphate, phosphoric acid, citrate, succinate, gluconate, histidine, acetic acid, ascorbate, tartaric 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.
  • the pharmaceutical composition comprises acetic acid as an additional buffering agent.
  • 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. [0524] 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.
  • ascorbic acid cysteine hydrochloride
  • sodium bisulfate sodium metabisulfite
  • sodium sulfite sodium sulfite
  • ascorbyl palmitate butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl
  • the preservative agent when the pharmaceutical composition comprises a preservative agent, is phenol, benzyl alcohol, or a combination thereof.
  • 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.
  • the pharmaceutical composition may further comprise an emulsifier.
  • Non- limiting examples of emulsifiers that may be included in the pharmaceutical composition include sodium carboxymethylcellulose, cetyl alcohol, glycerol monostearate, methylcellulose, and stearic acid.
  • the emulsifier when the pharmaceutical composition comprises an emulsifier, is sodium carboxymethylcellulose.
  • the pharmaceutical composition may further comprise a lipid. Lipids may enhance solubility and/or improve permeability of the non-naturally occurring melanocortin analog.
  • 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.
  • the pharmaceutical composition comprises a lipid
  • the lipid is N-(carbonyl-methoxypolyethylene glycol 2000)- 1,2-distearoyl-glycero-3-phosphoethanolamine sodium salt [0528]
  • 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.
  • the pharmaceutical composition when the pharmaceutical composition comprises a bulking agent, the bulking agent is mannitol.
  • the pharmaceutical composition when the pharmaceutical composition comprises a bulking agent, the bulking agent is mannitol.
  • the pharmaceutical composition is in the form of an aqueous solution or a suspension.
  • the pharmaceutical composition is in the form of an emulsion.
  • the pharmaceutical composition is in the form of an aqueous solution.
  • the pharmaceutical composition is in the form of an aqueous solution which is clear, colorless, and/or free of visible foreign matter.
  • 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.
  • the pharmaceutical composition has a pH ranging from at least 6.5 to at least 8.5.
  • the pharmaceutical composition has a pH of at least 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.
  • the pharmaceutical composition has a pH ranging from at least about 6.5 to at least about 8.5.
  • the pharmaceutical composition has a pH of at least 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.
  • 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.
  • the pharmaceutical composition has a pH ranging from about 7.3 to about 7.4.
  • the pharmaceutical composition has a pH of 7.3 or 7.4.
  • the pharmaceutical composition is basic and has a pH of at least 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.
  • the pharmaceutical composition has a pH ranging from at least 7.3 to at least 7.4.
  • the pharmaceutical composition has a pH of 7.3 or 7.4.
  • the pharmaceutical composition is basic and has a pH of at least 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.
  • the pharmaceutical composition has a pH ranging from at least about 7.3 to at least about 7.4. In some embodiments, the pharmaceutical composition has a pH of 7.3 or 7.4. [0536] In some embodiments, the pharmaceutical composition has an osmolality ranging from 250 mOsm/kg to 350 mOsm/kg.
  • 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.
  • 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.
  • the pharmaceutical composition has an osmolality ranging from about 275 mOsm/kg to about 330 mOsm/kg.
  • the pharmaceutical composition has an osmolality of about 279 mOsm/kg, about 314 mOsm/kg, or about 329 mOsm/kg. [0537] In some embodiments, the pharmaceutical composition has an osmolality ranging from 250 mOsm/kg to 350 mOsm/kg.
  • 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 at least 300 mOsm/kg.
  • the pharmaceutical composition has an osmolarity of at least 250 mOsm/kg, at least 260 mOsm/kg, at least 270 mOsm/kg, at least 280 mOsm/kg, at least 290 mOsm/kg, at least 300 mOsm/kg, at least 310 -128- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 mOsm/kg, at least 320 mOsm/kg, at least 330 mOsm/kg, at least 340 mOsm/kg, at least 350 mOsm/kg, or at least 360 mOsm/kg.
  • the pharmaceutical composition has an osmolality ranging from at least 275 mOsm/kg to at least 330 mOsm/kg. In some embodiments, the pharmaceutical composition has an osmolality of at least 279 mOsm/kg, at least 314 mOsm/kg, or at least 329 mOsm/kg. [0538] In some embodiments, the pharmaceutical composition has an osmolality ranging from 250 mOsm/kg to 350 mOsm/kg.
  • 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 at least about 300 mOsm/kg.
  • the pharmaceutical composition has an osmolarity of at least about 250 mOsm/kg, at least about 260 mOsm/kg, at least about 270 mOsm/kg, at least about 280 mOsm/kg, at least about 290 mOsm/kg, at least about 300 mOsm/kg, at least about 310 mOsm/kg, at least about 320 mOsm/kg, at least about 330 mOsm/kg, at least about 340 mOsm/kg, at least about 350 mOsm/kg, or at least about 360 mOsm/kg.
  • the pharmaceutical composition has an osmolality ranging from at least about 275 mOsm/kg to at least about 330 mOsm/kg. In some embodiments, the pharmaceutical composition has an osmolality of at least about 279 mOsm/kg, at least about 314 mOsm/kg, or at least about 329 mOsm/kg. [0539] In some embodiments, the pharmaceutical composition has a viscosity ranging from about 0.5 cP to about 5 cP.
  • 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.
  • 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.
  • the pharmaceutical composition has a viscosity of about 1.4 cP or about 1.6 cP.
  • the pharmaceutical composition has a viscosity ranging from at least 0.5 cP to at least 5 cP.
  • the pharmaceutical composition may have a viscosity ranging from at least 0.5 cP to at least 5 cP, at least 0.75 cP to at least 4.5 cP, at -129- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 least 1.0 cP to at least 4 cP, at least 1.2 cP to at least 3.5 cP, at least 1.3 cP to at least 3 cP, at least 1.4 cP to at least 2.5 cP, at least 1.5 cP to at least 2 cP, or at least 1.6 cP to at least 1.8 cP.
  • the pharmaceutical composition has a viscosity of at least 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.
  • the pharmaceutical composition has a viscosity of at least 1.4 cP or at least 1.6 cP. [0541]
  • the pharmaceutical composition has a viscosity ranging from at least about 0.5 cP to at least about 5 cP.
  • the pharmaceutical composition may have a viscosity ranging from at least about 0.5 cP to at least about 5 cP, at least about 0.75 cP to at least about 4.5 cP, at least about 1.0 cP to at least about 4 cP, at least about 1.2 cP to at least about 3.5 cP, at least about 1.3 cP to at least about 3 cP, at least about 1.4 cP to at least about 2.5 cP, at least about 1.5 cP to at least about 2 cP, or at least about 1.6 cP to at least about 1.8 cP.
  • the pharmaceutical composition has a viscosity of at least 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 at least about 1.4 cP or at least about 1.6 cP.
  • 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.
  • parenteral includes subcutaneous, intravenous, intraperitoneal, intramuscular, and intralesional, or infusion techniques.
  • the active ingredient(s) e.g., the non- naturally occurring melanocortin analog
  • the aforementioned carrier and/or excipient 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.
  • 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.
  • 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
  • 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, 35mM, 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.
  • the pharmaceutical composition comprises one or more antioxidants.
  • the pharmaceutical composition may comprise ascorbic acid, cysteine, sodium metabisulfite, propyl gallate, butylated hydroxytoluene, and/or butylated hydroxyanisole.
  • the pharmaceutical composition comprises a surfactant, such as a sorbitan ester.
  • the pharmaceutical composition comprises a flavoring or scent, such as an aromatic oil. -131- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00
  • 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.
  • the pharmaceutical composition comprises between 0.03 wt% and 1 wt% melanocortin analog solubilized or suspended in a solvent or vehicle.
  • 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%.
  • the pharmaceutical composition may comprise the non- naturally occurring melanocortin analog in an amount of at least 0.03 wt%, at least 0.05 wt%, at least 0.1 wt%, at least 0.15 wt%, at least 0.2 wt%, at least 0.25 wt%, at least 0.3 wt%, at least 0.35 wt%, at least 0.4 wt%, at least 0.45 wt%, at least 0.5 wt%, at least 0.55 wt%, at least 0.6 wt%, at least 0.65 wt%, at least 0.7 wt%, at least 0.75 wt%, at least 0.8 wt%, at least 0.85 wt%, at least 0.9 wt%, at least 0.95 wt%, or at least 1 wt%.
  • the pharmaceutical composition may comprise the non- naturally occurring melanocortin analog in an amount of at least about 0.03 wt%, at least about 0.05 wt%, at least about 0.1 wt%, at least about 0.15 wt%, at least about 0.2 wt%, at least about 0.25 wt%, at least about 0.3 wt%, at least about 0.35 wt%, at least about 0.4 wt%, at least about 0.45 wt%, at least about 0.5 wt%, at least about 0.55 wt%, at least about 0.6 wt%, at least about 0.65 wt%, at least about 0.7 wt%, at least about 0.75 wt%, at least about 0.8 wt%, at least about 0.85 wt%, at least about 0.9 wt%, at least about 0.95 wt%, or at least about 1 wt%.
  • the non-naturally occurring melanocortin analogs of the present technology may be formulated for administration using any means known in the art, including orally, rectally, vaginally, ocularly, intranasally, topically, parenterally, or by injection. If administered by injection, the peptide injection may be intravenous (IV), subcutaneous (SC), intramuscular (IM), intraperitoneal (IP), intracerebroventricular (ICV), or other means known in the art.
  • IV intravenous
  • SC subcutaneous
  • IM intramuscular
  • IP intraperitoneal
  • ICV intracerebroventricular
  • the non-naturally occurring melanocortin analog of the combination therapy may -132- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 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, anti-oxidants and other agents known in the art.
  • Administration includes topical delivery.
  • 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.
  • the pharmaceutical composition formulated for intranasal administration comprises a non-naturally occurring melanocortin analog at a concentration at 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 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.
  • the pharmaceutical composition is formulated for oral administration.
  • the pharmaceutical composition may be in the form of a tablet, capsule, lozenge, pill, sachet, or any other orally deliverable form know in the art.
  • the composition may be formulated to be delivered by nose drop, spray device, or topical solution.
  • the pharmaceutical composition may be formulated as an aerosol, atomizer, inhalation, insufflation, metered-dose inhaler, or nebulizer.
  • the pharmaceutical composition includes a propellant, such as hydrofluoroalkane.
  • the pharmaceutical composition may be configured to be administered using a spray device or nasal inhaler.
  • the spray device or nasal inhaler may be configured to deliver 1 ⁇ g to 100 ⁇ g per spray.
  • the spray -133- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 device or nasal inhaler may be configured to deliver 1 ⁇ g to 100 ⁇ g, 5 ⁇ g to 90 ⁇ g, 10 ⁇ g to 80 ⁇ g, 15 ⁇ g to 70 ⁇ g, 20 ⁇ g to 60 ⁇ g, 25 ⁇ g, to 50 ⁇ g, or 30 ⁇ g to 40 ⁇ g per spray.
  • Combination Therapy [0558]
  • the present technology relates to a combination therapy comprising a first non-naturally occurring melanocortin analog and a second non-naturally occurring melanocortin analog.
  • the first non-naturally occurring melanocortin analog is a non-naturally occurring melanocortin analog agonist.
  • the combination therapy may be useful in one or more methods of the present technology.
  • the combination therapies may be more effective than the first non-naturally occurring melanocortin analog or a second non-naturally occurring melanocortin analog administered alone.
  • the first non-naturally occurring melanocortin analog is selected from the group consisting of a non-naturally occurring melanocortin analog of any one of Formulae (I)-(IG) to the subject.
  • the non-naturally occurring melanocortin analog is selected from the group consisting of MC4-NN2-0453 (16-(tetrazol-5-yl)hexadecanoyl-Oeg- Gly-Ser-Gln-His-Dap[bis(carboxymethyl)amino]acetyl-Nle-c[Glu-Hyp-dPhe-Arg-Trp-Lys]- NH2), LY2112688 (Ac-dArg-c[Cys-Glu-His-dPhe-Arg-Trp-Cys]-NH2), Melanotan-II (Ac-Nle- [Asp-His-dPhe-Arg-Trp-Lys]-NH2), Afamelanotide (Ac-Ser-Tyr-Ser-Nle-Glu-His-dPhe-Arg- Trp-Gly-Lys-Pro-Val
  • the second non-naturally occurring melanocortin analog and the first non- naturally occurring melanocortin analog may be administered concurrently, sequentially, or -134- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 cyclically.
  • the second non-naturally occurring melanocortin analog and a non-naturally occurring melanocortin agonist are administered concurrently, sequentially, or cyclically.
  • the second non-naturally occurring melanocortin analog and a non-naturally occurring melanocortin antagonist are administered concurrently, sequentially, or cyclically.
  • the second non-naturally occurring melanocortin analog and the first non-naturally occurring melanocortin analog are administered concurrently.
  • the second non-naturally occurring melanocortin analog and the first non-naturally occurring melanocortin analog may be administered concurrently but separately, such as in separate compositions (e.g., the first pharmaceutical composition and the second pharmaceutical composition).
  • the administration may be simultaneous or stepwise.
  • the second non-naturally occurring melanocortin analog and the first non-naturally occurring melanocortin analog may be formulated in a single composition and may be administered as such.
  • administration of the second non-naturally occurring melanocortin analog is started at the same time as administration of the first non-naturally occurring melanocortin analog.
  • the subject may not have received any prior treatment with either the second non-naturally occurring melanocortin analog or the first non- naturally occurring melanocortin analog.
  • Concurrent administration of the second non-naturally occurring melanocortin analog and the first non-naturally occurring melanocortin analog may include continued administration of both treatments until the desired effect is achieved.
  • concurrent administration includes beginning treatment with the second non-naturally occurring melanocortin analog and the first non-naturally occurring melanocortin analog at the same time and continuing administration of the second non-naturally occurring melanocortin analog for a full treatment cycle and the first non-naturally occurring -135- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 melanocortin analog for a full treatment cycle.
  • the full treatment cycle of the second non-naturally occurring melanocortin analog is longer than the full treatment cycle of the first non-naturally occurring melanocortin analog. In other embodiments, the full treatment cycle of the second non-naturally occurring melanocortin analog is shorter than the full treatment cycle of the first non-naturally occurring melanocortin analog. Accordingly, although concurrent administration includes beginning treatment with the second non-naturally occurring melanocortin analog and the first non-naturally occurring melanocortin analog at the same time, administration of the second non-naturally occurring melanocortin analog may be completed before or after administration of the first non-naturally occurring melanocortin analog.
  • the second non-naturally occurring melanocortin analog and the non-naturally occurring analog may be administered simultaneously or stepwise.
  • Concurrent stepwise administration may be useful for combination therapies in which the second non-naturally occurring melanocortin analog should be administered once a week and the first non-naturally occurring melanocortin analog should be administered daily, or with any other regimen where treatment is being carried out simultaneously with the second non-naturally occurring melanocortin analog and the first non-naturally occurring melanocortin analog, but the administration schedules differ.
  • the second non-naturally occurring melanocortin analog may be administered at one time point and the non-naturally melanocortin analog may be administered at a second time point.
  • the time interval between the first time point and the second time point may be about 0.5-1 minutes, 2-3 minutes, 4-5 minutes, 6-8 minutes, 9-10 minutes, 12-15 minutes, 20-25 minutes, 30 to 60 minutes, 1 hour, 1-2 hours, 2-6 hours, 2-12 hours, 12-24 hours, 1-2 days, 2 days, 3 days, 4 days, 5 days, 6 days, or about 1 week, 2 weeks, 3 weeks, one month, or any period of time in between.
  • the second non-naturally occurring melanocortin analog and the first non-naturally occurring melanocortin analog are administered less than 15 minutes, less than 30 minutes, less than 45 minutes, less than 1 hour, less than 2 hours, less than 4 hours, less than 8 hours, less than 12 hours, less than -136- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 16 hours, less than 20 hours, less than 24 hours, less than 36 hours, or less than 48 hours apart. [0566] In some embodiments, the second non-naturally occurring melanocortin analog is administered once weekly and the first non-naturally occurring melanocortin analog is administered once, twice, or three times daily.
  • the first non-naturally occurring melanocortin analog may be administered 1 day, 2 days, 3 days, 4 days, 5 days, and/or 6 days after the second non-naturally occurring melanocortin analog.
  • the second non-naturally occurring melanocortin analog is administered once weekly and the first non-naturally occurring melanocortin analog is administered once weekly.
  • both agents are administered on a weekly basis, the second non-naturally occurring melanocortin analog and the first non-naturally occurring melanocortin analog may be administered on the same day, 1 day apart, 2 days apart, 3 days apart, 4 days apart, 5 days apart, or 6 days apart.
  • the second non-naturally occurring melanocortin analog is administered weekly and the first non-naturally occurring melanocortin analog is administered once every 2 weeks, once every 3 weeks, or once monthly.
  • the first non-naturally occurring melanocortin analog may be administered on the same day as the second non-naturally occurring melanocortin analog or on a different day than the second non-naturally occurring melanocortin analog once every 2 weeks, once every 3 weeks or once monthly.
  • the first non-naturally occurring melanocortin analog and/or the second non-naturally occurring melanocortin analog is present in a pharmaceutical composition of the present technology.
  • the combination therapies of the present technology may comprise the first non-naturally occurring melanocortin analog and the second non-naturally occurring melanocortin analog as distinct compositions.
  • the second non-naturally occurring melanocortin analog may be present in a first pharmaceutical composition and the non-naturally occurring analog may be present in a second pharmaceutical composition.
  • the first and second pharmaceutical compositions may be administered concurrently, sequentially, or cyclically.
  • pharmaceutical combinations of the present technology may be -137- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 formulated as a single pharmaceutical composition comprising a first non-naturally occurring melanocortin analog and a second non-naturally occurring melanocortin analog.
  • the second non-naturally occurring melanocortin analog is present in a first pharmaceutical composition and the first non-naturally occurring melanocortin analog is present in a second pharmaceutical composition.
  • the second non-naturally occurring melanocortin analog may be formulated with one or more pharmaceutically acceptable carriers and/or excipients to form the first pharmaceutical composition.
  • the first non-naturally occurring melanocortin analog may be formulated with one or more pharmaceutically acceptable carriers and/or excipients to form the second pharmaceutical composition.
  • the first and the second pharmaceutical compositions are different.
  • the first pharmaceutical composition comprising the second non-naturally occurring melanocortin analog and the second pharmaceutical composition comprising the first non-naturally occurring melanocortin analog are administered concurrently.
  • the first pharmaceutical composition and the second pharmaceutical composition are administered sequentially. In sequential administration, the first pharmaceutical composition may be administered before the second pharmaceutical composition, after the second pharmaceutical composition, or both.
  • the second pharmaceutical composition may be administered before the first pharmaceutical composition, after the first pharmaceutical composition, or both.
  • the first pharmaceutical composition and the second pharmaceutical composition may be administered cyclically.
  • EXAMPLES [0572] 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 -138- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 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 Non-Naturally Occurring Melanocortin Analog Synthesis-Generic [0573]
  • 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.
  • 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.
  • 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 solid- phase 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.
  • 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.
  • 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 alpha- -139- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 amine of the C-terminal amino acid residue may or may not be protected with an amine protecting group, as described below.
  • 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.
  • an amino acid residue may be coupled to a p-benzyloxybenzyl alcohol resin (Wang) or a 2-chlorotrityl chloride resin via an ester linkage.
  • an amino acid residue may be coupled to a benzhydrylamine (BHA) resin through an Fmoc-linker such as, for example, p- [(R,S)- ⁇ -[1-(9H-fluor-en-9-yl)-methoxyformamido]-2,4-dimethyloxybenzyl]-phenoxyacetic acid (Rink linker) via an amide linkage.
  • BHA benzhydrylamine
  • Fmoc-linker such as, for example, p- [(R,S)- ⁇ -[1-(9H-fluor-en-9-yl)-methoxyformamido]-2,4-dimethyloxybenzyl]-phenoxyacetic acid (Rink linker) via an amide linkage.
  • 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.
  • RP-HPLC reverse phase high performance liquid chromatography
  • HPLC high-performance liquid chromatograph
  • amino acid analysis amino acid analysis
  • mass spectrometry mass spectrometry
  • Example 2 Non-Naturally Occurring Melanocortin Analog Synthesis-Protecting Groups
  • 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.
  • 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 -140- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 place at that site.
  • 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.
  • a urethane-type protecting group such as benzyloxycarbonyl (Z) and substituted benzyloxycarbonyl, such as p- chlorobenzyloxycarbonyl, p-nitrobenz
  • 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.
  • 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.
  • 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).
  • DMF N,N-dimethylformamide
  • Example 3 Non-Naturally Occurring Melanocortin Analog Synthesis-Additional Modifications
  • N-terminus modifications such as acetylation
  • C-terminus modification e.g., amidation
  • 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-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H- -141- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 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
  • exemplary non-naturally occurring melanocortin analogs at the melanocortin receptors 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 Compounds were delivered as powder (1 mg) or 10 mM solutions (100 ⁇ l) 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. Table 1.
  • Cyclic AMP Homogenous Time-Resolved Fluorescence (HTRF) assay for Gs coupled receptor: [0005] 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 KCl, 1.25 mM MgSO4, 124 mM NaCl, 25 mM HEPES, 13.3 mM Glucose, 1.25 mM KH2PO4, 1.45 mM CaCl2, 0.5 g/l BSA, supplemented with 1mM IBMX or 25 ⁇ M Rolipram).
  • Group A melanocortin analogs also comprise Ala or dArg at the N-terminus and dVal-dPro or dTle-dPro at the C-terminus.
  • Group A non-naturally occurring melanocortin analogs are provided in Table 2. Table 2.
  • Group A non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula [0014]
  • Group B included non-naturally occurring melanocortin analogs B1 to B10, all of which are cyclic peptides comprising the motif c[Asp-His-p(F)dPhe-Arg-Trp-Lys] (SEQ ID NO: 161).
  • Group B melanocortin analogs also comprise Arg, Lys, dLys, His, or dHis at the -144- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 N-terminus and dVal-dPro or dTle-dPro at the C-terminus.
  • Group B non-naturally occurring melanocortin analogs are provided in Table 3. Table 3.
  • Group B non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analog NO 2 2 2 2 l of which are cyclic peptides comprising the motif c[Asp-His-p(F)dPhe-Arg-Trp-Lys] (SEQ ID NO: 161).
  • Group C melanocortin analogs also comprise Nle at the N-terminus.
  • Group C non-naturally occurring melanocortin analogs are provided in Table 4. Table 4.
  • Group C non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula 2 2 2 2 -145- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro- C8 26 NH2 l of which are cyclic peptides comprising a derivative of the motif c[Asp-His-p(F)dPhe-Arg-Trp- Lys] (SEQ ID NO: 161).
  • Derivatives of the motif of SEQ ID NO: 161 may include substitution of His with another amino acid, for example, Gln or dHis, substitution of Arg with another amino acid, for example, His, or substitution of Trp with another amino acid, for example, dNal(2’).
  • Group D non-naturally occurring melanocortin analogs are provided in Table 5. Table 5.
  • Group D non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analog NO H2 l of which are cyclic peptides comprising the motif c[Asp-His-dPhe-Arg-Trp-Lys] (SEQ ID NO: 164) or a derivative thereof.
  • Derivatives of the motif of SEQ ID NO: 164 included in Group E melanocortin analogs include insertions of a Pro between Asp and His or between Trp and Lys.
  • Group E non-naturally occurring melanocortin analogs are provided in Table 6. Table 6.
  • Group E non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula [0018]
  • Derivatives of the motif of SEQ ID NO: 164 may include substitution of -146- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 His with another amino acid, for example, Gln, Pro or dHis, or substitution of Arg with another amino acid, for example, cisPro(guan) or transPro(guan).
  • Group F non-naturally occurring melanocortin analogs are provided in Table 7. Table 7.
  • Group F non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analog NO 2 2 s a cyclic peptide comprising a derivative of the motif c[Asp-His-dPhe-Arg-Trp-Lys] (SEQ ID NO: 164).
  • the derivative of the motif of SEQ ID NO: 164 included in the Group G melanocortin analog includes at least one insertion between Asp and His.
  • the Group G non-naturally occurring melanocortin analog is provided in Table 8. Table 8.
  • Group G non-naturally occurring melanocortin analog Melanocortin SEQ ID Formula analo NO , l of which are cyclic peptides comprising the motif dAla-His-dPhe-Arg-Trp (SEQ ID NO: 163), or a derivative thereof. Derivatives of the motif of SEQ ID NO: 163 may include substitution of dAla with a similar amino acid, for example, Ala.
  • Group H non-naturally occurring melanocortin analogs are provided in Table 9. Table 9.
  • Group H non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula 2 -147- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 H2 39 Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 H2 of which are cyclic peptides comprising the motif His-p(Cl)dPhe-Arg-Trp (SEQ ID NO: 165).
  • Group I melanocortin analogs also comprise Nle at the N-terminus.
  • Group I non-naturally occurring melanocortin analogs are provided in Table 10. Table 10.
  • Group I non-naturally occurring melanocortin analogs Melanocortin SEQ ID analog NO Formula 2 2 2 , l of which are cyclic peptides comprising the motif His-p(F)dPhe-Arg-Trp (SEQ ID NO: 166).
  • Group J melanocortin analogs may be cyclized through a lactam bond between R 2 and R 7 , where the amine-containing residue, e.g., Lys, Orn, Dap, or Dab, is present at either the R 2 or R 7 position and the carboxylic acid-containing residue, e.g., Asp or Glu, is present at the other position.
  • Group J non-naturally occurring melanocortin analogs are provided in Table 11.
  • Group K melanocortin analogs may be cyclized through a lactam bond between R 2 and R 7 , where the amine-containing residue, e.g., Lys, Orn, or Dab, is present at either the R 2 or R 7 position and the carboxylic acid-containing residue, e.g., Asp or Glu, is present at the other position. Further, Group K melanocortin analogs may have a linear dVal-dPro C-terminus. Group K non-naturally occurring melanocortin analogs are provided in Table 12. Table 12.
  • Group K non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula 2 2 2 -149- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 K 5 182 Ac—Nle-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 K 184 Ac—Nle-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 2 2 2 H 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 l of which are cyclic peptides comprising the motif Asn-p(F)dPhe-Arg-Trp (SEQ ID NO: 167).
  • Group L melanocortin analogs may be cyclized through a lactam bond between R 2 and R 7 , where the amine-containing residue, e.g., Lys, Orn, Dap, or Dab, is present at either the R 2 or R 7 position and the carboxylic acid-containing residue, e.g., Asp or Glu, is present at the other position. Further, Group L melanocortin analogs may not have a linear C-terminus. Group L non-naturally occurring melanocortin analogs are provided in Table 13. Table 13.
  • Group L non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula -150- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 L 4 216 Ac—Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]—NH2 L 207 Ac—Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]—NH2 all of which are cyclic peptides comprising the motif Pro-dPhe-Arg-Trp (SEQ ID NO: 168) or derivatives thereof and cyclized through a lactam bond between Lys at R 2 and Glu R 7 .
  • Derivative of the motif of SEQ ID NO: 168 may include substitution or deletion of Pro.
  • Group M non-naturally occurring melanocortin analogs are provided in Table 14. Table 14.
  • Group M non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analog NO , l of which are cyclic peptides comprising the motif His-dPhe-Arg-Trp (SEQ ID NO: 169).
  • Group M melanocortin analogs may be cyclized through a lactam bond between R 2 and R 7 , where the amine-containing residue, e.g., Lys, Orn, Dap, or Dab, is present at either the R 2 or R 7 position and the carboxylic acid-containing residue, e.g., Asp or Glu, is present at the other position.
  • Group N non-naturally occurring melanocortin analogs are provided in Table 15. Table 15.
  • Group N non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula -151- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 N 4 193 Ac—Nle-c[Lys-His-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 N 194 Ac—Nle-c[Orn-His-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 nd O10, all of which are cyclic peptides comprising the motif His-p(F)dPhe-Arg-Trp-Orn (SEQ ID NO: 162), or a derivative thereof.
  • SEQ ID NO: 162 may include substitution of Arg with a similar amino acid, for example, His.
  • Group O non-naturally occurring melanocortin analogs are provided in Table 16. Table 16.
  • Group O non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analog NO 2 2 , all of which are cyclic peptides comprising the motif Asn-dPhe-Arg-Trp (SEQ ID NO: 170).
  • Group P melanocortin analogs may be cyclized through a lactam bond between R 2 and R 7 , where the amine-containing residue, e.g., Lys, Orn, Dap, or Dab, is present at either the R 2 or R 7 position and the carboxylic acid-containing residue, e.g., Asp or Glu, is present at the other position. Further, Group P melanocortin analogs may have a linear C-terminus or dVal-dPro or dArg-dVal. Group P non-naturally occurring melanocortin analogs are provided in Table 17. Table 17.
  • Group Q melanocortin analogs may be cyclized through a lactam bond between R 2 and R 7 , where the amine-containing residue, e.g., Lys, Orn, Dap, or Dab, is present at either the R 2 or R 7 position and the carboxylic acid-containing residue, e.g., Asp or Glu, is present at the other position. Further, Group Q melanocortin analogs may not have a linear C-terminus. Group Q non-naturally occurring melanocortin analogs are provided in Table 18. Table 18.
  • Group Q non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula -153- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 Q 2 218 Ac—Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]—NH 2 219 Ac—Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]—NH 2 l of which are cyclic peptides comprising the motif Asn-p(Cl)dPhe-Arg-Trp (SEQ ID NO: 171) and are cyclized through a lactam bond between Glu or Lys R 2 and Orn or Asp at R 7 .
  • Group Q non-naturally occurring melanocortin analogs are provided in Table 19.
  • Table 19 Group Q non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analog NO 2 H2 n 5 receptor [0031]
  • Administration of some non-naturally occurring melanocortin analogs activated melanocortin 1 receptor (MC1R) and melanocortin 5 receptor (MC5R) activity, as measured by cAMP levels (Table 12).
  • M1R melanocortin 1 receptor
  • M5R melanocortin 5 receptor
  • O10 was compared to sequences with different lactam cyclization types, different residues at the R 4 and R 3 positions, and different C-terminal residues.
  • the agonist activity of O10 and comparative sequences is provided in Table 15, below. Table 15.
  • results from this assay are provided in Table 24.
  • Table 24 Dose-response results of melanocortin analogs and control against PrRP Synthetic Max EC50 (nM)* Hill Top (%) -174- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 LY2112688 trifluoroacetate 2.33 >2000 - - An [0045] The antagonist activity of some of the non-naturally occurring melanocortin analogs was measured on PrRP by Aequorin assay. Results from this assay are provided in Table 25. Table 25.
  • Disposition of Remaining Test Article Formulations Remaining formulations will be stored at -60°C or lower.
  • Cynomolgus Monkey Specifications Species Cynomolgus Monkeys -180- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 This is an acceptable species to support PK Justification for Species studies for compounds intended to use in e or al ff g e [0061]
  • Environmental Conditions Environment controls will be set to maintain a temperature range of 20-26°C, a relative humidity range of 40 to 70%, and a 12-hour light/12-hour dark cycle. The light/dark cycle may be interrupted for study-related activities.
  • Housing Animals will be group-housed (up to four animals/sex/cage) in polysulfone cages with certified aspen shaving bedding or corncob bedding during acclimation and study period. While animals may be individually housed after surgery or when there is special requirement in protocol, as well as, for behavioral or health reasons or due to cage mate death. -181- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 [0063] Diet and Feeding: Animals were offered certified rodent breeding and growth diet ad libitum every day, unless fasted for study procedures.
  • Dose Administration The dose volume will be determined by the animals' body weight collected on the morning of dosing day.
  • Blood Sample Collection and Process At least 0.1 mL blood will be collected at each time point. All blood samples will be collected via jugular vein. All blood samples will be transferred into low binding EP tube with anticoagulant (0.5 M Potassium (K2) EDTA will be pre-added as a ratio of 50:1 for blood: anticoagulant), 0.05% Triton X-100 (e.g., 100uL Blood+2uL 2.5% Triton X-100) will be used for desorption the blood samples will be placed on wet ice. [0072] Blood samples will be centrifuged within 1hr of collection at 3,200 g 4°C for 10 minutes.
  • anticoagulant 0.5 M Potassium (K2) EDTA will be pre-added as a ratio of 50:1 for blood: anticoagulant
  • Triton X-100 e.g., 100uL Blood+2uL 2.5% Triton X-100
  • LC-MS/MS method development [0074] A LC-MS/MS method for the quantitative determination of test compound in biological matrix will be developed. [0075] N in 1 cassette LC-MS/MS method may be developed for samples coming from different studies as long as these studies belong to the same sponsor. -183- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 [0076] Cassette administration assay could be performed if the mass difference ( ⁇ Mass) among different analytes is ⁇ 4 Da.
  • the recommended injection order is C8, C6, C4, C2, study samples, C7, C5, C3, C1.
  • sample number within a batch is > 12, one standard curve and two sets of QCs with low, middle and high concentrations will be applied for bioanalysis. Meanwhile, QCs number should be more than 5% of study sample number.
  • Samples, coming from one client with the same type of matrix in different studies, are allowed to be quantified in one analysis run by using the developed N in 1 cassette LC-MS/MS method.
  • Acceptance criteria [0084] (1) Linearity: At least 75% of the calibration standards should fall within ⁇ 20% of their nominal values for biofluid and within ⁇ 25% of their nominal values for tissue and feces samples.
  • the truncated calibration curve should consist of at least 75% of the initial STDs. -184- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 [0085]
  • Absolute carryover is calculated by carryover contribution multiplies carryover impact, where the carryover contribution is calculated by the area ratio of the double blank or blank with the highest carryover (Area max of carryover blank) to the ULOQ with the minimum calculated value (Area min of ULOQ), and the carryover impact is calculated by the area ratio of one injection (Area of one injection) to the following injection (Area of the following injection).
  • the absolute carryover should be below the acceptable accuracy of the studies (e.g., 20% or 25%).
  • Carryover contribution Areamax of carryover blank / Areamin of ULOQ
  • Carryover impact Area of one injection / Area of the following injection
  • Absolute carryover Carryover contribution * Carryover impact Data Analysis
  • Plasma concentration versus time data for Compounds A-C in Rats and Cynomolgus Monkeys will be plotted in graph and analyzed by non-compartmental approaches.
  • Related PK parameters will be calculated according to dosing route, e.g., Cl, Vdss and C0 for intravenous administration, Cmax, Tmax or %F for extravascular administration, and T1 ⁇ 2, AUC(0-t), AUC(0-inf), MRT(0-t), MRT(0-inf) for all routes.
  • PK parameters were calculated according to dosing route, e.g., Cl, Vdss and C0 for intravenous administration, Cmax, Tmax or %F for extravascular administration, and T1 ⁇ 2, AUC(0-t), AUC(0-inf), MRT(0-t), MRT(0-inf) for all routes.
  • FIGS 3A-3C IP, SC administration
  • FIGS.4A-4G IP, SC administration
  • FIGS.5A-5C PO administration
  • Plasma and CSF concentrations over 24 hours after administration of Compound E (O10) or setmelanotide were also assessed. It was predicted that O10 will be efficacious for treating general obesity in part due to the PK values in plasma and CSF and the higher affinity for MC3R and MC4R relative to setmelanotide.
  • Table 39 Plasma Pharmacokinetic Results of Compound E (O10) in Rats after 24 hours AUC 0- AUC 0- Dose Cmax AUM Table 40.
  • Plasma Concentration Plasma pharmacokinetic measurements using 30 mg/kg were assessed in Cynomolgus monkey plasma up to 24 hours. Results are detailed in Table 44.
  • Table 44 Pharmacokinetic Data Compound 30 mg/kg Name PO Cynomolgus Monkey
  • the antagonist activity of exemplary non-naturally occurring melanocortin analogs at specific ion channels was measured using the Qube electrophysiological platform.
  • the non-naturally occurring melanocortin analogs and specific ion channel targets are provided in Table 45.
  • Ion channel targets and melanocortin analogs Melanocortin Ion channel targets MW + Saly Condition
  • the non-naturally occurring melanocortin analogs identified above were tested for antagonist activity at various ion channels at concentrations ranging from 0.1 mM to 30 mM.
  • Peak current is measured during the step to -15mV. [0100] The parameters measured were difference between the peak inward current on stepping to -15mV (i.e., peak of the current) and the leak current. All data were filtered for seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition and the amount of block was assessed by dividing the Test compound current amplitude by the Control current amplitude. Control is the mean Nav1.5 current amplitude collected 10 seconds at the end of the vehicle control; Test Compound is the mean Nav1.5 current amplitude collected 10 seconds at the end of test concentration application for each concentration.
  • hKv4.3/hKChIP2 Potassium Channel Assay – Qube APC After whole cell configuration is achieved, the cells are held at -80mV. Onset and steady state block of hKv4.3 current is measured using a pulse pattern from -80mV to 40mV amplitude for a 110ms duration, and finally a 100ms ramp (1.2 V/s) to -80mV. This paradigm is delivered once every 5s to monitor the current amplitude. [0102] The parameters measured were the maximum outward current evoked on stepping to 40mV from holding potential of -80mV. All data were filtered for seal quality, seal drop, and current amplitude.
  • Control data is the mean Kv4.3/KChIP2 current amplitude collected 10 seconds at the end of the vehicle control period;
  • Test compound data is the mean Kv4.3/KChIP2 current amplitude collected 10 seconds at the end of test concentration application for each concentration.
  • hCav1.2 (L-type) CiPA Calcium Channel Assay – Qube APC [0103] Onset and steady state block of peak hCav1.2 current is measured using a pulse pattern, repeated every 15 sec.
  • the calcium current amplitude is calculated by measuring the difference between the peak inward current on stepping to 0mV or the peak inward current at the ramp (i.e. peak of the current) and the leak current. The calcium current is assessed in vehicle control conditions and at the end of each five (5) minute compound application.
  • Late Current Sodium Channel Assay – Qube APC Onset and steady state block of Late Nav1.5 current is measured using a pulse pattern, repeated every 5 sec, consisting of a hyperpolarizing pulse to -120mV for a 200ms duration, depolarization to -15mV amplitude for a 40ms duration, followed by step to 40mV for 200ms and finally a 100ms ramp (1.2 V/s) to a holding potential of -80mV. Late current is measured as charge current elicited during the ramp with 50nM ATXII.
  • Control data is the mean hNav1.5 late current collected 15 seconds at the end of 50nM ATXII application (50nM ATXII control);
  • Test compound data is the mean ramp hNav1.5 current collected 15 seconds at the end of test concentration application for each concentration.
  • hERG Potassium Channel Assay - Qube APC After whole cell configuration is achieved, the cells are held at -80mV. Cells are held at this voltage for 50ms to measure the leak current, which is subtracted from the tail current on-line. The cells are depolarized to +40mV for 500ms and then to -80 mV over a 100ms ramp to elicit the hERG tail current. This paradigm is delivered once every 8s to monitor the current amplitude. All compounds were tested in the presence of 0.1% Pluronic F-68 Non-Ionic Surfactant and at approximately room temperature.
  • Control data is the mean hERG current amplitude collected for three pulses (24 seconds) at the end of the vehicle control;
  • Test compound data is the mean hERG current amplitude collected for three pulses (24 seconds) at the end of test concentration application for each concentration.
  • hKCNQ1/hminK Potassium Channel Assay – Qube APC After whole cell configuration is achieved, the cells are held at -80mV. KCNQ1/minK currents are evoked by a 1000ms pulse from -80mV to 60mV followed by a ramp from 60mV to -80mV over 115ms with the outward peak currents measured upon depolarization of the cell membrane. This paradigm is delivered once every 15s to monitor the current amplitude. [0110] The parameters measured were the maximum outward current evoked on stepping to +60mV from a holding potential of -80mV. All data were filtered for seal quality, seal drop, and current amplitude.
  • Control data is the mean hKCNQ1/hminK current amplitude collected 30 seconds at the end of vehicle control period;
  • Test compound data is the mean hKCNQ1/hminK current amplitude collected 30 seconds at the end of test concentration application for each concentration.
  • hKir2.1 Potassium Channel Assay – Qube APC [0111] After whole cell configuration is achieved, the cells are held at -30mV. Kir2.1 currents are evoked by a single 500ms pulse to -120mV before returning to the holding potential of -30mV. This paradigm is delivered once every 20s to monitor the current amplitude.
  • the parameters measured were the maximum inward current elicited on stepping to -120mV for 500ms from a holding potential of -30 mV. All data were filtered for -192- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition. Residual non-Kir2.1 current was eliminated via normalization to residual current after application of 100uM Barium Chloride. The amount of Test compound effect was then assessed by dividing the Test compound current amplitude by the Control current amplitude.
  • Control data is the mean Kir2.1 current amplitude collected 40 seconds at the end of the vehicle control;
  • Test compound data is the mean Kir2.1 current amplitude collected 30 seconds at the end of test concentration application for each concentration.
  • Results [0113] Where presented, IC50 values were determined by a non-linear, least squares regression analysis. Reference standards were run as an integral part of each assay to ensure the validity of the results obtained. Results from the ion channel assessment of non- naturally occurring melanocortin analogs are provided in Table 46. Table 46. Dose-response results of melanocortin analogs and reference compounds against ion channels.
  • Solution properties of non-naturally occurring melanocortin analogs and reference compounds in various biological media were assessed according to the conditions provided in Table 47.
  • Aqueous solubility ( ⁇ M) was determined by comparing the peak area of the principal peak in a calibration standard (200 ⁇ M) containing organic solvent (methanol/water, 60/40, v/v) with the peak area of the corresponding peak in a buffer sample.
  • chromatographic purity was defined as the peak area of the principal peak relative to the total integrated peak area in the HPLC chromatogram of the calibration standard.
  • the amount of compound in buffer was determined as the combined, volume-corrected, and weighted areas of the corresponding peaks in the aqueous phases of three organic- aqueous samples of different composition. An automated weighting system was used to ensure the preferred use of raw data from those samples with well quantifiable peak signals. The amount of compound in organic was calculated by subtraction. Subsequently, Log D was calculated as the Log10 of the amount of compound in the organic phase divided by the amount of compound in the aqueous phase.
  • Table 48 Protein binding of melanocortin analogs in plasma Compound Test Average % Average % Table 49.
  • Aqueous solubility of melanocortin analogs in plasma PBS
  • simulated gastric fluid SGF
  • simulated intestinal fluid SIF
  • Compound Test Concentration M
  • Average Solubility PB * F IF Table 51. Partition coefficient of melanocortin analogs and reference compounds
  • Compound Test Concentration M
  • Partition Coefficient* -197- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 *log D, n-octanol/PBS, pH 7.4 In Vitro Absorption [0122] In vitro absorption of non-naturally occurring melanocortin analogs was determined using permeability assays.
  • Fluorescein assessment for Permeability assays Fluorescein was used as the cell monolayer integrity marker. Fluorescein permeability assessment (in the A-B direction at pH 7.4 on both sides) was performed after the permeability assay for the test compound. The cell monolayer that had a fluorescein permeability of less than 1.5 x 10 -6 cm/s for Caco-2 and MDR1-MDCKII cells and 2.5 x 10 -6 cm/s for MDCKII cells was considered intact, and the permeability result of the test compound from intact cell monolayer is reported. [0130] Results of the in vitro absorption assessments described above are provided in Table 53. Table 53.
  • O10 may be efficiently manufactured using standard solid-phase peptide synthesis (SPPS).
  • SPPS solid-phase peptide synthesis
  • B07 a melanocortin antagonist
  • B07 has high structural homology to O10.
  • B07 has been made in GMP batches up to 1 kg and it is amenable to efficient SPPS with high overall yields.
  • Non-canonical residues and cyclic structure may restricts fermentation-based approaches, and peptide purification is performed using standard RP-HPLC techniques.
  • O10 may be amenable to liquid-phase peptide synthesis (LPPS) for late-stage clinical and commercial manufacturing, offering potential for significant reductions in -200- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 manufacturing cost.
  • LPPS liquid-phase peptide synthesis
  • Exemplary melanocortin analogs O7 and O10 and comparator melanocortin analog TCMCB07 were tested at concentrations ranging from 0.1 mM to 100 mM for inhibition of the seven CYPs.
  • the CYP inhibition assays were performed using human liver microsomes (HLM) and human recombinant CYP isozymes in 96-well plate format.
  • Example 9 Body Weight, Complete Blood Count, Clinical Chemistry, and Food Intake in an Animal Model Objective [0001] The objective of this study was to evaluate the pharmacodynamic (PD) characteristics and effects on food intake, body composition, and clinical chemistry following administration of exemplary non-naturally occurring melanocortin analogs of the present technology.
  • Non-naturally occurring melanocortin analogs were administered to Cynomolgus monkeys via two subcutaneous (s.c.) injections at different doses.
  • Primate specifications are outlined in Table 58.
  • Body weight, clinical observations, and food intake observations were recorded daily. Measurement of initial body composition using Dual-Energy X-Ray Absorptiometry (DEXA) was recorded at least once during this time. Standard blood markers (e.g., glucose, insulin, HDL-c, LDL-c, triglycerides, total cholesterol, alanine aminotransferase, aspartate aminotransferase) were measured once. [0008] Treatment Phase (Days 8-49): Body weight was recorded twice a week, clinical observation and food intake were recorded once a day. Standard hematology and clinical chemistry readouts as above were conducted before dosing and at the conclusion of the study on day 49. DEXA measurements of body composition were conducted biweekly.
  • DEXA Dual-Energy X-Ray Absorptiometry
  • Food intake measurement was observed at about 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 24 hours, 48 hours, and 72 hours after administration of saline or non- naturally occurring melanocortin analogs at 1 mg/kg and 3 mg/kg (Day 8 and Day 11) dosing.
  • Day 8 and Day 11 On Days 4-7, monkeys were acclimatized to a normal diet of two meals per day.
  • the lower dose of the non-naturally occurring melanocortin analogs were administered, and observations continued through Day 10.
  • Day 11 the higher dose of the non-naturally occurring melanocortin analogs was administered, and observations continued through Day 13, the conclusion of the study.
  • Blood collection according to Table 60 was conducted for the following: clinical chemistry (Serum), hematology (whole blood). Whole blood was collected at each time point with syringe via the cephalic or saphenous veins into labeled polypropylene tubes. -205- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 Table 60. Blood Sampling Animal Blood Minimum Volume Time Point Test Type Gr S m l T f Bl d S m les [0011] Clinical chemistry and hematology assessments were conducted, assessing the parameters outlined in Tables 61 and 62.
  • Clinical Chemistry including triglycerides, creatine kinase, lactate dehydrogenase, alanine amino transferase, aspartate amino transferase, bilirubin, alkaline phosphatase, total protein, albumin, globulin, glucose, urea nitrogen, creatine, urea acid, and C-reactive protein was assessed in monkey serum on days 1, 8 (2h), and 11 (2h). Results of each measurement are outlined in Tables 71-76.
  • Body composition was assessed, including body weight (kg), body height (m), BMI (kg/m 2 ), whole body bone mineral content (g), trunk bone mineral content (g), bone density (g/cm 2 ), trunk fat mass (g), trunk fat mass (%), trunk muscle mass (g), trunk muscle mass (%), fat mass (g), fat mass (%), muscle mass (g), muscle mass (%), and lean mass (%) (Tables 99-104) (FIGS. 13A-13N).
  • Table 103 Body Composition Change (Part 1)
  • Table 104 Body Composition Change (Part 2) -232- 146316.8034.WO00 ⁇ 181226204.17
  • Table 105 Body Weight (kg) (Day 1-22) D ay 1 Day 8 Day 15 Day 22 Day 29
  • Table 106 Body Weight (Percent Change) Gr Anim l M r m nt y 8 , , , lso assessed (FIGS.14A-14D; Tables 107-118). Blood levels chemistry levels were unchanged -234- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8023.WO00 by day 29 from baseline in monkeys orally administered O10 relative to those administered saline. Cage side observations showed no signs of gastric distress (assessed by stool changes) or nausea (assessed by food refusal).
  • Table 107 Clinical Chemistry Day 1 (Part A) Clinical Glu Alanine Aspartate Alkaline Gamma- Total Total Trigly Chemis cos Aminotran Aminotransf Phospha glutamyl Biliru Prote cerid ol 71 5 41 9 .6 80 3 Table 108: Clinical Chemistry Day 1 (Part B) Clinical (Total) Alb High density Low density Lactate Cre Urea Creatin e -235- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8023.WO00 um mmol Day 1 mmol/L g/L mmol/L mmol/L U/L ol/L /L U/L M 75 95 3 62 5 33 6 56 4 Table 109: Clinical Chemistry Day 15 (Part A) Clinical Meas Glu Alanine Aspartate Alkaline Gamma- Total Total Trigl Chemi urem cos Aminotran Aminotrans Phos ha lutam l Biliru Prot
  • the tanning effect comprised skin darkening without hyperpigmentation (e.g., an uneven distribution of melanin) compared to baseline. Notably, the tanning effect was only seen in typically sun- exposed skin, with no observation of ectopic tanning (e.g., palms, gums, etc.). Monkeys -244- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8023.WO00 were never exposed to sunlight. Pigmentation resolved back to baseline levels rapidly after treatment was discontinued. [0145] The slope of the O10 weight loss curve (FIG.12I) suggests that a lower dose of O10 may be employed for the same efficacy.
  • rats were subcutaneously administered 0.5 mg/kg of A07D, O7, O10, or O11 for days 1-7 and 1 mg/kg for days 8-17.
  • O11 and O7 did not appear to influence food consumption as a percent of food consumption in saline-treated rats, relative to O10 (FIG.11Q).
  • O10 treated rats gained only about 0.64% of their body weight compared to saline, which gained about 8.98% body weight (**) (FIG.12L).
  • Example 12 Cardiac Effects [0017] Changes in cardiac effects were assessed in rats subcutaneously administered O10 at either 0.5 mg/kg, 1 mg/kg, or 3 mg/kg. Control rats were administered saline. Animal specifications are outlined in Table 119.
  • ECG electrocardiogram
  • SBP Systolic blood pressure
  • DBP diastolic blood pressure
  • HR heart rate
  • QRS, ST, QT, P wave, T wave, and HR were assessed with ECG measurements.
  • Recording duration occurred from -15 min (pre-dose) to 180 min (after dosing).
  • Table 121 Blood Pressure Analysis (Part 1) Animal SBP(mmHg) mi -247- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8023.WO00 G6: Mean 107 111 110 108 111 108 110 107 110 O10 1 k SEM 1 1 2 1 2 5 4 4 3
  • Table 122 Blood Pressure Analysis (Part 2) Animal DBP(mmHg) Group Measureme 0mi 5mi 15mi 30mi 60mi 90mi 120mi 150mi 180mi Table 123: Blood Pressure Analysis (Part 3) Animal HR(BPM) Gr M r m mi -248- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8023.WO00 Table 124: ECG Results (Part 1) Animal Heart Rate (BPM) Group Measureme 0mi 5mi 15mi 30mi 60mi 90mi 120mi 150mi 180mi Animal PR Interval (s) Group Measurem 15
  • O10 was assessed for interaction with RFamide receptors, which are hypothesized to cause cardiac activation in MC4R-targeting small molecules and peptides (Table 129).
  • Table 129 O10 Assessment for RFamide Receptor Binding Antagonist mode, IC50 (nM) Agonist mode, EC 50 (nM) F 0
  • O10 did not agonize or antagonize RFamide receptors up to 1000 nM (top concentration tested), 1000x-100,000x above their respective EC50s on MC4R. Additionally, no hERG inhibition observed from O10 at concentrations up to 30 ⁇ M.
  • O10 was next screened for binding against a panel of 87 receptors and channels at 10 ⁇ M. Results showing an inhibition or stimulation higher than 50% were considered to represent significant effects of the test compounds. O10 only showed >50% inhibition of control on melanocortin receptors (FIG.
  • O10 was shown to have minimal inhibition at 10 ⁇ M for cytochrome P450 (CYP) enzymes (Table 130 and Table 131). O10 showed no meaningful impact on CYP induction or inhibition at physiologically relevant concentrations, demonstrating minimal drug-drug interactions.
  • CYP cytochrome P450
  • Table 130 Assessing Time Dependent CYP Inhibition O10 -252- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8023.WO00 4.0 1A HLM, phenacetin substrate - NADPH -253- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8023.WO00 0.5 2C9 HLM diclofenac substrate Table 131: Assessing O10 and CYP Induction mRNA Fold Induction of Hepatocytes with Different Treatments: Mean -254- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8023.WO00 1 3.1 20.4 3.4 (1.97, 5.31) (17.6, 23.2) (3.42, 3.55) 0.8 30.7 B6; Rifampicin (10 ⁇ M) for CYP3A4.
  • Example 14 Assessing Adipose Tissue Effects of O10 [0150] To assess adipose tissue effects from O10 administration, fat tissue was harvested from diet-induced obese cynomolgus monkeys orally administered 10 mg/kg O10 or saline control. O10-treated monkeys showed (1) smaller lipid droplets, (2) darker, dense staining likely attributed to higher mitochondrial concentrations, and (3) increased vascularization, relative to saline controls (FIG. 19; H&E staining, 200x), consistent with beige/brown adipocytes. This suggests that O10 administration may stimulate metabolic remodeling through adipose tissue browning, which in turn may increase metabolic rate and calorie burn and may improve insulin sensitivity.
  • Example 15 Assessing absorption, distribution, metabolism, and excretion of non- naturally occurring melanocortin analogs
  • Non-naturally occurring melanocortin analogs of the present technology, O10 and C2 were assessed for solution properties, in vitro absorption, and in vitro metabolism for absorption, distribution, metabolism, and excretion (ADME) properties.
  • Various ADME outcomes are outlined in Table 132.
  • Aqueous Solubility [0152] Aqueous solubility ( ⁇ M) was determined by comparing the peak area of the principal peak in a calibration standard (200 ⁇ M) containing organic solvent (methanol/water, 60/40, v/v) with the peak area of the corresponding peak in a buffer sample.
  • chromatographic purity was defined as the peak area of the principal peak relative to the total integrated peak area in the HPLC chromatogram of the calibration standard.
  • HPLC-UV Screen [0153] A chromatogram of the test compound (200 ⁇ M) along with a UV/VIS spectrum with labeled absorbance maxima, was generated.
  • Areap Peak area of analyte in protein matrix
  • Areab Peak area of analyte in buffer
  • Areac Peak area of analyte in control sample Partition Coefficient
  • the total amount of compound was determined as the peak area of the principal peak in a calibration standard (100 ⁇ M) containing organic solvent (methanol/water, 60/40, v/v).
  • the amount of compound in buffer was determined as the combined, volume-corrected, and weighted areas of the corresponding peaks in the aqueous phases of three organic- aqueous samples of different composition. An automated weighting system was used to ensure the preferred use of raw data from those samples with well quantifiable peak signals. The amount of compound in organic was calculated by subtraction. Subsequently, LogD was calculated as the Log10 of the amount of compound in the organic phase divided by the amount of compound in the aqueous phase.
  • Half-Life Determination [0156] At the end of the incubation at each of the time points, an equal volume of an organic mixture (acetonitrile/methanol, 50/50, v/v) was added to the incubation mixture.
  • ADME-Tox In Vitro Absorption Permeability [0157]
  • CR,end is the concentration of the test compound in the receiver chamber at the end time point.
  • ⁇ t is the incubation time.
  • A is the surface area of the cell monolayer.
  • CD,mid is the calculated mid-point concentration of the test compound in the donor side, which is the mean value of the donor concentration at time 0 minute and the donor concentration at the end time point.
  • CR,end is the concentration of the test compound in the receiver sample at the end time point.
  • CD0 is the concentration of the test compound in the donor sample at time zero. Concentrations of the test compound are expressed as peak areas of the test compound.
  • Fluorescein Assessment for Permeability Assays [0159] Fluorescein was used as the cell monolayer integrity marker. Fluorescein permeability assessment (in the A-B direction at pH 7.4 on both sides) was performed after the permeability assay for the test compound.
  • ADME-Tox In Vitro Metabolism Intrinsic Clearance (microsomes, S9, cryopreserved hepatocytes, recombinant CYP, recombinant UGT) [0160] Metabolic stability, expressed as percent of the parent compound remaining, was calculated by comparing the peak area of the compound at the time point relative to that at time-0.
  • the half-life (T1/2) was estimated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) vs. time, assuming first-order kinetics.
  • O10 is (1) about 408x (x, times) more potent on MC3R, (2) about 120x more potent on MC4R, and (3) has superior PK parameters as shown in at least rats, where the CSF half-life of O10 is about 2x longer, the plasma half-life is about 3x longer, the CSF AUC is about 1.5x higher, and the plasma AUC is 4.5x higher (also see Table 133 and Table 134) compared to setmelanotide.
  • Table 133 cAMP Signaling Assay – Agonist Mode; EC50 (nM) Setmelanotide O10 Table 134: 10mg/kg SC (rat) PK Parameters Setmelanotide O10 PK M F M M F M [0162] Second, as shown by at least the drug exposure over the EC50 analyses, O10 is present at efficacious doses in CSF for periods of time longer than setmelanotide, O10 remains present in the CSF at concentrations higher than the EC50.
  • O10 will be more efficacious for general obesity (e.g., obesity not caused by genetic factors related to the melanocortin system) due to higher affinity for -267- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 MC3R and MC4R and PK values in plasma and CSF (as shown in the rat) compared to setmelanotide.
  • O10 reduces food intake in a single dose via 1 and 3 mg/kg SC injection in DIO cynomolgus monkeys, whereas setmelanotide did not affect food intake in 39-week toxicity study via 3 mg/kg/day SC injection in standard BMI cynomolgus monkeys. It is predicted that the 10 and 30 mg/kg oral administration doses of O10 will be efficacious considering the PK data and superior potency of O10 on MC3R and MC4R activation (Table 135).
  • Table 135 PL parameters O1030 mg/kg, oral administration in monkeys PK Mean SD CV (%) Paramet [0164]
  • the oral PK results suggest that O10 will also be efficacious at 10 and 30 mg/kg PO administration.
  • the plasma PKs of a 1 mg/kg SC injection of O10 to an oral 10 mg/kg and 30 mg/kg administration of O10 were above the EC50. Food intake may thus be reduced following oral administration of O10.
  • Human neurokinin NK1 receptor (agonist radioligand) binding assay [0166] Cells membrane homogenates (about 50 ⁇ g) were incubated for 30 min at 22°C with 0.05 nM [ 125 I]-substance P LYS3 in the absence or presence of the test compound (i.e., O10) in a buffer containing 50 mM Tris-HCl (pH 7.4), 5 mM MnCl2, 0.2% BSA and 40 ⁇ g/ml bacitracin. Nonspecific binding was then determined in the presence of 1 ⁇ M [Sar 9 ,Met(O2) 11 ]-substance P.
  • Nonspecific binding was then determined in the presence of 1 ⁇ M NPY. -269- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 [0170] Following incubation, the samples were filtered rapidly under vacuum through glass fiber filters (GF/B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester. The filters were dried then counted for radioactivity in a scintillation counter using a scintillation cocktail. Results are expressed as a percent inhibition of the control radioligand specific binding.
  • GF/B glass fiber filters
  • MC1 and MC4 showed >50% inhibition of control O10 (MC1 (agonist radioligand): 97.4%; MC4(h) (agonist radioligand): 100.4%) (FIGS.21-23). [0030] Enzyme inhibition and uptake was also assessed for O10 (FIG.23) (Table 139 and Table 140).
  • Table 139 In Vitro Pharmacology: Enzyme and Uptake Assays – Test Compound Results -281- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 Compound Test % Inhibition of Control Values Concentration 1 st 2 nd Mean Table 140: In Vitro Pharmacology: Enzyme and Uptake Assays – Reference Compound Results Compound IC 50 (M) nH -282- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 Compound IC50(M) nH PDE3A (h) [0175] Results showing an inhibition (or stimulation for assays run in basal conditions) higher than 50% are considered to represent significant effects of the test compounds.
  • Results showing an inhibition (or stimulation) between 25% and 50% are indicative of weak to moderate effects (in most assays, they should be confirmed by further testing as they are within a range where more inter-experimental variability can occur).
  • Results showing an inhibition (or stimulation) lower than 25% are not considered significant and mostly attributable to variability of the signal around the control level.
  • Low to moderate negative values have no real meaning and are attributable to variability of the signal around the control level.
  • O10 had 97.4% binding inhibition of the control, and on MC4R, with 100.4% binding inhibition of the control. O10 also did not exhibit significant binding activity at any other receptor. Additional Embodiments [0181] Various embodiments of the present technology are set forth below in paragraphs [0182] to [0367]: [0182] 1.
  • a non-naturally occurring melanocortin analog for treating, preventing, or reducing hyperplasia in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • a method of treating, preventing, or reducing hypothalamic obesity in a subject in need thereof comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0193] 12.
  • a non-naturally occurring melanocortin analog for treating, preventing, or reducing hypothalamic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • the hypothalamic obesity comprises congenital hypothalamic damage, damage from tumors, or damage from trauma.
  • a method of treating, preventing, or reducing a proopiomelanocortin (POMC) deficiency in a subject in need thereof, comprising -296- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I). [0196] 15.
  • POMC proopiomelanocortin
  • a non-naturally occurring melanocortin analog for treating, preventing, or reducing a POMC deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • a non-naturally occurring melanocortin analog for treating, preventing, or reducing a leptin deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • a non-naturally occurring melanocortin analog for treating, preventing, or reducing a syndromic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I). [0201] 20.
  • syndromic obesity is selected from the group consisting of Prader–Willi syndrome, Wilms tumor, Aniridia, Genitourinary, Range of Developmental Delays (WAGR) syndrome, Bardet-Biedl syndrome, Fragile X syndrome, Cohen syndrome, Proprotein Convertase Subtilisin/Kexin Type 1 (PCSK1) deficiency, Alstrom syndrome, MC4 haploinsufficiency, 17p11.2 deletion syndrome, and 2q37 deletion syndrome. [0202] 21.
  • NASH non-alcoholic steatohepatitis
  • Non-naturally occurring melanocortin analog for treating, preventing, or reducing NASH in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • a method of treating, preventing, or reducing hyperinsulinism in a subject in need thereof comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • a non-naturally occurring melanocortin analog for treating, preventing, or reducing hyperinsulinism in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • a method of treating, preventing, or reducing a cardiovascular disease in a subject in need thereof comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • a non-naturally occurring melanocortin analog for treating, preventing, or reducing a cardiovascular disease in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • the cardiovascular disease comprises a stroke or a heart attack.
  • a method of treating, preventing, or reducing osteoarthritis in a subject in need thereof comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • 32. The method or the use of embodiment 30 or 31, wherein the method or the use further comprises reducing a risk of the cancer.
  • a method of treating, preventing, or reducing erectile dysfunction in a subject in need thereof comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • a non-naturally occurring melanocortin analog for treating, preventing, or reducing erectile dysfunction in a subject in need thereof comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • a non-naturally occurring melanocortin analog for treating, preventing, or reducing body weight gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • a method of maintaining body weight after a weight loss in a subject in need thereof comprising administering a non-naturally occurring -299- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • a non-naturally occurring melanocortin analog for maintaining body weight after a weight loss in a subject in need thereof comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • a non-naturally occurring melanocortin analog for treating, preventing, or reducing fat mass gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • a method of treating, preventing, or reducing glucose intolerance and/or diabetes mellitus in a subject in need thereof comprising administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • a non-naturally occurring melanocortin analog for treating, preventing, or reducing glucose intolerance and/or diabetes mellitus in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).
  • X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); -300- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 R 1 is selected from the group consisting of Nle, Arg, dArg, aspartic acid (Asp), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R 2 is selected from the group consisting of Asp, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), Lys, ornithine (Orn), D-cysteine (dCys), Ala, D-alanine (dAla), proline (Pro), glut
  • sequence of Formula (I) is a sequence of Formula (IA): X 1 -R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -R 8 -Y 1 -Y 2 -Y 3 -Y 4 (IA), wherein: X 1 is absent or is selected from the group consisting of Nle, Arg, and dArg; R 1 is selected from the group consisting of Nle, Arg, dArg, Asp, Ala, Lys, dLys, His, and dHis; R 2 is selected from the group consisting of Asp, Ala, dAla, Dab, Dap, Lys, Orn, Pro, and Glu R 3 is absent or selected from the group consisting of His, dHi
  • sequence of Formula (I) is a sequence of Formula (IA(i)): X 1 -R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -Y 1 -Y 2 -Y 3 -Y 4 (IA(i)), wherein: X 1 is absent or Nle; R 1 is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; R 2 is selected from the group consisting of Dab, Dap, Lys, Orn, Asp and Glu; R 3 is absent or selected from the group consisting of His, dHis, Pro, and Gln; R 4 is dPhe or p(F)dPhe; R
  • sequence of Formula (I) is a sequence of Formula (ID): R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -Y 1 -Y 2 (ID), wherein: R 1 is selected from Nle, Arg, and dArg; R 2 is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R 3 is absent or selected from the group consisting of Pro, Asn, and His; R 4 is selected from dPhe, p(F)dPhe, and p(Cl)dPhe; R 5 is Arg; R 6 is Trp; R 7 is selected from the group consisting of Glu, Asp, Lys, and Orn; Y 1 is absent, dVal, or dArg; -312- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.
  • sequence of Formula (I) is a sequence of Formula (IE): R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -Y 1 -Y 2 (IE), wherein: R 1 is Nle or Arg; R 2 is selected from the group consisting of Dab, Lys, Orn, and Glu; R 3 is Asn or His; R 4 is p(Cl)dPhe; R 5 is Arg; R 6 is Trp; R 7 is selected from the group consisting of Glu, Asp, Lys, and Orn; Y 1 is absent or dVal; Y 2 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Glu at R 2 and Orn or Lys at R 7 ; or a lactam bridge between Dab, Orn, or Lys at R 2 and Glu or As
  • sequence of Formula (I) is a sequence of Formula (IG): R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -Y 1 -Y 2 (IG), wherein: R 1 is Nle or Arg; R 2 is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R 3 is selected from the group consisting of Pro, Asn, and His; R 4 is dPhe; R 5 is Arg; R 6 is Trp; -314- 146316.8034.WO00 ⁇ 181226204.17 Docket No.: 146316.8034.WO00 R 7 is selected from the group consisting of Glu, Asp, Lys, and Orn; Y 1 is absent, dVal, or dArg; Y 2 is absent, dPro, or dVal; and the non-naturally occurring melanocortin analog
  • non-naturally occurring melanocortin analog is a first non-naturally occurring melanocortin analog
  • the method further comprises administering a second non- naturally occurring melanocortin analog selected from the group consisting of MC4- NN2-0453, LY2112688, Melanotan-II, Afamelanotide, Bremelanotide, AZD2820, MK- 0493, PF-00446687, setmelanotide, RM-718, and LB54640.
  • a second non- naturally occurring melanocortin analog selected from the group consisting of MC4- NN2-0453, LY2112688, Melanotan-II, Afamelanotide, Bremelanotide, AZD2820, MK- 0493, PF-00446687, setmelanotide, RM-718, and LB54640.
  • any one of embodiments 109-114 wherein the non-naturally occurring melanocortin analog is selected from the group consisting of MC4-NN2-0453, LY2112688, Melanotan-II, Afamelanotide, Bremelanotide, AZD2820, MK-0493, PF-00446687, setmelanotide, RM-718, and LB54640.
  • 116 The method or the use of any one of embodiments 109-115, wherein the MC4-NN2-0453 is administered at a dose of about 0.03, 0.06, 0.15, 0.30, 0.60, 1.00, or 1.50 mg/kg.
  • 117 117.
  • any one of embodiments 1-138 wherein the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily.
  • 140 The method or the use of any one of embodiments 1-139, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily.
  • 141 The method or the use of any one of embodiments 1-140, wherein the concentration of the non-naturally occurring melanocortin analog in the plasma or a tissue of the subject is at least about 5 ng/mL to at least about 2000 ng/mL about 24 hours after administration of the non-naturally occurring melanocortin analog.
  • the addictive substance is selected from the group consisting of an opioid, a painkillers, a stimulant, a narcotic, alcohol, a barbiturate, sedatives, marijuana, cannabis, tetrahydrocannabinol (THC), cannabidiol (CBD), or an inhalant.
  • THC tetrahydrocannabinol
  • CBD cannabidiol
  • 179 The method or the use of embodiment 178, wherein the opioid is selected from the group consisting of morphine, heroin, codeine, oxycodone, hydrocodone, and fentanyl. [0361] 180.
  • the stimulant is selected from the group consisting of caffeine, nicotine, methamphetamine, cocaine, and amphetamine.
  • the barbiturate is selected from the group consisting of phenobarbital, methohexital, butalbital, pentobarbital, primidone, and amobarbital.
  • the sedative is selected from the group consisting of a tranquilizer, xylazine, eszopiclone, zaleplon, zolpidem, and zopiclone.
  • invention 178 wherein the inhalant is selected from the group consisting of an aerosol, a butane, freon, helium, nitrous oxide, propane, and a nitrite.
  • the nicotine comprises nicotine in a tobacco chew, a nicotine pouch, or a smoking device.
  • smoking device is selected from the group consisting of cigarettes, electronic cigarettes, cigars, and vape products.
  • 186 The method or the use of any one of embodiments 1-185, wherein the subject has or had an opioid use disorder or an alcohol use disorder.

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Abstract

Provided herein are methods of reducing body weight and/or fat mass in a subject in need thereof relative to a control. In some embodiments, the present technology comprises a method of treating, preventing, or reducing body weight gain after a weight loss in a subject in need thereof. The methods comprise administering a non-naturally occurring melanocortin analog to the subject.

Description

Docket No.: 146316.8034.WO00 NON-NATURALLY OCCURRING MELANOCORTIN RECEPTOR AGONISTS AND USES THEREOF FOR MODULATING WEIGHT LOSS CROSS-REFERENCE TO RELATED APPLICATION(S) [0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/650,909, filed May 22, 2024; U.S. Provisional Patent Application No. 63/654,891, filed May 31, 2024; U.S. Provisional Patent Application No.63/655,556, filed June 3, 2024; and U.S. Provisional Patent Application No.63/711,605, filed October 24, 2024, all of which 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 May 20, 2025, is titled “146316_8034_WO00_SL .xml” and is 902,367 bytes in size. BACKGROUND [0003] The prevalence of obesity, diabetes, and metabolic syndrome has reached pandemic proportions, and is expected to continue to rise in the next two decades. These conditions place enormous stress on healthcare systems globally. Accordingly, various weight loss agents have been developed in an attempt to treat such conditions. Although some weight loss agents have been approved for ongoing use, many are not sufficiently effective in achieving desired amounts or types of weight loss. Further, commonly used weight loss agents are administered subcutaneously, requiring self-administered injections on a daily or weekly basis which may cause administration site irritation and discomfort. [0004] Accordingly, despite recent advances treatment for obesity, diabetes, and metabolic syndrome, there is a demand for novel and effective weight loss agents that may be delivered via less invasive administration routes. -1- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 SUMMARY [0005] The present technology comprises methods of reducing body weight and/or fat mass in a subject in need thereof, the methods comprising orally administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I): X1-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1 is selected from the group consisting of Nle, Arg, dArg, aspartic acid (Asp), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2 is selected from the group consisting of Asp, 2,3-diaminopropionic acid (Dap), 2,4- diaminobutyric acid (Dab), Lys, ornithine (Orn), D-cysteine (dCys), Ala, D-alanine (dAla), proline (Pro), glutamic acid (Glu), and phenylalanine (Phe); R3 is absent or selected from the group consisting of His, dHis, Pro, Phe, asparagine Asn, and glutamine (Gln); R4 is selected from the group consisting of D-phenylalanine (dPhe), Pro, para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5 is selected from the group consisting of Arg, His, cis-4-guanidyl-proline (cisPro(guan)), and trans-4-guanidyl-proline (transPro(guan)); R6 is selected from the group consisting of dPhe, tryptophan (Trp), and 2’-D- naphthylalanine (dNal(2’)); R7 is selected from the group consisting of Arg, Pro, ornithine (Orn), cysteine (Cys), Glu, Asp, and lysine (Lys); R8 is absent, Lys, or Trp; R9 is absent or Lys; -2- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Y1 is absent or selected from the group consisting of dArg, D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle); Y2 is absent or selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, 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 R2 and R7 when R2 is dCys, R4 is p(Cl)dPhe, and R7 is Cys; a lactam bridge between R2 and R7 when R1 is Dap, Dab, Orn, or Lys, and R7 is Glu or Asp; a lactam bridge between R1 or R2 and any one of R7-R9 when R1 or R2 is Asp, R4 is dPhe, or p(F)dPhe, and any one of R7-R9 is Lys; and a lactam bridge between R2 and R7 when R2 is Asp or Glu and R7 is Orn, provided that: when R3 is Pro, then R4 is dPhe and either (i) X1 and Y3 are both present; or (ii) R2 is Lys and R7 is Glu; when R4 is p(Cl)dPhe, then R3 is His or Asn and the non-naturally occurring melanocortin analog is not cyclized through a lactam bond between Asp at R2 and Lys at R7, wherein when R3 is His, then R2 is not Dap and when R3 is Asn then either (i) R2 is Glu, R7 is Orn and R1 is Nle; or (ii) R2 is Lys and R7 is Asp; when R2 or R3 is Phe, then R4 is Pro and R6 is dPhe; when R3 is His and R1 is Glu or Asp, then R2 is Ala, dAla, or Pro, R5 is Arg, and Y1- Y2 is dVal-dPro, wherein when R2 is Ala, then R1 is Nle and when R2 is dAla; and when R3 is absent or Asn, then R1 is Arg, R2 is Lys or Dap, R4 is dPhe or p(F)dPhe, and R7 is Glu. -3- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0006] In some embodiments, the present technology comprises a method of reducing body weight and/or fat mass in an obese subject, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0007] In some embodiments, the present technology comprises a method of treating, preventing, or reducing hyperplasia in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0008] In some embodiments, the present technology comprises a method of treating, preventing, or reducing hypothalamic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0009] In some embodiments, the present technology comprises a method of treating, preventing, or reducing a proopiomelanocortin (POMC) deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0010] In some embodiments, the present technology comprises a method of treating, preventing, or reducing a leptin deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0011] In some embodiments, the present technology comprises a method of treating, preventing, or reducing a syndromic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0012] In some embodiments, the present technology comprises a method of treating, preventing, or reducing non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). -4- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0013] In some embodiments, the present technology comprises a method of treating, preventing, or reducing hyperinsulinism in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0014] In some embodiments, the present technology comprises a method of treating, preventing, or reducing a cardiovascular disease in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0015] In some embodiments, the present technology comprises a method of treating, preventing, or reducing osteoarthritis in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0016] In some embodiments, the present technology comprises a method of treating, preventing, or reducing a cancer in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0017] In some embodiments, the present technology comprises a method of treating, preventing, or reducing erectile dysfunction in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0018] In some embodiments, the present technology comprises a method of treating, preventing, or reducing body weight gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0019] In some embodiments, the present technology comprises a method of maintaining body weight after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). -5- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0020] In some embodiments, the present technology comprises a method of treating, preventing, or reducing fat mass gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0021] In some embodiments, the present technology comprises a method of treating, preventing, or reducing glucose intolerance and/or diabetes mellitus in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). BRIEF DESCRIPTION OF THE DRAWINGS [0022] FIG. 1 illustrates 24-hour plasma concentrations of non-naturally occurring melanocortin analogs of the present technology following oral administration of Compound Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (C2) (SEQ ID NO: 14) to Cynomolgus Monkeys at 30.0 mg/kg. [0023] FIGS. 2A-2F illustrates 24-hour plasma concentrations of non-naturally occurring melanocortin analogs of the present technology following PO administration of Compound E (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (O10) (SEQ ID NO: 43)) to Cynomolgus Monkeys at 3 mg/kg, 10.0 mg/kg, 30.0 mg/kg, or 60 mg/kg. [0024] FIGS. 3A-3C illustrates 24-hour plasma and cerebrospinal fluid (CSF) concentrations of non-naturally occurring melanocortin analogs of the present technology following SC administration of Compound E of FIGS.2A-2F to Rats at 1.0 mg/kg, 3.0 mg/kg, and 10.0 mg/kg. [0025] FIGS. 4A-4G illustrate plasma and CSF concentrations of non-naturally occurring melanocortin analogs of the present technology. FIGS. 4A-4G illustrate 24-hour plasma and CSF concentrations of non-naturally occurring melanocortin analogs following IP administration of Compound E (SEQ ID NO: 43) to Rats at 1.0 mg/kg, 3.0 mg/kg, and 10.0 mg/kg. The shaded areas of 4D-4G represent the drug exposure at concentrations greater than the EC50. Area under the depicted lines represent the non-naturally occurring melanocortin analog exposure at concentrations greater than the EC50. -6- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0026] FIGS. 5A-5C illustrates 24-hour plasma and CSF concentrations of non- naturally occurring melanocortin analogs of the present technology following PO administration of Compound E (SEQ ID NO: 43) to Rats at 10.0 mg/kg and 30.0 mg/kg. [0027] FIGS.6A and 6B show preliminary weight loss and daily food intake results in animals administered 3 mg/kg of O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro- NH2) (SEQ ID NO: 43). [0028] FIGS.7A-7D show food intake (g) at baseline in monkeys having diet-induced obesity (n=6) from 0.5 to 72 hours after saline administration at day 1 (D1). FIG.7A shows net weight of food intake among individual monkeys. FIG.7B shows net weight of food intake for each group average. FIG.7C shows cumulative food intake among individual monkeys. FIG.7D shows cumulative food intake for each group average. [0029] FIGS. 8A-8H show food intake (g) in the same monkeys as FIGS. 7A-7D administered 1 mg/kg or 3 mg/kg of O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2) (SEQ ID NO: 43) on day 8 (D8). FIG.8A shows net weight of food intake among individual monkeys at day 8 (D8). FIG.8B shows net weight of food intake for each group average of monkeys administered the same compound at D8. FIG. 8C shows cumulative food intake among individual monkeys of FIG. 8A at D8. FIG. 8D shows cumulative food intake for each group average of monkeys of FIG.8C administered the same compound at D8. FIG. 8E shows net weight of food intake among individual monkeys at day 12 (D12). FIG.8F shows net weight of food intake for each group average of monkeys administered the same compound at D12. FIG. 8G shows cumulative food intake among individual monkeys at D12. FIG.8H shows cumulative food intake for each group average of monkeys administered the same compound at D12. [0030] FIGS. 9A and 9B show food intake patterns in diet-induced obese monkeys administered saline, compared to the same monkeys administered 1mg/kg or 3 mg/kg of O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2) (SEQ ID NO: 43) in FIGS. 8A-8H. [0031] FIGS. 10A-10C show changes in daily caloric intake (FIG. 10A), cumulative caloric intake (FIG.10B), percent change in caloric consumption from baseline through day -7- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 6 (FIG.10C) for diet-induced obese monkeys orally administered 10 mg/kg of or O10 (Ac- Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2) (SEQ ID NO: 43) (QD: once daily). [0032] FIGS. 11A-11P show changes in cumulative caloric intake, percent change in caloric consumption from baseline, food intake of a normal diet, food intake of a high fat diet, food intake in calories, and food preference for diet-induced obese monkeys orally administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2) (SEQ ID NO: 43), saline, or semaglutide (sema) (PO: oral administration; SC: subcutaneous administration; QD: once daily; BID: twice daily; BIW: twice weekly). [0033] FIG. 11Q shows normalized cumulative food consumption in rats subcutaneously administered 1 mg.kg or 3 mg/kg of MC4R selective agonists (A07D (Ac- Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2) (SEQ ID NO: 48), O7 (Ac-Nle-c[Glu-Pro- p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2) (SEQ ID NO: 106), or O11 (Ac-Nle-c[Glu-Pro-dPhe- Arg-Trp-Orn]-dVal-dPro-NH2) (SEQ ID NO: 62) (n=5 per group) or MC3R/MC4R co-agonists (O10) (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2) (SEQ ID NO: 43) (n=5) compared to saline controls (n=4). [0034] FIG. 11R shows an average percent change in caloric consumption from baseline in moneys orally administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]- dVal-dPro-NH2) (SEQ ID NO: 43) at a starting dose of 10 mg/kg and increased to 20 mg/kg and 30 mg/kg. [0035] FIGS.12A-12K show changes in body weight for diet included obese monkeys administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2) (SEQ ID NO: 43) orally and/or subcutaneously. Shown are changes in daily body weight and percent change in body weight from baseline (FIGS. 12A and 12B) for the diet-induced obese monkeys of FIGS.11A-11P through day 8. FIGS 12C shows percent change in body weight as a percentage of initial weight for the monkeys of FIGS. 12A and 12B through day 15 compared to those administered semaglutide (sema) alone. FIG. 12D shows body weight change as a percentage of initial weight in diet induced obese monkeys orally administered O10 at increasing dosages or administered semaglutide. FIG. 12E shows body weight change in the monkeys of FIG.12D. FIG.12F shows body weight change as a percentage of initial weight in diet included obese monkeys administered O10 at changing doses and -8- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 administration frequencies. FIG.12G shows body weight changes as a percentage of initial in monkeys orally administered O10 (PO) with dose changes or semaglutide. FIG. 12H shows body weight change after removal of O10 administration for the monkeys of FIG. 12G. FIG.12I shows percent change in body weight as a percentage of initial weight for diet induced obese monkeys orally administered O10 followed by subcutaneous administration. FIG. 12J shows body weight percent change after removal of O10 treatment in monkeys. FIG.12K shows body weight percent change at an oral O10 dosing regimen in accordance with the embodiments of the present technology. (PO: oral administration; SC: subcutaneous administration; QD: once daily; BID: twice daily; BIW: twice weekly). [0036] FIG. 12L shows changes in body weight as a percentage of day 1 in rats administered saline, a melanocortin 4 receptor (MC4R) selective agonist (A07D (Ac-Nle- c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2) (SEQ ID NO: 48), O7 (Ac-Nle-c[Glu-Pro- p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2) (SEQ ID NO: 106), or O11 (Ac-Nle-c[Glu-Pro-dPhe- Arg-Trp-Orn]-dVal-dPro-NH2) (SEQ ID NO: 62), or an equal dose of a melanocortin 3 receptor (MC3R)/MC4R coagonist ((O10)(Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2) (SEQ ID NO: 43). [0037] FIG. 12M shows an average percent change in normalized body weight from baseline in moneys orally administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]- dVal-dPro-NH2) at a starting dose of 10 mg/kg and increased to 20 mg/kg and 30 mg/kg. [0038] FIGS.13A-13N show changes in body composition for the diet-induced obese monkeys of FIGS.10A-10C. [0039] FIGS. 14A-14D show blood chemistry levels in diet-induced obese monkeys orally administered 10 mg/kg O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro- NH2) (SEQ ID NO: 43) once daily for week 1, 20mg/kg O10 once daily for week 2, and 15 mg/kg O10 twice daily weeks 3 and 4. [0040] FIGS. 15A-15C show measurements of systolic blood pressure (FIG. 15A), diastolic blood pressure (FIG. 15B), and heart rate (FIG. 15C) in rats subcutaneously administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2) at 0.5 mg/kg, 1 mg/kg, or 3 mg/kg. -9- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0041] FIGS.16A-16D show measurements of diastolic blood pressure (DBP), systolic blood pressure (SBP), heart rate, and heart rate corrected QT interval (QTc) in rats administered setmelanotide at 0.5 mg/kg, 1.0 mg/kg, 3.0 mg/kg, or 6.0 mg/kg, relative to control rats administered saline. [0042] FIGS.17A-17H show measurements of normalized heart rate (FIG.17A), QTc (FIG. 17B), systolic blood pressure (FIG. 17C), diastolic blood pressure (FIG. 17D), mean blood pressure (FIG.17E), QT interval (FIG.17F), QRS internal (FIG.17G), and RR internal (FIG.17H) in male cynomolgus monkeys orally (PO) administered O10 (Ac-Nle-c[Glu-His- p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2) (SEQ ID NO: 43) at 3, 10, 30, or 60 mg/kg, relative to those subcutaneously (SC) administered setmelanotide at 3 mg/kg or orally administered saline. (N = 3 to 5 animals per group). [0043] FIG. 18 shows results of O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2) (SEQ ID NO: 43) screened for binding against a panel of 87 targets at 10µM. X- axis represents the percent inhibition of control at 10µM. (MC1R: melanocortin 1 receptor; MC4R: melanocortin 4 receptor). [0044] FIG. 19 shows exemplary adipose tissue staining in diet-induced obese monkeys orally administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro- NH2) (SEQ ID NO: 43) at 10 mg/kg. [0045] FIG. 20 shows plasma concentration of O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg- Trp-Orn]-dVal-dPro-NH2) (SEQ ID NO: 43) in monkeys orally (PO) administered 3mg/kg, 10 mg/kg, 30 mg/kg, or 60 mg/kg O10. [0046] FIG.21 shows results of an in vitro pharmacology assessment of O10. Results showing an inhibition or stimulation higher than 50% are considered to represent significant effects of O10. [0047] FIGS. 22A and 22B show the results of an in vitro binding assay for O10 on selected targets (SEQ ID NO: 43). Results showing an inhibition or stimulation higher than 50% are considered to represent significant effects of O10. [0048] FIG. 23 shows effects of O10 on enzyme inhibition (SEQ ID NO: 43). Results are shown as percent inhibition of control values. -10- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 DETAILED DESCRIPTION [0049] The present technology comprises methods of treating, preventing, or reducing one or more symptoms or conditions associated with metabolic dysfunction in a subject in need thereof using a non-naturally occurring melanocortin analog. In some embodiments, the non-naturally occurring melanocortin analog is administered orally. In some embodiments, the method comprises suppressing appetite in a subject in need thereof using a non-naturally occurring melanocortin analog in accordance with the present technology. In some embodiments, the method comprises promoting fat loss in a subject in need thereof using a non-naturally occurring melanocortin analog in accordance with the present technology. In some embodiments, the method comprises reducing body weight and/or fat mass in a subject in need thereof using a non-naturally occurring melanocortin analog, or a pharmaceutical composition thereof, of the present technology. [0050] 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. [0051] Furthermore, the detailed description of various embodiments herein makes reference to the accompanying drawing/FIGS, which show various embodiments by way of illustration. While the embodiments are described in sufficient detail to enable those skilled in the art to practice the present technology, it should be understood that other embodiments may be realized, and that logical and mechanical changes may be made without departing from the spirit and scope of the present technology. Thus, the detailed description herein is presented for purposes of illustration only and not of limitation. For example, steps or functions recited in any description, method, system, or process, may be executed in any -11- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 order and are not limited to the order presented. Moreover, any of the steps or functions thereof may be outsourced to or performed by one or more third parties. Definitions [0052] 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. [0053] 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. [0054] 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. [0055] The terms “administering” or “administer” include delivery of non-naturally occurring melanocortin analogs (also referred to herein as peptides and synthetic 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. [0056] 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. -12- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 This can 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. [0057] 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. [0058] As used herein, a “pharmaceutically acceptable carrier” of the 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 pharmaceutical 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 pharmaceutical composition. The preparation of pharmaceutically acceptable carriers and formulations containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 21st 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 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. -13- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0059] As used herein, “pharmaceutically acceptable salt” refers to derivatives of the disclosed synthetic peptides wherein the parent peptide is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. [0060] The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non- toxic, inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, trifluoroacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like. These salts can be prepared in situ during the final isolation and purification of the synthetic peptide of the present technology, or by separately reacting a purified peptide of the present technology in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. [0061] The terms “treat,” “treatment,” and “treating” may also refer to the reduction or inhibition of the progression and/or duration of a disease (e.g., metabolic dysfunction), the reduction or amelioration of the severity of the disease, 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 or reduction (e.g. by more than 10%, 20%, 30%, 40%, 50%, or more than 60% of the baseline of glucose levels before administration) of circulating glucose levels (2) inhibiting or reducing rate of fat mass gain, (3) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with a pathology related to or caused in part by metabolic dysfunction, (4) an increase in disease-free, relapse-free, progression-free, and/or overall survival, duration, or rate, (5) a decrease in hospitalization rate, (6) a decrease in hospitalization length, (7) an increase in the oxidation of lipids or carbohydrates by at least by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or at least 80% relative to the initial oxidation rate, (8) a stabilization or reduction -14- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 (e.g. by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or at least 80% relative to the initial loss rate) in the rate of lean muscle mass loss, (9) an increase in lean muscle mass, (10) a reduction in mortality, (11) an increase in the response rate, the durability of response, or number of patients who respond, (12) ) a stabilization or reduction (e.g. by more than 10%, 20%, 30%, 40%, 50%, or more than 60% of the baseline of lactate levels before administration) of circulating lactate levels, (13) a decrease in the need for surgery (e.g. gastric bypass, liposuction, sleeve gastrectomy, bariatric surgery), and (14) preventing or reducing organ burden induced by metabolic dysfunction. 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 shortening the length or frequency of the disease. [0062] As used herein, the term “prevent,” “preventing,” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease. [0063] 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 being treated. The result can be a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate “effective amount” can differ from one individual to another. An appropriate “effective amount” in any individual case can be determined using techniques, such as a dose escalation study. [0064] The term “after administration” refers to any duration of time after the non- naturally occurring melanocortin analog or pharmaceutical composition thereof, and/or the weight loss agent has been administered to a subject. “After administration” can 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 -15- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 or more doses. Likewise, the term “prior to administration” refers to any duration of time before the non-naturally occurring melanocortin analog or pharmaceutical composition thereof, and/or the weight loss agent has been administered to a subject. Unless otherwise specified, durations of time encompassed by “after administration” or “prior to administration” can include seconds, minutes, hours, days, weeks, months, and years. [0065] The terms “subject” and “patient” refer to anyone being evaluated for disease 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 metabolic dysfunction. [0066] 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. [0067] “Melanocortin analogs,” “melanocortin 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 non-naturally occurring melanocortin peptides and truncated and/or modified versions of melanocortin full-length protein or peptides. For example, the full-length pro-opiomelanocortin 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 may be activating (e.g., agonist activity). In addition to peptides, the non-naturally occurring melanocortin analogs include small molecule analogs of melanocortin or portions thereof -16- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 comprised of organic compounds, inorganic compounds, or combinations of peptide and small molecule—i.e., peptide mimetics, or various combinations thereof. “Melanocortin peptides” can be structurally similar and/or functionally similar to biological melanocortin proteins in their ability to bind melanocortin receptors. Further, the non-naturally occurring 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. [0068] 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 can 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. [0069] A “melanocortin receptor agonist” or “melanocortin agonist” is a naturally occurring substance or manufactured drug substance (e.g., non-naturally occurring) or composition that can interact with a melanocortin receptor and initiate a pharmacological response characteristic of the melanocortin receptor. [0070] As used herein, an “opioid receptor agonist” refers to a ligand that, upon binding an opioid receptor, increases the receptor's signaling activity. A “delta opioid receptor agonist” refers to any compound or peptide that activates the delta opioid receptor (DOR) upon binding to the active site of the DOR. A “mu opioid receptor agonist” refers to any compound or peptide that activates the mu opioid receptor (MOR) upon binding to the active site of the MOR. [0071] The terms “bind,” “binding,” “complex,” and “complexing,” refer to all types of physical and chemical binding, reactions, complexing, attraction, chelating and the like. [0072] The “peptides” of the present technology can 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 -17- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 methods resulting from a combination of methods (a) through (d) listed above, or (f) produced by any other means for producing peptides. [0073] 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 non- amino acid residue groups at the N- and C-termini, such groups including acyl, acetyl, alkenyl, alkyl, N-alkyl, amine, or amide groups, among others. [0074] 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. [0075] “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 α-amino acids differ in the side-chain moiety that is attached to the α-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 -18- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 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. 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 disclosures of which are incorporated herein by reference in their entireties. [0076] 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 disclosed herein 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. [0077] 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. [0078] In the non-naturally occurring melanocortin analogs 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; “Gln” is glutamine; “Glu” is glutamic acid; “His” is histidine; “Ile” 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 “Val” is valine. Unless otherwise indicated, all amino -19- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 acids abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or combinations thereof can be used. Thus, for example, “L-Phe” or “lPhe” is L-phenylalanine; “D-Phe” or “dPhe” is D-phenylalanine; dVal is D-valine; dPro is D-proline; “D-/L-Phe” or “d/lPhe” is D-phenylalanine, L-phenylalanine, or combinations thereof; “Phe” is also D- phenylalanine, L-phenylalanine, or combinations thereof, and so on. [0079] An alpha (α)-amino acid has the generic formula H2N—CαHR—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 α-carbon). Other types of amino acids exist when the amino group is attached to a different carbon atom. For example, beta (β)-amino acids, the carbon atom to which the amino group is attached is separated from the carboxylate group by one carbon atom, Cβ. [0080] When β-amino acids are incorporated into peptides, two main types of β- peptides exist: those with the side chain residue, R, on the carbon next to the amine are called β3 peptides and those with the side chain residue on the carbon next to the carbonyl group are called β2 amino acids. Further, β-amino acids may adopt L- or D- stereochemistry. Unless otherwise indicated, all β-amino acid abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or combinations thereof. [0081] Gamma (γ)-amino acids are amino acids where the carbon atom to which the amino group attaches is separated from the carboxylate moiety by two carbon atoms. [0082] For additional modified and unusual amino acids, see §2422 of the MPEP, particularly Table 4 at 2400-24. Additionally, “Ac” indicates N-acetyl; “cyclo” and “c” refers to a cyclic structure; and “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 amidated C-terminus, i.e., —CO—NH2. [0083] Additional abbreviations are used herein as follows: Nle is norleucine; Nal(2’) is 2′-naphthylalanine; Nal(1') is 1′-naphthylalanine; Tle is tert-leucine; Orn is ornithine; cisPro(guan) is cis-4-guanidyl-proline; transPro(guan) is trans-4-guanidyl-proline; p(Cl)dPhe is para-chloro-phenylalanine; and p(F)dPhe is para-fluoro-phenylalanine. -20- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0084] 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.” [0085] 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. [0086] An “amine” includes compounds that contain an amine group (—NH2). [0087] 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. [0088] 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.” [0089] “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 melanocortin peptide by physiological enzymes and other factors, in such a manner or to a degree that side effects appear. According to one aspect, a 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 melanocortin analog that lacks a C-terminal extension. [0090] As used herein, a “composition” refers to a mixture of the active ingredient with other chemical components. -21- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0091] 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 [0092] 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 (MC1R), the melanocortin 2 receptor (MC2R), and the melanocortin 5 receptor (MC5R). Some of the non-naturally occurring melanocortin analogs may bind the MC4R with greater affinity than the MC3R. Alternatively, some melanocortin analogs may bind the MC3R with the same or generally similar affinity as the MC4R. [0093] The non-naturally occurring melanocortin analogs of the present technology may be full agonists 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%. [0094] The non-naturally occurring melanocortin analogs of the present technology may be partial agonists. A partial agonist may comprise a non-naturally occurring melanocortin analog having a maximum effect Emax agonist value of less than 85%. [0095] 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). [0096] The non-naturally occurring melanocortin analogs of the present technology may be one or more of (i) a full MC4R agonist (ii) a full MC3R agonist; and (iii) a partial MC3R agonist with no MC3R antagonist activity. In some embodiments, the non-naturally occurring melanocortin is a full MC4R agonist. In some embodiments, the non-naturally occurring melanocortin agonist is a full MC3R agonist and a full MC3R agonist. In some embodiments, the non-naturally occurring melanocortin analog is a full MC4R agonist and -22- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 partial MC3R agonist with no MC3R antagonist activity. In some embodiments, the non- naturally occurring melanocortin analogs of the present technology have an MC3R Emax agonist value of 50-84%. In some embodiments, the non-naturally occurring melanocortin analogs of the present technology have a MC3R:MC4R half maximal effective concentration (EC50) selectivity ratio of less than or equal to 49. In some embodiments, the non-naturally occurring melanocortin analogs of the present technology comprise non-naturally occurring MC4R agonists or non-naturally occurring MC3R agonists. [0097] The non-naturally occurring melanocortin analogs in accordance with the present technology may have 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 MC4R and/or MC3R. For example, in some embodiments, the non-naturally occurring melanocortin analogs comprise one or more of (i) blood brain barrier passage capabilities, (ii) one or more pharmaceutical- like pharmacokinetic measurements (e.g., a pharmacokinetic measurement of a weight loss agent pharmaceutical composition or an oral non-naturally occurring melanocortin analog pharmaceutical), (iii) degradation resistance; (iv) equipotency on MC3R and MC4R activity, or (v) oral potency. In some embodiments, the oral potency is greater than a subcutaneous administration potency for an equivalent dose. In some embodiments, the non-naturally occurring melanocortin analogs comprise two or more of (i)-(v). In some embodiments, the non-naturally occurring melanocortin analogs comprise each of (i)-(v). Accordingly, in some embodiments, the non-naturally occurring melanocortin analogs have one or more beta hairpin (β-hairpin) and/or beta turn (β-turn) structures. The presence of amino acids that are structurally rigid, such as, for example, Pro, dPro, transPro(guan), and cisPro(guan), may lead to formation of β-hairpin and/or β-turn structures in the non-naturally occurring melanocortin analog. Additionally, disulfide bridges (e.g., cyclization via disulfide bond) may induce and/or stabilize beta-turn structures of the non-naturally occurring melanocortin analogs. In general, cyclization and D-amino acids may induce and/or stabilize beta-turns. Further, in some embodiments, melanocortin analogs include a D-valine-D-proline (dVal- dPro) chain as their C-terminus, which may provide enhanced transport and resistance to degradation. -23- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0098] The presence of certain structural features may impart the non-naturally occurring melanocortin analogs of the present technology with specific binding properties. For example, inclusion of p(F)dPhe or dPhe at the R4 position may result in enhanced binding and activation of the melanocortin 4 receptor. Accordingly, melanocortin analogs having p(F)dPhe or dPhe at the R4 position may be full agonists on MC4R. Further, inclusion of His at the R3 position may result in full agonism on MC3R as well. By contrast, inclusion of His at the R3 position may decrease activity on the melanocortin 3 receptor, resulting in only partial agonism on MC3R. [0099] Non-naturally occurring melanocortin analogs in accordance with the present technology may induce or increase body weight and/or fat mass loss in a subject in need thereof while reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject. Additionally, the non-naturally occurring melanocortin analogs of the present technology may avoid cardiac activation typically seen in conventional melanocortin peptide and small molecule agonists. For example, a subject may maintain a stable heart rate, systolic blood pressure, and/or diastolic blood pressure following administration of a melanocortin analog of the present technology. [0100] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I): X1-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1 is selected from the group consisting of Nle, Arg, dArg, aspartic acid (Asp), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2 is selected from the group consisting of Asp, 2,3-diaminopropionic acid (Dap), 2,4- diaminobutyric acid (Dab), Lys, ornithine (Orn), D-cysteine (dCys), Ala, D-alanine (dAla), proline (Pro), glutamic acid (Glu), and phenylalanine (Phe); R3 is absent or selected from the group consisting of His, dHis, Pro, Phe, asparagine Asn, and glutamine (Gln); -24- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 R4 is selected from the group consisting of D-phenylalanine (dPhe), Pro, para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5 is selected from the group consisting of Arg, His, cis-4-guanidyl-proline (cisPro(guan)), and trans-4-guanidyl-proline (transPro(guan)); R6 is selected from the group consisting of dPhe, tryptophan (Trp), and 2’-D- naphthylalanine (dNal(2’)); R7 is selected from the group consisting of Arg, Pro, ornithine (Orn), cysteine (Cys), Glu, Asp, and lysine (Lys); R8 is absent, Lys, or Trp; R9 is absent or Lys; Y1 is absent or selected from the group consisting of dArg, D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle); Y2 is absent or selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, 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 R2 and R7 when R2 is dCys, R4 is p(Cl)dPhe, and R7 is Cys; a lactam bridge between R2 and R7 when R1 is Dap, Dab, Orn, or Lys, and R7 is Glu or Asp; a lactam bridge between R1 or R2 and any one of R7-R9 when R1 or R2 is Asp, R4 is dPhe, or p(F)dPhe, and any one of R7-R9 is Lys; and a lactam bridge between R2 and R7 when R2 is Asp or Glu and R7 is Orn, provided that: -25- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 when R3 is Pro, then R4 is dPhe and either (i) X1 and Y3 are both present; or (ii) R2 is Lys and R7 is Glu; when R4 is p(Cl)dPhe, then R3 is His or Asn and the non-naturally occurring melanocortin analog is not cyclized through a lactam bond between Asp at R2 and Lys at R7, wherein when R3 is His, then R2 is not Dap and when R3 is Asn then either (i) R2 is Glu, R7 is Orn and R1 is Nle; or (ii) R2 is Lys and R7 is Asp; when R2 or R3 is Phe, then R4 is Pro and R6 is dPhe; when R3 is His and R1 is Glu or Asp, then R2 is Ala, dAla, or Pro, R5 is Arg, and Y1- Y2 is dVal-dPro, wherein when R2 is Ala, then R1 is Nle and when R2 is dAla; and when R3 is absent or Asn, then R1 is Arg, R2 is Lys or Dap, R4 is dPhe or p(F)dPhe, and R7 is Glu. [0101] 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); R1 is selected from the group consisting of Nle, Arg, dArg, aspartic acid (Asp), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2 is selected from the group consisting of Asp, 2,3-diaminopropionic acid (Dap), 2,4- diaminobutyric acid (Dab), Lys, ornithine (Orn), D-cysteine (dCys), Ala, D-alanine (dAla), proline (Pro), glutamic acid (Glu), and phenylalanine (Phe); R3 is absent or selected from the group consisting of His, dHis, Pro, Phe, asparagine Asn, and glutamine (Gln); R4 is selected from the group consisting of D-phenylalanine (dPhe), Pro, para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5 is selected from the group consisting of Arg, His, cis-4-guanidyl-proline (cisPro(guan)), and trans-4-guanidyl-proline (transPro(guan)); R6 is selected from the group consisting of dPhe, tryptophan (Trp), and 2’-D- naphthylalanine (dNal(2’)); -26- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 R7 is selected from the group consisting of Arg, Pro, ornithine (Orn), cysteine (Cys), Glu, Asp, and lysine (Lys); R8 is absent, Lys, or Trp; R9 is absent or Lys; Y1 is absent or selected from the group consisting of dArg, D-valine (dVal), D-proline (dPro), and D-tert-leucine (dTle); Y2 is absent or selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, 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 R2 and R7 when R2 is dCys, R4 is p(Cl)dPhe, and R7 is Cys; a lactam bridge between R2 and R7 when R1 is Dap, Dab, Orn, or Lys, and R7 is Glu or Asp; a lactam bridge between R1 or R2 and any one of R7-R9 when R1 or R2 is Asp, R4 is dPhe, or p(F)dPhe, and any one of R7-R9 is Lys; and a lactam bridge between R2 and R7 when R2 is Asp or Glu and R7 is Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 49); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 51); His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 52); dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 53); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 54); -27- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 55); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 57); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c[dCys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 59); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 61); Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c[Asp-Phe-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 64); Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 66); Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 68) Ac-Nle-c[dCys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 70); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 71); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 73); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 74); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 75); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 76); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 77); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 78); Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 79); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 80); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 81); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 82); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 83); -28- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 84); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 85); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 86); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 87); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 88); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 89); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 90); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 91); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 92); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 93); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 104); Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 106); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 94); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 118); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 119); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 95); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 120); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 121); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 122); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 123); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 107); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 108); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 109); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 110); -29- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 111); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 112); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 113); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 114); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 115); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 116); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 117); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 96); Ac-Nle-c[Asp-Pro-dPhe-Arg-dTrp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 97); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 99); Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 124); Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 125); Ac-Nle-c[Dap-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 281); Ac-Nle-c[Dab-Pro-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 282); Ac-Nle-c[Lys-Pro-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 283); Ac-Nle-c[Lys-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 284); Ac-Nle-c[Orn-Pro-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 285); Ac-Nle-c[Orn-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 286); Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 287); Ac-Nle-c[Dap-Pro-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 288); Ac-Nle-c[Dab-Pro-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 289); Ac-Nle-c[Lys-Pro-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 290); Ac-Nle-c[Orn-Pro-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 291); Ac-Nle-c[Orn-Pro-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 292); -30- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 293); Ac-dArg-c[Orn-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 294); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 100); Ac-Nle-c[Asp-Pro-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 103); Ac-Nle-c[Asp-Pro-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 98); Ac-Nle-c[Dap-Pro-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 295); Ac-Nle-c[Dab-Pro-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 296); Ac-Nle-c[Lys-Pro-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 297); Ac-Nle-c[Lys-Pro-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 298); Ac-Nle-c[Orn-Pro-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 299); Ac-Nle-c[Orn-Pro-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 300); Ac-Nle-c[Glu-Pro-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 301); Ac-Nle-c[Glu-Pro-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 105); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 271); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-NH2 (SEQ ID NO: 272); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 273); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 274); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 275); Ac-dArg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 131); Ac-Arg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 132); Ac-Lys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 133); Ac-dLys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 134); Ac-His-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 135); Ac-dHis-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 136); -31- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 126); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 127); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 128); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 141); Ac-dArg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 143); Ac-Arg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 144); Ac-Lys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 151); Ac-dLys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 145); Ac-His-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 152); Ac-dHis-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 146); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 302); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 303); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 139); Ac-Nle-c[Asp-Phe-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 149); Ac-Ala-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 130); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 137); Ac-Nle-c[Asp-His-p(Cl)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 138); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 140); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 129); Ac-Ala-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 142); Ac-Nle-c[Asp-dHis-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 148); Ac-Nle-c[Asp-Gln-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 150); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 147); Ac-Nle-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 304); -32- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-Nle-c[Dab-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 305); Ac-Nle-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 306); Ac-Nle-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 307); Ac-Nle-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 308); Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 309); Ac-Arg-c[Dap-Asn-p(Cl)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 310); Ac-Arg-c[Dab-Asn-p(Cl)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 311); Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 312); Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 313); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 314); Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 315); Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 316); Ac-Arg-c[Dab-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 317); Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 318); Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 319); Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 320); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 321); Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 322); Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 323); Ac-Nle-c[Dap-His-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 324); Ac-Nle-c[Dap-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 325); Ac-Nle-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 326); Ac-Nle-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 327); Ac-Arg-c[Dap-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 328); -33- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 157); Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 155); Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 154); Ac-Nle-c[Asp-Phe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 153); Ac-Nle-c[Asp-Phe-Phe-Pro-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 156); Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 276); Ac-Nle-c[Asp-Ala-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 277); Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 159); Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 160); Ac-Arg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 278); Ac-dArg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 279); Ac-Nle-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 280); Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 158); Ac-Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]-dArg-dVal-NH2 (SEQ ID NO: 329); Ac-Arg-c[Glu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 330); Ac-Nle-c[Glu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 331); Ac-Arg-c[Glu-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 332); Ac-Nle-c[Glu-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 333); Ac-Arg-c[Lys-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 334); Ac-Nle-c[Lys-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 335); Ac-Nle-c[Lys-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 336); Ac-Arg-c[Glu-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 337); Ac-Nle-c[Glu-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 338); Ac-Nle-c[Lys-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 339); and -34- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-Arg-c[Lys-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 340), wherein c represents cyclization via a lactam or disulfide bond. [0102] In some embodiments of Formula (I), R4 is dPhe or p(F)dPhe. In further embodiments, the sequence of Formula (I) is a sequence of Formula (IA): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4 (IA), wherein: X1 is absent or is selected from the group consisting of Nle, Arg, and dArg; R1 is selected from the group consisting of Nle, Arg, dArg, Asp, Ala, Lys, dLys, His, and dHis; R2 is selected from the group consisting of Asp, Ala, dAla, Dab, Dap, Lys, Orn, Pro, and Glu R3 is absent or selected from the group consisting of His, dHis, Asn, Pro, and Gln; R4 is dPhe or p(F)dPhe; R5 is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6 is Trp or dNal(2’); R7 is selected from the group consisting of Pro, Orn, Glu, Asp, and Lys; R8 is absent or Lys; Y1 is absent or selected from the group consisting of dArg, dVal, dPro, and dTle; Y2 is absent or selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, 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 lactam bridge between R2 and R7 when R2 is Dap, Dab, Orn, or Lys, and R7 is Glu or Asp; -35- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 a lactam bridge between R1 or R2 and R7 or R8 when R1 or R2 is Asp and R7 or R8 is Lys; and a lactam bridge between R2 and R7 when R2 is Asp or Glu and R7 is Orn. [0103] In some embodiments, when R4 is dPhe or p(F)dPhe, then the non-naturally occurring melanocortin analog is cyclized between R2 and R7. In further embodiments, the sequence of Formula (I) is a sequence of Formula (IA(i)): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4 (IA(i)), wherein: X1 is absent or Nle; R1 is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; R2 is selected from the group consisting of Dab, Dap, Lys, Orn, Asp and Glu; R3 is absent or selected from the group consisting of His, dHis, Pro, and Gln; R4 is dPhe or p(F)dPhe; R5 is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6 is Trp or dNal(2’); R7 is selected from the group consisting of Orn, Glu, Asp, and Lys; Y1 is absent or selected from the group consisting of dArg, dVal, dPro, and dTle; Y2 is absent or selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, dVal, or dPro; Y4 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Asp or Glu at R2 and Orn or Lys at R7; or a lactam bridge between Dap, Dab, Orn, or Lys at R2, and Glu or Asp at R7. -36- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0104] In some embodiments of the sequence of Formula (I), R4 is p(F)dPhe. In further embodiments, R3 is His. In some embodiments, the sequence of Formula (I) is a sequence of Formula (IB): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4 (IB), wherein: X1 is absent or Nle; R1 is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; R2 is selected from the group consisting of Asp, Dap, Dab, Lys, Orn, and Glu; R3 is His; R4 is p(F)dPhe; R5 is Arg; R6 is Trp; R7 is selected from the group consisting of Orn, Glu, Asp, and Lys; Y1 is selected from the group consisting of dVal, dPro, and dTle; Y2 is selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, dVal, or dPro; Y4 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Asp or Glu at R2 and Orn or Lys at R7; or a lactam bridge between Dap, Dab, Orn, or Lys at R2, and Glu or Asp at R7. [0105] In some embodiments of the sequence of Formula (I), R4 is dPhe. In further embodiments, the non-naturally occurring melanocortin analog is cyclized between R2 and R7 or R8. In some embodiments, the sequence of Formula (I) is a sequence of Formula (IC): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3 (IC), wherein: -37- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 X1 is absent or norleucine (Nle); R1 is Nle or Asp; R2 is selected from the group consisting of Asp, Dap, Dab, Lys, Orn, Glu, and Pro; R3 is selected from the group consisting of His, dHis, Pro, and Gln; R4 is dPhe; R5 is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6 is Trp; R7 is selected from the group consisting of Orn, Glu, Asp, Orn, Lys, and Pro; R8 is absent or Lys; Y1 is dVal or dPro; Y2 is dVal or dPro; Y3 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R1 or R2 and R7 or R8 when R1 or R2 is Asp and R7 or R8 is Lys; a lactam bridge between R2 and R7 when R2 is Dap, Dab, Orn, or Lys, and R7 is Glu or Asp; and a lactam bridge between R2 and R7 when R2 is Asp or Glu and R7 is Orn. [0106] In some embodiments, the non-naturally occurring melanocortin analog is cyclized between a lactam bond between R2 and R7. In some embodiments, the sequence of Formula (I) is a sequence of Formula (ID): R1-R2-R3-R4-R5-R6-R7-Y1-Y2 (ID), wherein: R1 is selected from Nle, Arg, and dArg; -38- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 R2 is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3 is absent or selected from the group consisting of Pro, Asn, and His; R4 is selected from dPhe, p(F)dPhe, and p(Cl)dPhe; R5 is Arg; R6 is Trp; R7 is selected from the group consisting of Glu, Asp, Lys, and Orn; Y1 is absent, dVal, or dArg; Y2 is absent, dPro, or dVal; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between Glu or Asp at R2 and Orn at R7; a lactam bridge between Glu at R2 and Lys at R7; a lactam bridge between Asp at R2, Asn at R3, and Lys at R7; and a lactam bridge between Dap, Dab, Orn, or Lys at R2 and Glu or Asp at R7. [0107] In some embodiments, when the non-naturally occurring melanocortin analog is cyclized between a lactam bond between R2 and R7, then R4 is p(Cl)dPhe. In further embodiments, the sequence of Formula (I) is a sequence of Formula (IE): R1-R2-R3-R4-R5-R6-R7-Y1-Y2 (IE), wherein: R1 is Nle or Arg; R2 is selected from the group consisting of Dab, Lys, Orn, and Glu; R3 is Asn or His; R4 is p(Cl)dPhe; R5 is Arg; R6 is Trp; -39- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 R7 is selected from the group consisting of Glu, Asp, Lys, and Orn; Y1 is absent or dVal; Y2 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Glu at R2 and Orn or Lys at R7; or a lactam bridge between Dab, Orn, or Lys at R2 and Glu or Asp at R7 [0108] In some embodiments when the non-naturally occurring melanocortin analog is cyclized between a lactam bond between R2 and R7, then R4 is p(F)dPhe. In further embodiments, the sequence of Formula (I) is a sequence of Formula (IF): R1-R2-R3-R4-R5-R6-R7-Y1-Y2 (IF), wherein: R1 is selected from Nle, Arg, and dArg; R2 is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3 is absent, Asn, or His; R4 is p(F)dPhe; R5 is Arg; R6 is Trp; R7 is selected from the group consisting of Glu, Asp, Lys, and Orn; Y1 is absent or dVal; Y2 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between Glu or Asp at R2 and Orn at R7; a lactam bridge between Glu at R2 and Lys at R7; a lactam bridge between Asp at R2, Asn at R3, and Lys at R7; and -40- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 a lactam bridge between Dap, Dab, Orn, or Lys at R2 and Glu or Asp at R7. [0109] In some embodiments when the non-naturally occurring melanocortin analog is cyclized between a lactam bond between R2 and R7, then R4 is dPhe. In further embodiments, the sequence of Formula (IG) is a sequence of Formula (IG): R1-R2-R3-R4-R5-R6-R7-Y1-Y2 (IG), wherein: R1 is Nle or Arg; R2 is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3 is selected from the group consisting of Pro, Asn, and His; R4 is dPhe; R5 is Arg; R6 is Trp; R7 is selected from the group consisting of Glu, Asp, Lys, and Orn; Y1 is absent, dVal, or dArg; Y2 is absent, dPro, or dVal; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between Glu or Asp at R2 and Orn at R7; a lactam bridge between Glu at R2 and Lys at R7; a lactam bridge between Asp at R2, Asn at R3, and Lys at R7; and a lactam bridge between Dap, Dab, Orn, or Lys at R2 and Glu or Asp at R7. [0110] In some embodiments, the non-naturally occurring melanocortin analog of any one of Formulae (I)-(IG) has one or more beta hairpin (β-hairpin) and/or beta turn (β-turn) structures. In some embodiments, the presence of Pro, dPro, transPro(guan), and/or cisPro(guan), provides the β-hairpin and/or β-turn structures of the non-naturally occurring melanocortin analog. In some embodiments, the disulfide bond of the sequence according -41- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 to Formula (I), if present, provides the β-hairpin and/or β-turn structures of the non-naturally occurring melanocortin analog. [0111] As will be appreciated by the skilled artisan, non-naturally occurring melanocortin analogs comprising a sequence of any one of Formulae (I)-(IG), 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 (I)-(IG) may be at X1 or R1. Analogously, the C-terminus of a non-naturally occurring melanocortin analog comprising a sequence of any one of Formulae (I)-(IG) may be at any of R7, R8, R9, Y1, Y2, Y3, and Y4. [0112] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an acyl group. In some embodiments, the acyl group is acetyl ). [0113] In some of the non-naturally occurring melanocortin analog, if present, is not modified. [0114] In the sequence of any one of Formulae (I)-(IG), Y1Y2Y3Y4 or a fragment thereof represents a C-terminus of the non-naturally occurring melanocortin analog. In some embodiments, Y1 and Y2 are present and Y3-Y4 are absent. In some embodiments, Y3-Y4 are absent, and Y1 is D-valine and Y2 is D-proline. In some embodiments, Y3-Y4 are absent, and Y1 is D-proline and Y2 is D-valine. In some embodiments, Y3-Y4 are absent, and Y1 is D-tert-leucine and Y2 is D-proline. [0115] In some embodiments, Y1-Y3 are present and Y4 is absent. In some embodiments, Y4 is absent and Y1 is D-proline, Y2 is D-valine, and Y3 is D-proline. In some embodiments, Y4 is absent, and Y1 is D-tert-leucine, Y2 is D-tert-leucine, and Y3 is D-valine. [0116] In some embodiments, Y1-Y4 are present. In some embodiments, Y1-Y4 are present and Y1 is D-valine, Y2 is D-valine, Y3 is D-valine, and Y4 is D-proline. -42- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0117] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified by an amide In the sequence of any one of Formulae (I)-(IG), a non-naturally with a C- terminus modified by an amide may be - [0118] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is not modified. In the sequence of any one of Formulae (I)-(IG), a non- naturally occurring melanocortin analog with an unmodified C-terminus may be represented by -OH. [0119] Non-naturally occurring melanocortin analogs comprising a sequence of any one of Formulae (I)-(IG) are 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 R2 and R7 when R2 is dCys, R4 is p(Cl)dPhe, and R7 is Cys; a lactam bridge between R1 or R2 and any one of R7-R9 when R1 or R2 is Asp, R4 is dPhe, or p(F)dPhe, and any one of R7-R9 is Lys; a lactam bridge between R2 and R7 when R1 is Dap, Dab, Orn, or Lys, and R7 is Glu or Asp; and a lactam bridge between R2 and R7 when R2 is Asp or Glu and R7 is Orn. [0120] In some embodiments of the sequence of any one of Formulae (I)-(IG), R3 is His. In further embodiments, R3 is His and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between the Asp at R2 and the Lys at R7. In still further embodiments, R4 is p(F)dPhe or dPhe. [0121] In some embodiments, X1, Y3, and Y4 are all absent. In further embodiments, R1 is selected from Nle, Ala, Arg, dArg, Lys, dLys, His, and dHis and R4 is p(F)dPhe. In still further embodiments, Y1 is dVal and Y2 is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IG) is selected from the group consisting of: Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 3); Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 4); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 14); -43- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 15); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 16); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 17); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 18); and Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 19), wherein c represents cyclization through R2 and R7 via a lactam bond. [0122] In other further embodiments, Y1 is dTle, Y2 is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IG) is selected from the group consisting of: Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 7); Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 8); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 24); Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 27); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 28); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 29); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 30); and Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 31), wherein c represents cyclization through R2 and R7 via a lactam bond. [0123] In some embodiments, R1 is Nle and R4 is dPhe. In further embodiments, Y1 is dVal or dPro, Y2 is dPro or dVal. In some embodiments, the sequence of any one of Formulae (I)-(IG) is: Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 33); or Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 42), wherein c represents cyclization through R2 and R7 via a lactam bond. -44- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0124] Alternatively, in some embodiments, at least one of X1, Y3 and Y4 is present. In further embodiments, R1 is Nle, and R4 is p(F)dPhe. In some embodiments, the sequence of any one of Formulae (I)-(IG) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 6); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 20); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 22); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 23); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 25); and Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 26), wherein c represents cyclization through R2 and R7 via a lactam bond [0125] In some embodiments, when R3 is His, R4 is p(F)dPhe or dPhe, and the non- naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R2 and Lys at R7, then R5 is Arg. Alternatively, in some embodiments, R5 is an amino acid other than Arg. In further embodiments, R5 is selected from His, transPro(guan), cisPro(guan). In some embodiments, the sequence of any one of Formulae (I)-(IG) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 21); Ac-Nle-c[Asp-His-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 46); and Ac-Nle-c[Asp-His-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 47), wherein c represents cyclization through R2 and R7 via a lactam bond. [0126] In some embodiments, when R3 is His, R4 is p(F)dPhe or dPhe, and the non- naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R2 and Lys at R7, then R6 is Trp. Alternatively, in some embodiments, R6 is an amino acid other than Trp. In further embodiments, R6 is dNal(2’). In some embodiments, the sequence of any one of Formulae (I)-(IG) is: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro- NH2 (SEQ ID NO: 5), wherein c represents cyclization through R2 and R7 via a lactam bond. -45- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0127] In some embodiments of the sequence of any one of Formulae (I)-(IG), R3 is His and the non-naturally occurring melanocortin analog is cyclized through a bond other than a lactam bond between Asp at R2 and Lys at R7. In some embodiments, the non- naturally occurring melanocortin analog is cyclized through R2 and R7 via a bond other than a lactam bond between Asp at and Lys. For example, the non-naturally occurring melanocortin analog may be cyclized through R2 and R7 via a disulfide bond or a lactam formed between amino acids other than Asp and Lys. [0128] In some embodiments, the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp or Glu at R2 and Orn at R7 or Glu at R2 and Lys at R7. In further embodiments, R4 is selected from dPhe, p(Cl)dPhe, and p(F)dPhe. In some embodiments, the sequence of any one of Formulae (I)-(IG) is selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 11); Ac-Nle-c[Glu-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 12); Ac—Nle-c[Asp-His-dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 201); Ac—Nle-c[Glu-His-dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 203); Ac—Nle-c[Glu-His-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 202); Ac—Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 183); and Ac—Nle-c[Glu-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 252), wherein c represents cyclization through R2 and R7 via a lactam bond. [0129] In other embodiments, the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Dab, Dap, Orn, or Lys at R2 and Asp or Glu at R7. In further embodiments, R4 is selected from dPhe, p(Cl)dPhe, and p(F)dPhe. In some -46- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 embodiments, the sequence of any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Nle-c[Dap-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 172); Ac—Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 173); Ac—Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 174); Ac—Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 175); Ac—Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 176); Ac—Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 177); Ac—Nle-c[Lys-His-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 188); Ac—Nle-c[Lys-His-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 189); Ac—Nle-c[Dap-His-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 190); Ac—Nle-c[Dab-His-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 191); Ac—Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 192); Ac—Nle-c[Lys-His-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 193); Ac—Nle-c[Orn-His-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 194); Ac—Nle-c[Orn-His-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 195); Ac—Arg-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 242); Ac—Arg-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 243); Ac—Arg-c[Orn-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 244); Ac—dArg-c[Orn-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 245); Ac—dArg-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 246); Ac—Nle-c[Dab-His-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 248); Ac—Nle-c[Orn-His-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 249); and Ac—Nle-c[Orn-His-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 250), -47- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 wherein c represents cyclization through R2 and R7 via a lactam bond. [0130] In still other embodiments, the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between dCys at R2 and Cys at R7. In further embodiments, R4 is p(Cl)dPhe. In some embodiments, the sequence of any one of Formulae (I)-(IG) is Ac-Nle-c[dCys-His-p(Cl)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 2), wherein c represents cyclization through R2 and R7 via a disulfide bond. [0131] Alternatively, in some embodiments, the non-naturally occurring melanocortin analog is cyclized through Asp at a residue position other than R2 and/or Lys at a residue position other than R7. For example, the non-naturally occurring melanocortin analog may be cyclized through Asp at R1 and Lys at R7 or through Asp at R2 and Lys at R8. [0132] In some embodiments, the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R2 and Lys at R8. In further embodiments, the sequence of any one of Formulae (I)-(IG) is: Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Pro-Lys]- dVal-dPro-NH2 (SEQ ID NO: 35), wherein c represents cyclization through R2 and R8 via a lactam bond. [0133] In some embodiments, the non-naturally occurring melanocortin analog is cyclized between a lactam bond between Asp at R1 and Lys at R7. In further embodiments, R2 is Ala or dAla and R4 is dPhe. In some embodiments, the sequence of any one of Formulae (I)-(IG) is selected from the group consisting of: Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 38); Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 40); and Ac-Nle-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 41), wherein c represents cyclization through R1 and R7 via a lactam bond. [0134] In other further embodiments, R2 is Pro, and R4 is Phe. In some embodiments, the sequence of any one of Formulae (I)-(IG) is: Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 13), wherein c represents cyclization through R1 and R7 via a lactam bond. -48- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0135] In some embodiments of the sequence of any one of Formulae (I)-(IG), R3 is an amino acid other than His. In some embodiments, R3 is Asn. In further embodiments, R2 is Asp or Glu, R7 is Lys or Orn. In still further embodiments, Y1 is dVal, Y2 is dPro and Y3-Y4 are absent. In yet further embodiments, the sequence of any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Nle-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 184); Ac—Nle-c[Asp-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 185); Ac—Nle-c[Glu-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 186); Ac—Nle-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 187); Ac—Nle-c[Asp-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 204); Ac—Nle-c[Glu-Asn-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 205); Ac—Nle-c[Glu-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 206); Ac—Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 231); Ac—Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 232); Ac—Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 233); Ac—Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 234); Ac—Arg-c[Glu-Asn-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 240); Ac—Arg-c[Glu-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 241); Ac—Nle-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 253); and Ac—Arg-c[Asp-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 261), wherein c represents cyclization through R2 and R7 via a lactam bond. [0136] In other embodiments, Y1-Y4 are absent. In still further embodiments, the sequence of any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]—NH2 (SEQ ID NO: 213); Ac—Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Orn]—NH2 (SEQ ID NO: 214); -49- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac—Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Lys]—NH2 (SEQ ID NO: 215); Ac—Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]—NH2 (SEQ ID NO: 216); Ac—Arg-c[Asp-Asn-dPhe-Arg-Trp-Lys]—NH2 (SEQ ID NO: 223); Ac—Arg-c[Asp-Asn-dPhe-Arg-Trp-Orn]—NH2 (SEQ ID NO: 224); Ac—Arg-c[Glu-Asn-dPhe-Arg-Trp-Lys]—NH2 (SEQ ID NO: 225); and Ac—Arg-c[Glu-Asn-dPhe-Arg-Trp-Orn]—NH2 (SEQ ID NO: 226), wherein c represents cyclization through R2 and R7 via a lactam bond. [0137] In some embodiments, when R3 is Asn, then R2 is Dap, Dab, Lys, or Orn and R7 is Asp or Glu. In further embodiments, Y1 is dArg or dVal, Y2 is dVal or dPro and Y3-Y4 are absent. In still further embodiments, the sequence of any one of Formulae (I)-(IG) is selected form the group consisting of: Ac—Nle-c[Dab-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 178); Ac—Nle-c[Lys-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 179); Ac—Nle-c[Lys-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 180); Ac—Nle-c[Orn-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 181); Ac—Nle-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 182); Ac—Nle-c[Dab-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 196); Ac—Nle-c[Lys-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 197); Ac—Nle-c[Lys-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 198); Ac—Nle-c[Orn-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 199); Ac—Nle-c[Orn-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 200); Ac—Arg-c[Dab-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 227); Ac—Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 228); Ac—Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 229); Ac—Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 230); -50- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac—Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 235); Ac—Arg-c[Lys-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 236; Ac—Arg-c[Lys-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 237); Ac—Arg-c[Orn-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 238; Ac—Arg-c[Orn-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 239); Ac—Nle-c[Dap-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 247); Ac—Nle-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 251); Ac—Nle-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 255); Ac—Arg-c[Dap-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 257); Ac—Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 258); Ac—Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 259); Ac—Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 260); and Ac—Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dArg-dVal—NH2 (SEQ ID NO: 262), wherein c represents cyclization through R2 and R7 via a lactam bond. [0138] In other embodiments, Y1-Y4 are absent. In still further embodiments, the sequence of any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 207); Ac—Arg-c[Dap-Asn-p(F)dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 208); Ac—Arg-c[Dab-Asn-p(F)dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 209); Ac—Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 210); Ac—Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 211); Ac—Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 212); Ac—Arg-c[Orn-Asn-dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 217); Ac—Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 218); -51- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac—Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 219); Ac—Arg-c[Lys-Asn-dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 220); Ac—Arg-c[Lys-Asn-dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 221); Ac—Arg-c[Orn-Asn-dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 222); and Ac—Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 256), wherein c represents cyclization through R2 and R7 via a lactam bond. [0139] Alternatively, in some embodiments, R3 is absent or selected from dHis, Gln and Pro. In further embodiments, R2 is Asp or Lys, R4 is dPhe or p(F)dPhe, R5 is Arg, R6 is Trp, and R7 is Lys or Glu. In some embodiments, the sequence of any one of Formulae (I)- (IG) is selected from the group consisting of: Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 9); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 10); Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 32); Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 36); Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 37); Ac—Nle-c[Lys-Pro-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 254); and Ac—Arg-c[Lys-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 263), wherein c represents cyclization through R2 and R7 via a lactam bond. [0140] In some embodiments of the sequence of Formula (I), R3 is an amino acid other than His and R9 is absent. Alternatively, in some embodiments, R9 is present. In some embodiments, the sequence of any one of Formulae (I)-(IG) is: Ac-Nle-c[Asp-Phe-Phe-Pro- His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 34), wherein c represents cyclization through R1 and R9 via a lactam bond. [0141] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I). In some embodiments, the non-naturally occurring -52- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-47 and 172- 263. [0142] 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: 3-10, 14-33, 35- 47, 172-187, 190-247, 254, 255, 257, 258, and 260-263. [0143] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(i)). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: SEQ ID NOs: 3- 10, 14-33, 36, 37, 42-47, 172-187, 190-247, 254, 255, 257, 258, and 260-263. [0144] 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: 3-8, 14-31, 43, 44, 172-187, 207-216, 227-234, 242-247, 257, 258, and 263. [0145] 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: 10, 13, 33, 35- 37, 42, 45-47, 190-206, 217-226, 235-241, 254, 255, and 260-262. [0146] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (ID). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 172-263. [0147] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IE). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 188, 189, 248- 250, 252, 253, 256, and 259. [0148] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IF). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 172-187, 207- 216, 227-234, 242-247, 257, 258, and 263. -53- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0149] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IG). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 190-206, 217- 226, 235-241, 254, 255, and 260-262. [0150] Non-naturally occurring melanocortin analogs of any one of Formulae (I)-(IG) may be an agonist of the melanocortin 4 receptor and an agonist of the melanocortin 3 receptor. In some embodiments, non-naturally occurring melanocortin analogs of any one of Formulae (I)-(IG) are full agonists of the melanocortin 4 receptor and full agonists of the melanocortin 3 receptor. In other embodiments, non-naturally occurring melanocortin analogs of any one of Formulae (I)-(IG) are full agonists of the melanocortin 4 receptor and partial agonists of the melanocortin 3 receptor. Non-Naturally Occurring Melanocortin Analog Synthesis [0151] 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 non-naturally occurring melanocortin analogs 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 non-naturally occurring melanocortin analogs of the present technology. [0152] The process for synthesizing the non-naturally occurring melanocortin analogs 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. -54- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0153] Solid phase peptide synthesis methods are well known and practiced in the art. In such methods, the synthesis of peptides can 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). [0154] 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. [0155] 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. [0156] 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. [0157] 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 -55- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 between an Fmoc-Linker, such as p-[(R,S)-α-[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. [0158] 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 non-naturally occurring melanocortin analogs 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. [0159] 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. [0160] 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 (DCM) or 1-methyl-2-pyrrolidone (NMP). Suitable cyclic coupling reagents include, for example, 2-(1H-benzotriazol-1-yl)- 1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate (HBTU), benzotriazole-1-yl-oxy- -56- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole-1-yl-oxy- tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP), 2-(7-aza-1H-benzotriazol-1- yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TATU), 2-(2-oxo-1 (2H)-pyridyl)-1,1,3,3- tetramethyluronium tetrafluoroborate (TPTU) or N,N′-dicyclohexylcarbodiimide/1- hydroxybenzotriazole (DCCl/HOBt). Coupling is convention initiated by use of a suitable base, such as N,N-diispropylethylamine (DIPEA), sym-collidine or N-methylmorpholine (NMM). [0161] Following cleavage of peptides from the solid phase following their synthesis, the peptide can 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, can also be employed. Once purified, the peptide can 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 [0162] The non-naturally occurring melanocortin analogs 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 non-toxic 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. -57- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0163] When the non-naturally occurring melanocortin analogs 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 non- naturally occurring melanocortin analogs of the present technology are prepared in a suitable solvent for the non-naturally occurring melanocortin analogs 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 non-naturally occurring melanocortin analogs 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. Methods [0164] The present technology also provides methods of treating, preventing, reducing, or otherwise ameliorating one or more symptoms or conditions associated with metabolic dysfunction comprising administering a non-naturally occurring melanocortin analog to a subject in need thereof. The methods of the present technology may promote fat loss, prevent muscle loss, decrease body weight, accelerate weight loss, decrease fat mass to lean mass ratio, improve body composition and/or BMI, reduce waist circumference, or any combination thereof. [0165] The present technology comprises methods of reducing body weight and/or fat mass in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog of the present technology to the subject. [0166] In some embodiments, the present technology comprises methods of reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject. In some embodiments, the lean mass is lean muscle mass. -58- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0167] In some embodiments, the present technology comprises methods of treating, preventing, reducing, or otherwise ameliorating glucose intolerance and/or diabetes mellitus in the subject. [0168] In some embodiments, the present technology comprises a method of reducing body weight and/or fat mass in an obese subject (e.g., an obese subject without diabetes mellitus or an obese subject having diabetes mellitus), comprising administering a non- naturally occurring melanocortin analog to the subject. [0169] In some embodiments, the methods of the present technology (i) reduce a lipid droplets size (e.g., an average lipid droplet size); (ii) increase an adipose tissue mitochondrial number or adipose tissue mitochondrial concentration; (iii) increase an adipose tissue vascularization level; (iv) increase, maintain, or prevent reduction of a beige or brown adipocyte level; (v) increase a metabolic rate; (vi) increase a calorie burn level; and/or (vii) increase, maintain, or prevent reduction of an insulin sensitivity level, relative to a control. [0170] In some embodiments, the methods of the present technology comprise reducing a lipid droplet, or an average lipid droplet, size by about 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, or 95%, relative to a control. [0171] In some embodiments, the methods of the present technology comprise reducing a lipid droplet, or an average lipid droplet, size by at least 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, or 95%, relative to a control. [0172] In some embodiments, the methods of the present technology comprise reducing a lipid droplet, or an average lipid droplet, size by at least about 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, or 95%, relative to a control. [0173] In some embodiments, the methods of the present technology comprise one or more of (i) increasing an adipose tissue mitochondrial number; (ii) increasing an adipose tissue mitochondrial concentration; (iii) increasing an adipose tissue vascularization level; increasing a beige adipocyte level; (iv) increasing a brown adipocyte level; (v) increasing a metabolic rate; (vi) increasing a calorie burn level; or (vii) increasing an insulin sensitivity -59- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 level, by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% or more, relative to a control. [0174] In some embodiments, the methods of the present technology comprise one or more of (i) increasing an adipose tissue mitochondrial number; (ii) increasing an adipose tissue mitochondrial concentration; (iii) increasing an adipose tissue vascularization level; increasing a beige adipocyte level; (iv) increasing a brown adipocyte level; (v) increasing a metabolic rate; (vi) increasing a calorie burn level; or (vii) increasing an insulin sensitivity level, by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% or more, relative to a control. [0175] In some embodiments, the methods of the present technology comprise one or more of (i) increasing an adipose tissue mitochondrial number; (ii) increasing an adipose tissue mitochondrial concentration; (iii) increasing an adipose tissue vascularization level; increasing a beige adipocyte level; (iv) increasing a brown adipocyte level; (v) increasing a metabolic rate; (vi) increasing a calorie burn level; or (vii) increasing an insulin sensitivity level, by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% or more, relative to a control. [0176] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating hyperplasia in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. [0177] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating hypothalamic obesity (e.g., congenital hypothalamic damage and/or or damage from tumors or trauma) in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. [0178] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating a proopiomelanocortin (POMC) deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. [0179] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating a leptin deficiency in a subject in need -60- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. [0180] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating a syndromic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. Nonlimiting examples of syndromic obesity include Prader–Willi syndrome, Wilms tumor, Aniridia, Genitourinary, Range of Developmental Delays (WAGR) syndrome, Bardet- Biedl syndrome, Fragile X syndrome, Cohen syndrome, Proprotein Convertase Subtilisin/Kexin Type 1 (PCSK1) deficiency, Alstrom syndrome, MC4 haploinsufficiency, 17p11.2 deletion syndrome, and 2q37 deletion syndrome. [0181] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating non-alcoholic steatohepatitis (NASH) (i.e., metabolic dysfunction-associated steatohepatitis (MASH)), in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. [0182] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating hyperinsulinism in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. [0183] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating Type 2 Diabetes in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. [0184] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating a cardiovascular disease (e.g., stroke and/or heart attack) in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. [0185] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating osteoarthritis in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. [0186] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating a cancer (e.g., decreasing a risk of cancer) -61- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. [0187] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating erectile dysfunction in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. [0188] In some embodiments, the method further comprises reducing obesity-related inflammation in the subject. [0189] In some embodiments, method further comprises preserving or improving kidney function in the subject. [0190] The present technology also provides methods of reducing obesity-related inflammation in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject. [0191] The present technology further provides methods of preserving or improving kidney function in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject. [0192] In some embodiments, the method comprises orally administering a non- naturally occurring melanocortin analog comprising a sequence of any one of Formulae (I)- (IG) to the subject. Any of the sequences of Formulae (I)-(IG) listed above may be used in the methods of the present technology. In some embodiments, the method comprises orally administering a non-naturally occurring melanocortin analog comprising a sequence of any one of Formulae (I)-(IG)to the subject. Any of the sequences of any one of Formulae (I)-(IG)) listed above may be used in the methods of the present technology. [0193] The present technology also provides methods of reducing body weight and/or fat mass in a subject in need thereof, comprising orally administering about 15 mg/kg to about 100 mg/kg of a non-naturally occurring melanocortin analog to the subject. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of any one of Formulae (I)-(IG). -62- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0194] The present technology also provides methods of treating, preventing, or reducing glucose intolerance and/or diabetes mellitus in a subject in need thereof, comprising orally administering about 15 mg/kg to about 100 mg/kg of a non-naturally occurring melanocortin analog to the subject. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of any one of Formulae (I)-(IG). [0195] The present technology also provides methods of reducing obesity-related inflammation in a subject in need thereof, comprising orally administering about 15 mg/kg to about 100 mg/kg of a non-naturally occurring melanocortin analog to the subject. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of any one of Formulae (I)-(IG). [0196] The present technology also provides methods of preserving or improving kidney function in a subject in need thereof, comprising orally administering about 15 mg/kg to about 100 mg/kg of a non-naturally occurring melanocortin analog to the subject. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of any one of Formulae (I)-(IG). [0197] The present technology also provides methods of reducing body weight and/or fat mass in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog having a sequence selected from the group consisting of SEQ ID NOs: 11, 12, and 43-45 to the subject. [0198] In some embodiments, the method further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject. In some embodiments, the lean mass is lean muscle mass. [0199] In some embodiments, the method further comprises treating, preventing, or reducing glucose intolerance and/or diabetes mellitus in the subject. [0200] The present technology also provides methods of treating, preventing, or reducing glucose intolerance and/or diabetes mellitus in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog having a sequence selected from the group consisting of SEQ ID NOs: 11, 12, and 43-45 to the subject. -63- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0201] In some embodiments, the method further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject. In some embodiments, the lean mass is lean muscle mass. In some embodiments, the method further comprises reducing body weight and/or fat mass in the subject. [0202] In some embodiments, the method further comprises reducing obesity-related inflammation in the subject. In some embodiments, the method further comprises preserving or improving kidney function in the subject. [0203] The present technology also provides methods of reducing obesity-related inflammation in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject. [0204] The present technology also provides methods of preserving or improving kidney function in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject. [0205] In some embodiments of the methods, after administration of the non-naturally occurring melanocortin analog, the subject’s body weight is more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog. [0206] In some embodiments of the methods after administration of the non-naturally occurring melanocortin analog, the subject’s fat mass is more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog. [0207] In some embodiments of the methods of the present technology, the subject exhibits about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, or about a 10% reduction in body weight about 10 days, about 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology. -64- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0208] In some embodiments of the methods of the present technology, the subject exhibits at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, or at least a 10% reduction in body weight at least 10 days, at least 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology. [0209] In some embodiments of the methods of the present technology, the subject exhibits at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, or at least about a 10% reduction in body weight at least about 10 days, at least about 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology. [0210] In some embodiments of the methods of the present technology, the subject exhibits about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, about a 10%, about a 12.5%, about a 15%, about a 17.5%, about a 20%, about a 25%, or about a 30% reduction in fat mass about 10 days, about 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology. [0211] In some embodiments of the methods of the present technology, the subject exhibits at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, at least a 10%, at least a 12.5%, at least a 15%, at least a 17.5%, at least a 20%, at least a 25%, or at least a 30% reduction in fat mass at least 10 days, at least 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology. [0212] In some embodiments of the methods of the present technology, the subject exhibits at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, at least about a 10%, at least about a 12.5%, at least about a 15%, at least about a 17.5%, at least about a 20%, at least about a 25%, or at least about a 30% reduction in fat mass at least about 10 days, at least about 20 days, or at least about 30 days after -65- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 administration of a first dose of a non-naturally occurring melanocortin analog of the present technology. [0213] In some embodiments of the methods of the present technology, the subject exhibits no change, about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, or about a 10% reduction in lean mass loss about 10 days, about 20 days, or about 30 days after administration of a first dose of a non- naturally occurring melanocortin analog of the present technology. [0214] In some embodiments of the methods of the present technology, the subject exhibits no change, at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, or at least a 10% reduction in lean mass loss at least 10 days, at least 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology. [0215] In some embodiments of the methods of the present technology, the subject exhibits no change, at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, or at least about a 10% reduction in lean mass loss at least about 10 days, at least about 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology. [0216] In some embodiments of the method of the present technology, the subject exhibits no change, about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, or about a 10% increase in lean mass about 10 days, about 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology. [0217] In some embodiments of the method of the present technology, the subject exhibits no change, at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, or at least a 10% increase in lean mass at least 10 days, at least 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology. -66- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0218] In some embodiments of the method of the present technology, the subject exhibits no change, at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, or at least about a 10% increase in lean mass at least about 10 days, at least about 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology. [0219] In some embodiments, the subject exhibits about a 5%, about a 10%, about a 12.5%, about a 15%, about a 17.5%, about a 20%, about a 25%, about a 30%, about a 35%, about a 40%, about a 45%, about a 50%, about a 60%, or about a 70% reduction in food intake per day about 10 days, about 20 days, or about 30 days after administration of a first dose of the combination therapy. In some embodiments, the reduction in food intake occurs about 0.5 hours, about 1 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 10 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 4 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, or about 6 weeks after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology. [0220] Food intake may reflect cumulative food intake, net food intake, or both. Cumulative food intake may represent total food intake. Net food intake may represent the difference between total food intake and energy expenditure. Cumulative and net food intake may represent a food intake measurement from start to end of dosing, from start to an intermediate time point of dosing (i.e., a time point after the start of dosing but prior to the end of dosing), from an intermediate time point to end of dosing, or between two or more intermediate time points. [0221] The methods of the present technology alter a subject’s preference for food having high-fat content or low-fat content or is otherwise calorically dense or less calorically dense. In some embodiments, the methods of the present technology increase a subject’s preference for one or more of a lower-fat food or a less calorically dense food relative to the food preference of the subject at baseline or of a control. In some embodiments, the methods of the present technology decrease the subject’s preference for one or more of a higher-fat -67- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 food or a more calorically dense food relative to the food preference of the subject at baseline or of a control. [0222] In some embodiments of the methods of the present technology, the blood glucose level of the subject is decreased following administration of the combination therapy. In some embodiments, the blood glucose level of the subject is decreased following administration of a first dose of the combination therapy. [0223] In some embodiments, the subject exhibits at least about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, about a 10%, about a 15%, about a 20%, about a 25%, or about a 30% reduction in a blood glucose level about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog, relative to a control. [0224] In some embodiments, the subject exhibits at least at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, or at least a 30% reduction in a blood glucose level at least 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog, relative to a control. [0225] In some embodiments, the subject exhibits at least about at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, at least about a 10%, at least about a 15%, at least about a 20%, at least about a 25%, or at least about a 30% reduction in a blood glucose level at least about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog, relative to a control. [0226] In some embodiments, the subject of the methods of the present technology may experience no change in or a reduction in one or more of an alkaline phosphatase level, a total protein level, an albumin level, a globulin level, a gamma-glutamyl transferase (GGT), a glucose level, a urea nitrogen level, a creatine level, a urea acid level, or a C-reactive -68- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 protein level in a biological sample from the subject. Nonlimiting examples of biological samples include a circulatory fluid sample (e.g., blood, serum, lymphatic fluid), a urine sample, or a tissue sample. [0227] In some embodiments, the subject exhibits at least about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, about a 10%, about a 15%, about a 20%, about a 25%, or about a 30% reduction in an alkaline phosphatase level, a total protein level, an albumin level, a globulin level, a GGT, a glucose level, a urea nitrogen level, a creatine level, a urea acid level, or a C-reactive protein level in the biological sample about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology, relative to a control. [0228] In some embodiments, the subject exhibits at least at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, or at least a 30% reduction in an alkaline phosphatase level, a total protein level, an albumin level, a globulin level, a GGT, a glucose level, a urea nitrogen level, a creatine level, a urea acid level, or a C-reactive protein level in the biological sample at least 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology, relative to a control. [0229] In some embodiments, the subject exhibits at least about at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, at least about a 10%, at least about a 15%, at least about a 20%, at least about a 25%, or at least about a 30% reduction in an alkaline phosphatase level, a total protein level, an albumin level, a globulin level, a GGT, a glucose level, a urea nitrogen level, a creatine level, a urea acid level, or a C-reactive protein level in the biological sample at least about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology, relative to a control. -69- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0230] In some embodiments, the subject of the methods of the present technology experiences no change or a reduction in one or more of a total white blood cell count level, a neutrophil level, a lymphocyte level, a monocyte level, an eosinophil level, a basophil level, a red cell distribution width level, a platelet count level, a mean platelet volume in a biological sample from the subject. [0231] In some embodiments, the subject exhibits at least about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, about a 10%, about a 15%, about a 20%, about a 25%, or about a 30% reduction in a total white blood cell count level, a neutrophil level, a lymphocyte level, a monocyte level, an eosinophil level, a basophil level, a red cell distribution width level, a platelet count level, a mean platelet volume in a biological sample from the subject. In some embodiments, the reduction occurs about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology, relative to a control. [0232] In some embodiments, the subject exhibits at least at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, or at least a 30% reduction in a total white blood cell count level, a neutrophil level, a lymphocyte level, a monocyte level, an eosinophil level, a basophil level, a red cell distribution width level, a platelet count level, a mean platelet volume in a biological sample from the subject. In some embodiments, the reduction occurs at least 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least 30 days after administration of a first dose of a non- naturally occurring melanocortin analog of the present technology, relative to a control. [0233] In some embodiments, the subject exhibits at least about at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, at least about a 10%, at least about a 15%, at least about a 20%, at least about a 25%, or at least about a 30% reduction in a total white blood cell count level, a neutrophil level, a lymphocyte level, a monocyte level, an eosinophil level, a basophil level, a red cell distribution width level, a platelet count level, a mean platelet volume in a biological sample from the subject. In some -70- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 embodiments, the reduction occurs at least about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology, relative to a control. [0234] In some embodiments, the subject of the methods of the present technology experiences no change or an increase in one or more of a red blood cell count, a hemoglobin level, a hematocrit level, a mean corpuscular volume level, a mean corpuscular hemoglobin level, or a mean corpuscular hemoglobin concentration level in a biological sample from the subject, relative to a control. In some embodiments, the red blood cell count, a hemoglobin level, the hematocrit level, the mean corpuscular volume level, the mean corpuscular hemoglobin level, or the mean corpuscular hemoglobin concentration level is increased in the biological sample by at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or 300%, after administration of a first dose of a non- naturally occurring melanocortin analog, relative to a control. [0235] In some embodiments, the subject of the methods of the present technology may experience no change in or an increase in an albumin to globulin ratio in a biological sample from the subject, relative to a control. In some embodiments, the albumin to globulin ratio is increased in the biological sample by at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or 300%, after administration of a first dose of a non-naturally occurring melanocortin analog, relative to a control. [0236] In some embodiments, the subject administered a non-naturally occurring melanocortin analog of the present technology exhibits one or more of: (a) a reduction in fat mass by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (b) a reduction in epididymal fat mass at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; -71- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 (c) a reduction in perirenal fat mass at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (d) a reduction in body weight at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (e) a reduction in body mass at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (f) an increase in lean mass by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, or 500% relative to baseline or a control; (g) an increase in muscle mass by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, or 500% relative to baseline or a control; (h) an increase in glucose tolerance by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, or 500% relative to baseline or a control; (i) a reduction in a fat mass to lean mass ratio at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (j) a reduction in BMI by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (k) a reduction in waist circumference at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (l) a reduction in an adverse cardiovascular event by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; -72- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 (m) a reduction in brain mass loss by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (n) a reduction in a hemoglobin A1c level by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (o) a reduction in nausea by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (p) a reduction in vomiting by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (q) a reduction in diarrhea by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (r) a reduction in inflammation by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (s) a reduction in obesity-related inflammation by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (t) an increase in kidney function by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, or 500% relative to baseline or a control; (u) a reduction in hyperplasia by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; -73- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 (v) a reduction in alcohol use by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (w) a reduction in metabolic dysfunction by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (x) a reduction in a symptom associated with metabolic dysfunction by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (y) a reduction in blood sugar by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (z) a reduction in weight gain after treatment with a weight loss agent or a non-naturally occurring melanocortin analog is terminated by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (aa) a reduction in body weight measured in kg by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; (bb) a reduction in BMI by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; (cc) a reduction in trunk fat mass by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; (dd) an increase in a bone mineral content level by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, or 300%, relative to baseline or a control; -74- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 (ee) an increase in a whole-body bone mineral content level by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, or 300%, relative to baseline or a control; (ff) an increase in a trunk bone mineral content level by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, or 300%, relative to baseline or a control; (gg) an increase in a bone density level by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, or 300%, relative to baseline or a control; (hh) an increase in a trunk muscle mass by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, or 300%, relative to baseline or a control; (ii) a reduction in food intake by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; (jj) a reduction in caloric intake by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; (kk) a reduction in a high-fat food intake by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; (ll) a reduction in a calorically dense food intake by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; (mm) an increase in a low-fat food intake by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; or -75- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 (nn) an increase in a less calorically dense food intake by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control. [0237] In some embodiments, any one of (a)-(nn) is maintained for at about 2 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after administration of the non-naturally occurring melanocortin analog. [0238] In some embodiments, any one of (a)-(nn) is maintained for at least 2 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after administration of the non-naturally occurring melanocortin analog. [0239] In some embodiments, any one of (a)-(nn) is maintained for at least about 2 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after administration of the non-naturally occurring melanocortin analog. [0240] In some embodiments, any one of (a)-(nn) occurs during or after administration of a first, a second, and/or a third dose of the non-naturally occurring melanocortin analog. In some embodiments, any one of (a)-(nn) is greater during or after administration the second dose relative to during or after administration of the first dose. In some embodiments, any one of (a)-(nn) is greater during or after administration the third dose relative to during or after administration of the first dose or the second dose. [0241] 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). Weight Loss Agents -76- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0242] Administration of the non-naturally occurring melanocortin analogs of the present technology may comprise rebound-resistant weight loss (i.e., prevention of weight gain after treatment completion) and/or increased muscle retention, relative to a control (e.g., administration of a conventional weight loss agent alone). The rebound resistant weight loss may comprise a prevention or a reduction in fat mass gain and/or BMI increase, relative to the control. In some embodiments, the non-naturally occurring melanocortin analog is administered as a combination therapy with a weight loss agent, where the combination therapy achieves the same weight loss as administration of the weight loss agent alone, but at a reduced dose or dosing frequency relative to the weight loss agent. [0243] In some embodiments, the rebound-resistant weight loss is maintained for about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration of the non-naturally occurring melanocortin analog is complete and/or discontinued. [0244] In some embodiments, the rebound-resistant weight loss is maintained for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration of the non-naturally occurring melanocortin analog is complete and/or discontinued. [0245] In some embodiments, the rebound-resistant weight loss is maintained for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration of the non-naturally occurring melanocortin analog is complete and/or discontinued. [0246] In other embodiments, the subject’s weight increases no more than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, or less than about 1%. [0247] In some embodiments, the present technology comprises a method of suppressing appetite in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and/or after administration of the weight loss agent. Administration of the non-naturally occurring melanocortin analog prior to, during, and/or after administration of the weight loss agent may produce an additive -77- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 or synergistic effect on suppressing the subject’s appetite. In some embodiments, the weight loss agent is a GLP-1 receptor agonist and the non-naturally occurring melanocortin analog is a melanocortin agonist and administration of the combination therapy produces an additive effect on suppressing the subject’s appetite. In some embodiments, the weight loss agent is a dual GLP-1/GIP receptor agonist and the non-naturally occurring melanocortin analog is a melanocortin agonist and administration of the combination therapy produces a synergistic effect on suppressing the subject’s appetite. [0248] In some embodiments, the method reduces food intake of the subject. Administration of the non-naturally occurring melanocortin analog prior to, during, and/or after administration of the weight loss agent may produce an additive or synergistic effect on reducing the subject’s food intake. In some embodiments, the method reduces fat body mass and/or body weight of the subject. In some embodiments, the reduction in food intake is a reduction in caloric intake. [0249] In other embodiments, the subject’s weight increases no more than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, or less than about 1% at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration of the non-naturally occurring melanocortin analog is complete and/or discontinued. [0250] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating body weight gain a during or after use of a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. [0251] In some embodiments, the present technology comprises a method of maintaining body weight after use of a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. [0252] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating a fat mass gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. -78- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0253] The methods of the present technology may decrease the risk and/or incidence of adverse cardiovascular events associated with the use of a weight loss agent including, but not limited to, cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, angina, sinus tachycardia, sinus bradycardia, coronary artery bypass grafting, percutaneous coronary intervention, heart failure, carotid endarterectomy, peripheral vascular disease, or any combination thereof. Cardiac Effects [0254] The methods of the present technology may prevent or decrease the risk and/or incidence of adverse cardiac effects associated with the use of conventional melanocortin analogs, melanocortin peptides, and/or melanocortin receptor agonists. In some embodiments, the subject of the present technology experiences no or substantially no adverse cardiac effects and/or no change in cardiac outcomes during or after administration of a non-naturally occurring melanocortin analog of the present technology, relative to a control (e.g., a subject administered conventional melanocortin analogs, melanocortin peptides, and/or melanocortin receptor agonists). In some embodiments, the adverse cardiac effect and/or change in cardiac outcomes comprises one or more of a change in blood pressure (e.g., systolic blood pressure, diastolic blood pressure, mean arterial blood pressure), heart rate, QT interval, QRS interval, RR interval, or QTc, relative to a control. In some embodiments, the adverse cardiac effect and/or change in cardiac outcomes is a transient change in blood pressure (e.g., systolic blood pressure, diastolic blood pressure, mean arterial blood pressure), heart rate, QT interval, QRS interval, RR interval, or QTc, relative to a control. In some embodiments, the transient change in blood pressure comprises an increase in blood pressure in the evening, at night, during a sleep cycle, or during a dark cycle after administration of the conventional melanocortin analogs, melanocortin peptides, and/or melanocortin receptor agonists. Tanning and Hyperpigmentation [0255] The present technology comprises a method of inducing a tanning effect in a subject during or after administration of a non-naturally occurring melanocortin analog. In some embodiments, the tanning effect comprises skin darkening without hyperpigmentation (e.g., an uneven distribution of melanin) compared to subjects who have not received the -79- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 non-naturally occurring melanocortin analog or compared to the same subject at baseline (e.g., prior to receiving a dose of the non-naturally occurring melanocortin analog). In some embodiments, the tanning effect is not clinically significant, occurs in response to UV or sun exposure, and/or is not substantially ectopic. The tanning effect may occur in combination with weight loss. The weight loss may comprise a retention in muscle mass (e.g., lean muscle mass) and a loss of fat mass. In some embodiments, the tanning effect is observed about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20 days after administration of a non- naturally occurring melanocortin analog. In some embodiments, the tanning effect occurs at a dose of greater than 100 mg or at least about 200 mg. [0256] In some embodiments, the tanning effect is reduced after completion and/or discontinuation of the non-naturally occurring melanocortin analog dosing. In some embodiments, the tanning effect is reduced at least about 1 day, 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks, 3 week, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks, 15 weeks, or 20 weeks after completion and/or discontinuation of the non-naturally occurring melanocortin analog dosing. [0257] In some embodiments the reduced tanning effect comprises reversal of about 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80% 90%, 95%, 99%, or 100% of the total area of skin darkening. In some embodiments, the tanning effect does not comprise ectopic skin hyperpigmentation and/or tanning effects (e.g., of the palms or gums). [0258] In some embodiments the reduced tanning effect comprises reversal of at least 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80% 90%, 95%, 99%, or 100% of the total area of skin darkening. In some embodiments, the tanning effect does not comprise ectopic skin hyperpigmentation and/or tanning effects (e.g., of the palms or gums). [0259] In some embodiments the reduced tanning effect comprises reversal of at least about 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80% 90%, 95%, 99%, or 100% of the total area of skin darkening. In some embodiments, the tanning effect does not comprise ectopic skin hyperpigmentation and/or tanning effects (e.g., of the palms or gums). [0260] The non-naturally occurring melanocortin analog may be useful in treating, preventing, or otherwise ameliorating one or more hypopigmentation diseases. Nonlimiting -80- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 examples of hypopigmentation disease include albinism (e.g., oculocutaneous albinism), vitiligo, piebaldism, nevus depigmentosus, hypomelanosis of Ito, phenylketonuria, tuberous sclerosis, dyschromatosis symmetrica hereditaria, Waardenburg syndrome, Hermansky- Pudlak syndrome, Chediak-Higashi syndrome, Griscelli syndrome, and Tietz syndrome, and acquired hypopigmentary diseases such as leukoderma Sutton, Vogt-Koyanagi Harada syndrome, leukoderma senile, leukoderma after sea bathing, and leukoderma syphiliticum. [0261] The methods of the present technology may prevent or decrease the risk and/or incidence of hyperpigmentation associated with the use of conventional melanocortin analogs, melanocortin peptides, and/or melanocortin receptor agonists. In some embodiments, the subject of the present technology experiences no or substantially no hyperpigmentation during or after administration of a non-naturally occurring melanocortin analog of the present technology, relative to a control (e.g., a subject administered conventional melanocortin analogs, melanocortin peptides, and/or melanocortin receptor agonists). In some embodiments, the hyperpigmentation comprises one or more of hyperpigmentation of the skin, nose, cheeks, or site of administration of the non-naturally occurring melanocortin analog. Subjects [0262] InIn some embodiments, the subject of the present technology has an addiction or is susceptible to an addiction. In some embodiments, the subject of the present technology has used or is using one or more addictive substances. [0263] In some embodiments, the subject of the present technology has pain or is susceptible to pain. [0264] In some embodiments, the subject has or had an alcohol use disorder (AUD) or an opioid use disorder (OUD). In some embodiments, the subject is at risk of developing an AUD or an OUD. [0265] In some embodiments, the subject has used or is using an addictive substance. In some embodiments, the subject has used or is using a medication to treat an addiction. In some embodiments, the frequency or amount of the addictive substance and/or rescue medication is reduced during or after administration of the non-naturally occurring -81- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 melanocortin analog. In some embodiments, the frequency or amount of the addictive substance and/or rescue medication is reduced as the dose or dosage of the non-naturally occurring melanocortin analog increases. In some embodiments, the frequency or amount of the addictive substance and/or rescue medication comprises a downward titration during or after administration of a non-naturally occurring melanocortin analog. [0266] Nonlimiting examples of rescue medications include opioid agonists (e.g., partial or full opioid agonists), opioid antagonists, and non-opioid medications. [0267] The addictive substances of the present technology may comprise a substance in a prescription medication, a substance in an over-the-counter medication, a recreational substance, or an illegal substance. Nonlimiting examples of addictive substances include opioids (e.g., morphine, heroin, codeine, oxycodone, hydrocodone, fentanyl), painkillers, stimulants (e.g., caffeine, nicotine, methamphetamines, cocaine, amphetamines), narcotics, alcohol, barbiturates (e.g., phenobarbital, methohexital, butalbital, pentobarbital, primidone, and amobarbital), sedatives (e.g., tranquilizers, xylazine, eszopiclone, zaleplon, zolpidem, zopiclone), marijuana, cannabis, tetrahydrocannabinol (THC), and cannabidiol (CBD), or inhalants (e.g., aerosols, butanes, freon, helium, nitrous oxide, propane, nitrites). [0268] In some embodiments, the sedative comprises barbiturates (e.g., phenobarbital, methohexital, butalbital, pentobarbital, primidone, and amobarbital) or benzodiazepines (e.g., alprazolam, lorazepam, clonazepam, diazepam, temazepam). [0269] In some embodiments, the nicotine comprises nicotine in a tobacco chew, a nicotine pouch, or a smoking device (e.g., cigarettes, electronic cigarettes, cigars, vape products). [0270] In some embodiments, the subject has received or is receiving a conventional medication used to treat an addiction. In some embodiments, the conventional medication used to treat an addiction comprises one or more of buprenorphine, naltrexone, acamprosate, methadone, naloxone, nalmefene, xycodone, levo‐alpha‐acetylmethadol (LAAM), codeine, or a slow-release morphine (e.g., a slow-release oral morphine). -82- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0271] In some embodiments, the subject has a body mass index (BMI) of about 18.5 kg/m2 to about 35 kg/m2. In some embodiments, the subject has a BMI of about 20 kg/m2 or greater. In some embodiments, the subject has a BMI of about 18.5 kg/m2 or greater. [0272] In some embodiments, the subject has a BMI of greater than 24.9 kg/m2. In some embodiments, the subject has a BMI of 25 kg/m2 to 29.9 kg/m2. In some embodiments, the subject has a BMI of greater than or equal to 30 kg/m2. [0273] In some embodiments, the subject is an overweight subject. Overweight subjects include those having a body weight about 3% or more, 5% or more, 10% or more, 20% or more, or 30% or less, than the upper end of "normal" BMI (e.g., 24.9 kg/m2). [0274] In some embodiments, the subject is an obese subject. Obese subjects include those having a BMI of greater than or equal to 30 kg/m2. [0275] In some embodiments, the subject has a metabolic dysfunction. In some embodiments, the metabolic dysfunction is selected from the group consisting of obesity, diabetes mellitus, metabolic syndrome, insulin resistance, non-alcoholic fatty liver disease, polycystic ovarian syndrome, metabolic acidosis, hypothyroidism, hyperlipidemia, Cushing Syndrome, and metabolic myopathies. In other embodiments, the subject has another condition which is not metabolic dysfunction, but administration of the weight loss agent provides therapeutic benefit to the non-metabolic dysfunction condition. [0276] In some embodiments, the subject with a metabolic dysfunction has previously received treatment with the weight loss agent. A subject who has previously received treatment with the weight loss agent has completed at least one full treatment cycle with the weight loss agent. In other embodiments, the subject with a metabolic dysfunction is currently receiving treatment with the weight loss agent. A subject who is currently receiving treatment with the weight loss has received at least one dose of the weight loss agent. In still other embodiments, the subject with a metabolic dysfunction has not received any treatment with the weight loss agent. A subject who has not received any treatment with the weight loss agent has not received even a single dose of the weight loss agent. [0277] In accordance with the present technology, a subject who has been treated with a weight loss agent has received a weight loss agent in an amount sufficient to induce at -83- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 least minimum weight loss. Likewise, a subject how is currently undergoing treatment with a weight loss agent is receiving a weight loss agent in an amount sufficient to induce at least minimum weight loss. [0278] In some embodiments, the subject has previously received treatment with the weight loss agent and has not lost body weight and/or fat mass. Alternatively, in some embodiments, the subject has previously received treatment with the weight loss agent and has lost body weight and/or fat mass. In such embodiments, the subject may still be overweight or obese. The subject may have stopped treatment with the weight loss agent because they were unable to continue losing body weight and/or fat mass with the weight loss agent. [0279] In embodiments in which the subject has previously received treatment with the weight loss agent, the subject’s body weight may be more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog. [0280] In embodiments in which the subject has previously received treatment with the weight loss agent, the subject’s fat mass may be more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog. [0281] In some embodiments, the subject is currently receiving treatment with the weight loss agent and has not lost any body weight. Alternatively, in some embodiments, the subject is currently receiving treatment with the weight loss agent and has lost body weight and/or fat mass. In some embodiments, the subject is currently receiving treatment with the weight loss agent, has lost body weight and/or fat mass, and has failed to lose sufficient body weight and/or fat mass following administration of the weight loss agent. The subject who is currently receiving treatment with the weight loss agent may still be overweight or obese. -84- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0282] In embodiments in which the subject is currently receiving treatment with the weight loss agent, the subject’s body weight may be more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog. [0283] In embodiments in which the subject is currently receiving treatment with the weight loss agent, the subject’s fat mass may be more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog. [0284] In some embodiments, the subject has not received any treatment with the weight loss agent and has failed to lose sufficient or any weight using other weight loss methods. In some embodiments, the subject has not received any treatment with the weight loss agent and has not attempted to lose weight using any other methods. In such embodiments, the subject may begin treatment with non-naturally occurring melanocortin analog and the weight loss agent at the same time. A subject who begins administration of the weight loss agent and the non-naturally occurring melanocortin analog at the same time, and continues with concurrent administration of the two therapies, may experience greater body weight and/or fat mass loss compared to a subject who is administered only one of the therapies, e.g., only the weight loss agent or only the non-naturally occurring melanocortin analog. [0285] In embodiments in which the subject begins treatment with the non-naturally occurring melanocortin analog and the weight loss agent at the same time, the subject’s body weight may be more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, or more than 55% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog. [0286] In embodiments in which the subject begins treatment with the non-naturally occurring melanocortin analog and the weight loss agent at the same time, the subject’s fat mass may be more than 10%, more than 15%, more than 20%, more than 25%, more than -85- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 30%, more than 35%, more than 40%, more than 45%, more than 50%, or more than 55% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog. [0287] In some embodiments, the method prevents or reduces muscle mass loss (e.g., involuntary muscle mass loss) in the subject. In some embodiments, the subject’s muscle mass is not more than 5%, not more than 10%, not more than 15%, not more than 20%, not more than 25%, or not more than 30% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and/or the weight loss agent. [0288] In some embodiments, the weight loss agent is administered to the subject for treating or preventing one of one or more metabolic dysfunctions. Nonlimiting examples of metabolic dysfunctions include obesity, diabetes mellitus, metabolic syndrome, insulin resistance, non-alcoholic fatty liver disease, polycystic ovarian syndrome, metabolic acidosis, hypothyroidism, hyperlipidemia, Cushing Syndrome, and metabolic myopathies. [0289] The subject of the present technology may be 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. Distribution [0290] In some embodiments, the non-naturally occurring melanocortin analogs of the present technology comprise an increased distribution relative to a control. The increased distribution may be an increase in distribution of the non-naturally occurring melanocortin analogs at a given time point relative to a control administered at the same dose and measured at the same time point. The distribution may be measured at an intermediate time point or a final time point. [0291] In some embodiments, the measurement of distribution comprises measuring a volume of distribution at the terminal phase (Vd or Vdß), a central volume of distribution (V), -86- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 a peripheral volume of distribution (V2), an apparent volume of distribution (Vz), or a measurement of distribution comprises measuring a volume of distribution at steady state (Vss). A high or increased Vd, Vdß, Vz, and/or Vss may suggest large distribution beyond the tissue, plasma, and/or serum compartment, relative to the control. [0292] In some embodiments, the increase in distribution comprises a measurement about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs. [0293] In some embodiments, the increase in distribution comprises a measurement at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs. [0294] In some embodiments, the increase in distribution comprises a measurement at least about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs. [0295] In some embodiments, the increase in distribution comprises a measurement during administration of the non-naturally occurring melanocortin analogs. [0296] In some embodiments, the increase in distribution comprises a measurement at the completion of administration of the non-naturally occurring melanocortin analogs. Additional pD and pK Embodiments [0297] In some embodiments, the non-naturally occurring melanocortin analog of the present technology exhibits one or more of the following: (a) an increase in half-life relative to a control; (b) a reduction in clearance relative to a control; (c) an increase in tissue concentration relative to a control; (d) an increase in plasma concentration relative to a control; -87- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 (e) an increase in serum concentration relative to a control; (f) an increase in distribution relative to a control; (g) an increase in an AUC measurement relative to a control; (h) an increase in a DNAUC measurement relative to a control; (i) an increase in Tfinal relative to a control; (j) an increase in Cmax relative to a control; (k) an increase in Cmin relative to a control; (l) an increase in DNCmin relative to a control; (m) an increase in MRT relative to a control; (n) an increase in Cavg relative to a control; (o) an increase in Ctrough relative to a control; (p) an increase in CT relative to a control; (q) an increase in Vd relative to a control; (r) a reduction in Tmax relative to a control; or (s) a reduction in Q relative to a control. [0298] In some embodiments, the non-naturally occurring melanocortin analog of the present technology exhibits one or more of the following, relative to a control: (a) an increase in half-life by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (b) a reduction in clearance by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to a control; (c) an increase in tissue concentration by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; -88- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 (d) an increase in plasma concentration by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (e) an increase in serum concentration by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (f) an increase in distribution by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (g) an increase in an AUC by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% measurement relative to a control; (h) an increase in a DNAUC measurement by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (i) an increase in Tfinal by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (j) an increase in Cmax by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (k) an increase in Cmin by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (l) an increase in DNCmin by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; -89- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 (m) an increase in MRT by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (n) an increase in Cavg by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (o) an increase in Ctrough by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (p) an increase in CT by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (q) an increase in Vd by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (r) a reduction in Tmax by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to a control; or (s) a reduction in Q by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to a control. Doses and Formulations [0299] In some embodiments, the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) 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. -90- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0300] In some embodiments, the non-naturally occurring melanocortin analog or pharmaceutical composition thereof can 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). [0301] 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 can 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. -91- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0302] In some embodiments, the methods comprise administering a non-naturally occurring melanocortin analog at a first dose and a second to a subject in need thereof, wherein the second dose is greater than the first dose. In some embodiments, the subject is administered a third dose that is greater than the first and the second dose. [0303] In some embodiments, the methods comprise administered the non-naturally occurring melanocortin analog to the subject in increase doses or increased dosages, relative to the first dose. [0304] In some embodiments, the 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 30 mg/kg or 60 mg/kg per body weight of the subject once daily. [0305] In some embodiments, the 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 30 mg/kg or 60 mg/kg per body weight of the subject once daily. [0306] In some embodiments, the 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 30 mg/kg or 60 mg/kg per body weight of the subject once daily. [0307] 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. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily. [0308] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 0.1 mg to at least 100 mg once daily. In some -92- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 10 mg or at least 50 mg once daily. [0309] In some embodiments, the 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 30 mg/kg or 60 mg/kg per body weight of the subject once daily. [0310] In some embodiments, the 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 30 mg/kg or 60 mg/kg per body weight of the subject once daily. [0311] In some embodiments, the 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 30 mg/kg or 60 mg/kg per body weight of the subject once daily. [0312] In some embodiments, the non-naturally occurring melanocortin analog is MC4- NN2-0453 and is administered at a dose of about 0.03, 0.06, 0.15, 0.30, 0.60, 1.00, or 1.50 mg/kg. In some embodiments, the MC4-NN2-0453 is administered as a single dose. [0313] In some embodiments, the non-naturally occurring melanocortin analog is MC4- NN2-0453 and is administered at a dose of at least 0.03, 0.06, 0.15, 0.30, 0.60, 1.00, or 1.50 mg/kg. In some embodiments, the MC4-NN2-0453 is administered as a single dose. [0314] In some embodiments, the non-naturally occurring melanocortin analog is MC4- NN2-0453 and is administered at a dose of at least about 0.03, 0.06, 0.15, 0.30, 0.60, 1.00, or 1.50 mg/kg. In some embodiments, the MC4-NN2-0453 is administered as a single dose. [0315] In some embodiments, the non-naturally occurring melanocortin analog is MC4- NN2-0453 and is administered at a dose of about 0.75, 1.5, 3.0, or 5.0 mg/day. In some embodiments, the subject is administered two or more doses of the MC4-NN2-0453. -93- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0316] In some embodiments, the non-naturally occurring melanocortin analog is MC4- NN2-0453 and is administered at a dose of at least 0.75, 1.5, 3.0, or 5.0 mg/day. In some embodiments, the subject is administered two or more doses of the MC4-NN2-0453. [0317] In some embodiments, the non-naturally occurring melanocortin analog is MC4- NN2-0453 and is administered at a dose of at least about 0.75, 1.5, 3.0, or 5.0 mg/day. In some embodiments, the subject is administered two or more doses of the MC4-NN2-0453. [0318] In some embodiments, when two or more doses of MC4-NN2-0453 are administered, the doses comprise two or more different doses selected from the group consisting of 0.75, 1.5, 3.0, and 5.0 mg/day. In some embodiments, the two or more doses are administered as ascending doses. In some embodiments, the MC4-NN2-0453 is administered once daily. [0319] In some embodiments, the non-naturally occurring melanocortin analog is LY2112688 and is administered at a dose of about 0.45 mg or 1.0 mg. In some embodiments, the LY2112688 is administered at a first dose of about 0.45 mg and a second dose of 1.0 mg. [0320] In some embodiments, the non-naturally occurring melanocortin analog is LY2112688 and is administered at a dose of about 0.5 mg/kg/day. [0321] In some embodiments, the non-naturally occurring melanocortin analog is LY2112688 and is administered at a dose of at least 0.45 mg or 1.0 mg. In some embodiments, the LY2112688 is administered at a first dose of at least 0.45 mg and a second dose of 1.0 mg. [0322] In some embodiments, the non-naturally occurring melanocortin analog is LY2112688 and is administered at a dose of at least 0.5 mg/kg/day. [0323] In some embodiments, the non-naturally occurring melanocortin analog is LY2112688 and is administered at a dose of at least about 0.45 mg or 1.0 mg. In some embodiments, the LY2112688 is administered at a first dose of at least about 0.45 mg and a second dose of 1.0 mg. -94- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0324] In some embodiments, the non-naturally occurring melanocortin analog is LY2112688 and is administered at a dose of at least about 0.5 mg/kg/day. [0325] In some embodiments, the non-naturally occurring melanocortin analog is Melanotan-II and is administered at a dose of about 0.01 mg/kg. In some embodiments, the dose is a first dose. The first dose may be escalated by 0.005 mg/kg increments to 0.03 mg/kg or to 0.025 mg/kg. [0326] In some embodiments, the non-naturally occurring melanocortin analog is Melanotan-II and is administered at a dose of about 0.01 mg/kg, about 0.025 mg/kg, or about 0.03 mg/kg. [0327] In some embodiments, the non-naturally occurring melanocortin analog is Melanotan-II and is administered at a dose of at least 0.01 mg/kg. In some embodiments, the dose is a first dose. The first dose may be escalated by 0.005 mg/kg increments to 0.03 mg/kg or to 0.025 mg/kg. [0328] In some embodiments, the non-naturally occurring melanocortin analog is Melanotan-II and is administered at a dose of at least 0.01 mg/kg, at least 0.025 mg/kg, or at least 0.03 mg/kg. [0329] In some embodiments, the non-naturally occurring melanocortin analog is Melanotan-II and is administered at a dose of at least about 0.01 mg/kg. In some embodiments, the dose is a first dose. The first dose may be escalated by 0.005 mg/kg increments to 0.03 mg/kg or to 0.025 mg/kg. [0330] In some embodiments, the non-naturally occurring melanocortin analog is Melanotan-II and is administered at a dose of at least about 0.01 mg/kg, at least about 0.025 mg/kg, or at least about 0.03 mg/kg. [0331] In some embodiments, the non-naturally occurring melanocortin analog is Afamelanotide and is administered at a dose of about 0.08 mg/kg to about 0.21 mg/kg. In some embodiments, the Afamelanotide is administered as a daily dose. The subject may be administered about ten daily doses. -95- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0332] In some embodiments, the non-naturally occurring melanocortin analog is Afamelanotide and is administered at a dose of at least 0.08 mg/kg to at least 0.21 mg/kg. In some embodiments, the Afamelanotide is administered as a daily dose. The subject may be administered at least ten daily doses. [0333] In some embodiments, the non-naturally occurring melanocortin analog is Afamelanotide and is administered at a dose of at least about 0.08 mg/kg to at least about 0.21 mg/kg. In some embodiments, the Afamelanotide is administered as a daily dose. The subject may be administered at least about ten daily doses. [0334] In some embodiments, the non-naturally occurring melanocortin analog is Afamelanotide and is administered at a dose of about 16 mg. In some embodiments, the Afamelanotide may be administered about once every 60 days. In some embodiments, the Afamelanotide is administered using a subcutaneous implant. [0335] In some embodiments, the non-naturally occurring melanocortin analog is Afamelanotide and is administered at a dose of at least 16 mg. In some embodiments, the Afamelanotide may be administered at least once every 60 days. In some embodiments, the Afamelanotide is administered using a subcutaneous implant. [0336] In some embodiments, the non-naturally occurring melanocortin analog is Afamelanotide and is administered at a dose of at least about 16 mg. In some embodiments, the Afamelanotide may be administered at least about once every 60 days. In some embodiments, the Afamelanotide is administered using a subcutaneous implant. [0337] In some embodiments, the non-naturally occurring melanocortin analog is Bremelanotide and is administered at a dose of about 1.75 mg, 4.0 mg, or 6.0 mg. [0338] In some embodiments, the non-naturally occurring melanocortin analog is Bremelanotide and is administered at a dose of at least about 7.0 mg or at least about 10 mg. In some embodiments, the dose is administered intranasally. [0339] In some embodiments, the non-naturally occurring melanocortin analog is Bremelanotide and is administered at a dose of at least 1.75 mg, 4.0 mg, or 6.0 mg. -96- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0340] In some embodiments, the non-naturally occurring melanocortin analog is Bremelanotide and is administered at a dose of at least at least 7.0 mg or at least at least 10 mg. In some embodiments, the dose is administered intranasally. [0341] In some embodiments, the non-naturally occurring melanocortin analog is Bremelanotide and is administered at a dose of at least about 1.75 mg, 4.0 mg, or 6.0 mg. [0342] In some embodiments, the non-naturally occurring melanocortin analog is Bremelanotide and is administered at a dose of at least at least about 7.0 mg or at least at least about 10 mg. In some embodiments, the dose is administered intranasally [0343] In some embodiments, the non-naturally occurring melanocortin analog is MK- 0493 and is administered at a dose of about 10 mg or about 30 mg. [0344] In some embodiments, the non-naturally occurring melanocortin analog is MK- 0493 and is administered at a dose of about 1 mg/kg to about 4 mg/kg. [0345] In some embodiments, the non-naturally occurring melanocortin analog is MK- 0493 and is administered at a dose of about 2 mg/kg, about 6 mg/kg, or about 20 mg/kg. [0346] In some embodiments, the non-naturally occurring melanocortin analog is MK- 0493 and is administered at a dose of at least 10 mg or at least 30 mg. [0347] In some embodiments, the non-naturally occurring melanocortin analog is MK- 0493 and is administered at a dose of at least 1 mg/kg to at least 4 mg/kg. [0348] In some embodiments, the non-naturally occurring melanocortin analog is MK- 0493 and is administered at a dose of at least 2 mg/kg, at least 6 mg/kg, or at least 20 mg/kg. [0349] In some embodiments, the non-naturally occurring melanocortin analog is MK- 0493 and is administered at a dose of at least about 10 mg or at least about 30 mg. [0350] In some embodiments, the non-naturally occurring melanocortin analog is MK- 0493 and is administered at a dose of at least about 1 mg/kg to at least about 4 mg//kg. [0351] In some embodiments, the non-naturally occurring melanocortin analog is MK- 0493 and is administered at a dose of at least about 2 mg/kg, at least about 6 mg/kg, or at least about 20 mg/kg. -97- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0352] In some embodiments, the non-naturally occurring melanocortin analog is PF- 00446687 and is administered at a dose of about 200 mg, 175 mg, 125 mg, 100 mg, or 20 mg. In some embodiments, the subject is administered one dose of PF-00446687 comprising about 200 mg, 175 mg, 125 mg, 100 mg, or 20 mg. In some embodiments, the subject is administered two doses of PF-00446687, each dose comprising about 200 mg, 175 mg, 125 mg, 100 mg, or 20 mg. [0353] In some embodiments, the non-naturally occurring melanocortin analog is PF- 00446687 and is administered at a dose of at least 200 mg, 175 mg, 125 mg, 100 mg, or 20 mg. In some embodiments, the subject is administered one dose of PF-00446687 comprising at least 200 mg, 175 mg, 125 mg, 100 mg, or 20 mg. In some embodiments, the subject is administered two doses of PF-00446687, each dose comprising at least 200 mg, 175 mg, 125 mg, 100 mg, or 20 mg. [0354] In some embodiments, the non-naturally occurring melanocortin analog is PF- 00446687 and is administered at a dose of at least about 200 mg, 175 mg, 125 mg, 100 mg, or 20 mg. In some embodiments, the subject is administered one dose of PF-00446687 comprising at least about 200 mg, 175 mg, 125 mg, 100 mg, or 20 mg. In some embodiments, the subject is administered two doses of PF-00446687, each dose comprising at least about 200 mg, 175 mg, 125 mg, 100 mg, or 20 mg. [0355] In some embodiments, the non-naturally occurring melanocortin analog is setmelanotide and is administered at a dose of about 0.5 mg, 1.0 mg, 2.0 mg, or 3.0 mg. [0356] In some embodiments, the non-naturally occurring melanocortin analog is setmelanotide and is administered at a dose of at least 0.5 mg, 1.0 mg, 2.0 mg, or 3.0 mg. [0357] In some embodiments, the non-naturally occurring melanocortin analog is setmelanotide and is administered at a dose of at least about 0.5 mg, 1.0 mg, 2.0 mg, or 3.0 mg. In some embodiments, the dose is administered once daily. [0358] In some embodiments, the dose is administered once daily. In some embodiments, the setmelanotide is administered at two or more doses. When the setmelanotide is administered at two or more doses, the second dose may be greater than the first dose. -98- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0359] In some embodiments, the non-naturally occurring melanocortin analog is administered about 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. [0360] 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. [0361] 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. [0362] In some embodiments, the non-naturally occurring melanocortin analog is administered at least about once daily in an amount ranging from at least about 0.5 mg/kg to at least about 10 mg/kg, at least about 1 mg/kg to at least about 7.5 mg/kg, or at least about 2.5 mg/kg to at least about 5 mg/kg per body weight of the subject. [0363] 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 non-naturally occurring melanocortin analog (i.e., pharmaceutical combination) 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. [0364] 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 non-naturally occurring melanocortin analog (i.e., pharmaceutical combination) 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 -99- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 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. [0365] 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 non-naturally occurring melanocortin analog (i.e., pharmaceutical combination) 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. [0366] In some embodiments, a method disclosed herein is performed on the subject for about a period of 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. [0367] In some embodiments, a method disclosed herein is performed on the subject for at least a period of 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. [0368] In some embodiments, a method disclosed herein is performed on the subject for at least about a period of 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. Concentrations after Administration [0369] In some embodiments, the concentration of the non-naturally occurring melanocortin analog in the plasma or a tissue of the subject is about 5 ng/mL to about 2000 ng/mL about 24 hours after administration of the non-naturally occurring melanocortin analog. [0370] In some embodiments, the concentration of the non-naturally occurring melanocortin analog in the plasma or a tissue of the subject is at least 5 ng/mL to at least 2000 ng/mL about 24 hours after administration of the non-naturally occurring melanocortin analog. -100- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0371] In some embodiments, the concentration of the non-naturally occurring melanocortin analog in the plasma or a tissue of the subject is at least about 5 ng/mL to at least about 2000 ng/mL about 24 hours after administration of the non-naturally occurring melanocortin analog. [0372] In some embodiments, the non-naturally occurring melanocortin analog is administered to the subject until the concentration of the non-naturally occurring melanocortin analog in the plasma or a tissue of the subject is at least about 5 ng/mL to at least about 2000 ng/mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 5 ng/mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 10 ng/mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 50 ng/mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 100 ng/mL after administration of the non- naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 200 ng/mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 300 ng/mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 400 ng/mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 500 ng/mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the wherein concentration is at least about 750 ng/mL after administration of the non- naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 1000 ng/mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 1500 ng/mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 2000 ng/mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is a maximum concentration (Cmax). Modes of Administration -101- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0373] The non-naturally occurring melanocortin analogs of the present technology may be administered using any means known in the art, including orally, ocularly, intranasally, topically, parenterally, by injection, rectally, or vaginally. If administered by injection, the non-naturally occurring melanocortin analog injection may be intravenous (IV), subcutaneous (SC), intramuscular (IM), intraperitoneal (IP), intracerebroventricular (ICV), or other means known in the art. The non-naturally occurring melanocortin analog 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, anti-oxidants and other agents known in the art. In general, any route of administration by which the non-naturally occurring melanocortin analogs are introduced across an epidermal layer of cells may be employed. Administration includes topical delivery. 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. [0374] 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. Dosing [0375] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg/mL to about 500 mg/mL. [0376] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 0.1 mg/mL to at least 500 mg/mL. -102- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0377] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 0.1 mg/mL to at least about 500 mg/mL. [0378] 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. 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. [0379] The methods disclosed herein 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 combination therapy (i.e., pharmaceutical combination) 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. [0380] The methods disclosed herein 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 combination therapy (i.e., pharmaceutical combination) 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. [0381] The methods disclosed herein 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 combination therapy (i.e., pharmaceutical combination) 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, -103- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 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. [0382] In some embodiments, a method disclosed herein is performed on the subject for 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. [0383] In some embodiments, at least one active ingredient of the combination therapy is administered to a subject in a continuous doing schedule. As used herein, a “continuous dosing schedule” is an administration or dosing regimen without dose interruptions, e.g., without days off treatment. Repetition of 21-day or 28-day treatment cycles without dose interruptions is an exemplary continuous dosing schedule. [0384] In some embodiments, the 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 30 mg/kg or 60 mg/kg per body weight of the subject once daily. [0385] 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. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily. [0386] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg/kg to about 1000 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 550 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 -104- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 administered at a dose of about 30 mg/kg or 60 mg/kg per body weight of the subject once daily. [0387] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 5 mg/kg to at least 1000 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 550 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. [0388] 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 1000 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 550 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. [0389] 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 -105- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 mg/kg, about 450 mg/kg, or about 500 mg/kg, about 550 mg/kg, about 600 mg/kg, about 650 mg/kg, about 700 mg/kg, about 750 mg/kg, about 800 mg/kg, about 850 mg/kg, about 900 mg/kg, about 950 mg/kg, or about 1000 mg/kg per body weight of the subject once daily. [0390] 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, at least 550 mg/kg, at least 600 mg/kg, at least 650 mg/kg, at least 700 mg/kg, at least 750 mg/kg, at least 800 mg/kg, at least 850 mg/kg, at least 900 mg/kg, at least 950 mg/kg, or at least 1000 mg/kg per body weight of the subject once daily. [0391] 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, at least about 550 mg/kg, at least about 600 mg/kg, at least about 650 mg/kg, at least about 700 mg/kg, at least about 750 mg/kg, at least about 800 mg/kg, at least about 850 mg/kg, at least about 900 mg/kg, at least about 950 mg/kg, or at least about 1000 mg/kg per body weight of the subject once daily. [0392] 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. [0393] 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. -106- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0394] 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. [0395] 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. [0396] 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. [0397] 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. [0398] 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. [0399] 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. [0400] 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. [0401] 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. [0402] 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. [0403] 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. [0404] 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. [0405] 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. [0406] 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. -107- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0407] 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. [0408] 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. [0409] 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. [0410] 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. [0411] 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. [0412] 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. [0413] 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. [0414] 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. [0415] 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. [0416] 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. [0417] 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. [0418] 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. [0419] 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 -108- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 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, about 500 mg/kg, about 550 mg/kg, about 600 mg/kg, about 650 mg/kg, about 700 mg/kg, about 750 mg/kg, about 800 mg/kg, about 850 mg/kg, about 900 mg/kg, about 950 mg/kg, or about 1000 mg/kg per body weight of the subject twice daily. [0420] 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. [0421] 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. [0422] 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. [0423] 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. [0424] 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. [0425] 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. [0426] 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. [0427] 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. [0428] 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. [0429] 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 -109- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 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, at least 500 mg/kg, at least 550 mg/kg, at least 600 mg/kg, at least 650 mg/kg, at least 700 mg/kg, at least 750 mg/kg, at least 800 mg/kg, at least 850 mg/kg, at least 900 mg/kg, at least 950 mg/kg, or at least 1000 mg/kg per body weight of the subject twice daily. [0430] 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 twice daily. [0431] 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 twice daily. [0432] 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 twice daily. [0433] 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 twice daily. [0434] 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 twice daily. [0435] 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 twice daily. [0436] 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 twice daily. [0437] 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 twice daily. [0438] 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 twice daily. [0439] 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, -110- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 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, at least about 500 mg/kg, at least about 550 mg/kg, at least about 600 mg/kg, at least about 650 mg/kg, at least about 700 mg/kg, at least about 750 mg/kg, at least about 800 mg/kg, at least about 850 mg/kg, at least about 900 mg/kg, at least about 950 mg/kg, or at least about 1000 mg/kg per body weight of the subject twice daily. [0440] 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. [0441] 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. [0442] 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. [0443] 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. [0444] 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. [0445] 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. [0446] 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. [0447] 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. [0448] 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. -111- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0449] 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. [0450] 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. [0451] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose that is a projected human equivalent dose (HED) based on a nonhuman primate dose. [0452] In some embodiments, the HED based on a 10 mg/kg nonhuman primate dose ranges from about 300 mg to about 550 mg. [0453] In some embodiments, the HED based on a 10 mg/kg nonhuman primate dose ranges from at least 300 mg to at least 550 mg. [0454] In some embodiments, the HED based on a 10 mg/kg nonhuman primate dose ranges from at least about 300 mg to at least about 550 mg. [0455] 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. [0456] In some embodiments, the non-naturally occurring melanocortin analog is administered at a first dose once daily for at least 5 days to at least 10 days. In some embodiments, the non-naturally occurring melanocortin analog is administered at a second dose once daily for at least 5 days to at least 10 days, after administration of the first dose. -112- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 In some embodiments, the non-naturally occurring melanocortin analog is administered at a third dose twice daily for at least 7 days to at least 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. [0457] In some embodiments, the non-naturally occurring melanocortin analog is administered at a first dose once daily for at least about 5 days to at least about 10 days. In some embodiments, the non-naturally occurring melanocortin analog is administered at a second dose once daily for at least about 5 days to at least 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 at least about 7 days to at least 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. [0458] In some embodiments, the non-naturally occurring melanocortin analogs or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) is administered at a second dose that is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% greater than the first dose. [0459] In some embodiments, the non-naturally occurring melanocortin analogs or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) is administered at a second dose that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% greater than the first dose. [0460] In some embodiments, the non-naturally occurring melanocortin analogs or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) is administered at a second dose that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% greater than the first dose. -113- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0461] In some embodiments, the non-naturally occurring melanocortin analogs or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) is administered at a third dose that about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% greater than the first dose and/or the second dose. [0462] In some embodiments, the non-naturally occurring melanocortin analogs or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) is administered at a third dose that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% greater than the first dose and/or the second dose. [0463] In some embodiments, the non-naturally occurring melanocortin analogs or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) is administered at a third dose that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% greater than the first dose and/or the second dose. [0464] In some embodiments, the dosage of the second dose is greater than the dosage of the first dose. In some embodiments, the first dose is administered about once a day and the second dose is administered about twice a day. [0465] In some embodiments, the dosage of the second dose is greater than the dosage of the first dose. In some embodiments, the first dose is administered at least once a day and the second dose is administered at least twice a day. [0466] In some embodiments, the dosage of the second dose is greater than the dosage of the first dose. In some embodiments, the first dose is administered at least about once a day and the second dose is administered at least about twice a day. [0467] In some embodiments, the dosage of the third dose is greater than the dosage of the first dose and/or the second dose. In some embodiments, the first dose and/or the second dose is administered about once a day, and the third dose is administered about twice a day. -114- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0468] In some embodiments, the dosage of the third dose is greater than the dosage of the first dose and/or the second dose. In some embodiments, the first dose and/or the second dose is administered at least once a day, and the third dose is administered at least twice a day. [0469] In some embodiments, the dosage of the third dose is greater than the dosage of the first dose and/or the second dose. In some embodiments, the first dose and/or the second dose is administered at least about once a day, and the third dose is administered at least about twice a day. [0470] In some embodiments, the non-naturally occurring melanocortin analog is administered using two or more different administration routes. The two or more different administration routes may comprise an oral administration and a subcutaneous administration. The oral administration may occur before, during, or after the subcutaneous administration. [0471] In some embodiments, the first dose and the second dose comprise different routes of administration. In some embodiments, the first dose comprises an oral dose and the second dose comprises a subcutaneous dose. In some embodiments, the first dose and/or second dose and the third dose comprise different routes of administration. In some embodiments, the first dose and/or the second dose comprises an oral dose and the third dose comprises a subcutaneous dose. [0472] In some embodiments, the second dose is administered at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks after the first dose. [0473] In some embodiments, the third dose is administered at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks after the first dose and/or the second dose. [0474] In some embodiments, the second dose is administered at least at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 -115- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks after the first dose. [0475] In some embodiments, the third dose is administered at least at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks after the first dose and/or the second dose. [0476] In some embodiments, the second dose is administered at least about at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, or at least about 6 weeks after the first dose. [0477] In some embodiments, the third dose is administered at least about at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, or at least about 6 weeks after the first dose and/or the second dose. [0478] In some embodiments, the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) is administered at two or more dosage amounts, each dosage amount differing from the other. [0479] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 0.5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day. In some embodiments, the non-naturally occurring melanocortin analog is administered 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, twice, 3 times, 4 times, 5 times, or 10 times per day. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day. In some embodiments, the administration is performed once per day. -116- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0480] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 0.5 mg to at least 500 mg in a dose volume of at least 1 mL to 20 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 50 mg to at least 100 mg in a dose volume of at least 2 mL to 10 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 75 mg in a dose volume of at least 5 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day. In some embodiments, the administration is performed once per day. [0481] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 0.5 mg to at least about 500 mg in a dose volume of at least about 1 mL to 20 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 50 mg to at least about 100 mg in a dose volume of at least about 2 mL to 10 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 75 mg in a dose volume of at least about 5 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day. In some embodiments, the administration is performed once per day. [0482] In some embodiments, the non-naturally occurring melanocortin analog is administered as a single dosage unit. In some embodiments, the non-naturally occurring melanocortin analog dose is administered as multiple dosage units. In some embodiments, the multiple dosage units individually comprise about 2.5 mg/mL to about 100 mg/mL of the non-naturally occurring melanocortin analog. In some embodiments, the multiple dosage units individually comprise about 2.5 mg/mL to about 10 mg/mL of the non-naturally occurring melanocortin analog. In some embodiments, the multiple dosage units individually comprise about 6 mg/mL of the non-naturally occurring melanocortin analog. In some embodiments, the non-naturally occurring melanocortin analog is administered as about 5 -117- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 dosage units to about 10 dosage units. In some embodiments, the non-naturally occurring melanocortin analog is administered as 5 dosage units. In some embodiments, the non- naturally occurring melanocortin analog is administered as 10 dosage units. [0483] In some embodiments, the non-naturally occurring melanocortin analog is administered as a single dosage unit. In some embodiments, the non-naturally occurring melanocortin analog dose is administered as multiple dosage units. In some embodiments, the multiple dosage units individually comprise at least 2.5 mg/mL to at least 100 mg/mL of the non-naturally occurring melanocortin analog. In some embodiments, the multiple dosage units individually comprise at least 2.5 mg/mL to at least 10 mg/mL of the non-naturally occurring melanocortin analog. In some embodiments, the multiple dosage units individually comprise at least 6 mg/mL of the non-naturally occurring melanocortin analog. In some embodiments, the non-naturally occurring melanocortin analog is administered as at least 5 dosage units to at least 10 dosage units. In some embodiments, the non-naturally occurring melanocortin analog is administered as 5 dosage units. In some embodiments, the non- naturally occurring melanocortin analog is administered as 10 dosage units. [0484] In some embodiments, the non-naturally occurring melanocortin analog is administered as a single dosage unit. In some embodiments, the non-naturally occurring melanocortin analog dose is administered as multiple dosage units. In some embodiments, the multiple dosage units individually comprise at least about 2.5 mg/mL to at least about 100 mg/mL of the non-naturally occurring melanocortin analog. In some embodiments, the multiple dosage units individually comprise at least about 2.5 mg/mL to at least about 10 mg/mL of the non-naturally occurring melanocortin analog. In some embodiments, the multiple dosage units individually comprise at least about 6 mg/mL of the non-naturally occurring melanocortin analog. In some embodiments, the non-naturally occurring melanocortin analog is administered as at least about 5 dosage units to at least about 10 dosage units. In some embodiments, the non-naturally occurring melanocortin analog is administered as 5 dosage units. In some embodiments, the non-naturally occurring melanocortin analog is administered as 10 dosage units. Pharmaceutical Compositions -118- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0485] The non-naturally occurring melanocortin analogs of the present technology may be present in a pharmaceutical composition. In some embodiments, the non-naturally occurring melanocortin analog is present in a pharmaceutical composition in a concentration of about 0.1 mg/mL to about 500 mg/mL. [0486] In some embodiments, the non-naturally occurring melanocortin analog is present in a pharmaceutical composition in a concentration of at least 0.1 mg/mL to at least 500 mg/mL. [0487] In some embodiments, the non-naturally occurring melanocortin analog is present in a pharmaceutical composition in a concentration of at least about 0.1 mg/mL to at least about 500 mg/mL. [0488] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 0.1 mg/mL to 500 mg/mL, relative to a total volume of the pharmaceutical composition. For example, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 0.1 mg/mL to 500 mg/mL, 0.5 mg/mL to 250 mg/mL, 1 mg/mL to 100 mg/mL, 2.5 mg/mL to 50 mg/mL, or 5 mg/mL to 25 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 50 mg/mL, relative to a total volume of the pharmaceutical composition. [0489] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and/or excipient. In some embodiments, the pharmaceutical composition contains about 0.1 to about 99.9999 wt.%, about 1 to 99.999 wt.%, preferably 5 to 99.99 wt.%, preferably 10 to 99.9 wt.%, preferably 15 to 99 wt.%, preferably 20 to 90 wt.%, preferably 30 to 85 wt.%, preferably 40 to 80 wt.%, preferably 50 to 75 wt.%, preferably 60 to 70 wt.% of the pharmaceutically acceptable carrier and/or excipient relative to a total weight of the pharmaceutical composition. [0490] In some embodiments, the pharmaceutically acceptable carrier and/or excipient of the pharmaceutical composition is at least one selected from the group consisting of -119- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 water, a buffer, an inorganic salt, a fatty acid, a vegetable oil, a synthetic fatty ester, a surfactant, and a polymer. [0491] In some embodiments, the pharmaceutically acceptable carrier and/or excipient is water. In some embodiments, the pharmaceutically acceptable carrier and/or excipient is a buffer. [0492] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of any one of Formulae(I)-(IG) and the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 5 mg/mL to 100 mg/mL, relative to a total volume of the pharmaceutical composition. For example, the non-naturally occurring melanocortin analog comprising a sequence of any one of Formulae (I)-(IG) is present in the pharmaceutical composition in a concentration of 5 mg/mL to 100 mg/mL, 10 mg/mL to 75 mg/mL, 15 mg/mL to 50 mg/mL, 20 mg/mL to 40 mg/mL, or 25 mg/mL to 30 mg/mL, relative to a total volume of the pharmaceutical composition. In some embodiments, the non-naturally occurring melanocortin analog comprising a sequence of any one of Formulae (I)-(IG) is present in the pharmaceutical composition in a concentration of about 50 mg/mL, relative to a total volume of the pharmaceutical composition. [0493] In some embodiments, the pharmaceutical composition formulated for parenteral administration (e.g., subcutaneous administration) comprises the non-naturally occurring melanocortin analog of any one of Formulae (I)-(IG) at a concentration at 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 more, depending on the specific non-naturally occurring melanocortin analog selected, the desired response, the route of administration, the formulation and other factors known to those of skill in the art. In some embodiments, the non-naturally occurring melanocortin analog comprises any one of SEQ ID NOs: 299, 302, and 405. [0494] In some embodiments, the non-naturally occurring melanocortin analog crosses blood-brain-barrier (BBB) of the subject. -120- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0495] The pharmaceutical compositions comprising the carriers and/or excipients of the present technology facilitate delivery (e.g., parenteral administration, in particular subcutaneous injection) of the non-naturally occurring melanocortin analogs to a subject. Other purposes of the pharmaceutical compositions comprising the carriers and/or excipients are to enhance dispersion, solubility, and stability of the non-naturally occurring melanocortin analog, and to reduce adverse injection site reactions. [0496] The carriers and/or excipients of the pharmaceutical composition may generally include one or more of the following components: a pH buffered aqueous solution comprising (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 pharmaceutical composition. [0497] In some embodiments, the carrier and/or excipient is isotonic. [0498] To achieve a desirable tonicity, the pharmaceutical composition of the present technology 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 pharmaceutical composition. [0499] 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. [0500] 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, -121- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 deionized distilled water, and reverse osmosis water. In some embodiments, the water present in the pH buffered aqueous solution is water for injection. [0501] 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. [0502] 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. [0503] 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. [0504] 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. [0505] 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. [0506] 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. -122- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0507] 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. [0508] 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. [0509] 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. [0510] 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. [0511] 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. -123- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0512] 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. [0513] 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. [0514] In some embodiments, a weight ratio of sodium acetate to Tris is at least 1:4 to at least 4:1, at least 2:7 to at least 7:2, at least 1:3 to at least 3:1, at least 2:5 to at least 5:2, at least 1:2 to at least 2:1, at least 2:3 to at least 3:2, or at least 1:1. In some embodiments, the weight ratio of sodium acetate to Tris is at least 1:1. [0515] In some embodiments, a weight ratio of sodium acetate to Tris is at least about 1:4 to at least about 4:1, at least about 2:7 to at least about 7:2, at least about 1:3 to at least about 3:1, at least about 2:5 to at least about 5:2, at least about 1:2 to at least about 2:1, at least about 2:3 to at least about 3:2, or at least about 1:1. In some embodiments, the weight ratio of sodium acetate to Tris is at least about 1:1. [0516] 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. [0517] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is at least 1:1 to at least 20:1, at least 3:2 to at least 15:1, at least 2:1 to at least 12:1, at least 3:1 to at least 10:1, at least 4:1 to at least 9:1, at least 5:1 to at least 8:1, or at least 6:1 to at least 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is at least 7:1. -124- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0518] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is at least about 1:1 to at least about 20:1, at least about 3:2 to at least about 15:1, at least about 2:1 to at least about 12:1, at least about 3:1 to at least about 10:1, at least about 4:1 to at least about 9:1, at least about 5:1 to at least about 8:1, or at least about 6:1 to at least about 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is at least about 7:1. [0519] 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. [0520] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to Tris is at least 1:1 to at least 20:1, at least 3:2 to at least 15:1, at least 2:1 to at least 12:1, at least 3:1 to at least 10:1, at least 4:1 to at least 9:1, at least 5:1 to at least 8:1, or at least 6:1 to at least 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to Tris is at least 7:1. [0521] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to Tris is at least about 1:1 to at least about 20:1, at least about 3:2 to at least about 15:1, at least about 2:1 to at least about 12:1, at least about 3:1 to at least about 10:1, at least about 4:1 to at least about 9:1, at least about 5:1 to at least about 8:1, or at least about 6:1 to at least about 7:1. In some embodiments, the weight ratio of the non- naturally occurring melanocortin analog to Tris is at least about 7:1. [0522] 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, tartaric 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. -125- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0523] 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. [0524] 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. [0525] 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. [0526] The pharmaceutical composition may further comprise an emulsifier. Non- limiting 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. [0527] 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 -126- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 composition comprises a lipid, the lipid is N-(carbonyl-methoxypolyethylene glycol 2000)- 1,2-distearoyl-glycero-3-phosphoethanolamine sodium salt [0528] 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. [0529] 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. [0530] 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. [0531] In some embodiments, the pharmaceutical composition has a pH ranging from at least 6.5 to at least 8.5. In some embodiments, the pharmaceutical composition has a pH of at least 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. [0532] In some embodiments, the pharmaceutical composition has a pH ranging from at least about 6.5 to at least about 8.5. In some embodiments, the pharmaceutical composition has a pH of at least 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. [0533] 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 -127- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 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. [0534] In some embodiments, the pharmaceutical composition is basic and has a pH of at least 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 at least 7.3 to at least 7.4. In some embodiments, the pharmaceutical composition has a pH of 7.3 or 7.4. [0535] In some embodiments, the pharmaceutical composition is basic and has a pH of at least 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 at least about 7.3 to at least about 7.4. In some embodiments, the pharmaceutical composition has a pH of 7.3 or 7.4. [0536] 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. [0537] 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 at least 300 mOsm/kg. In some embodiments, the pharmaceutical composition has an osmolarity of at least 250 mOsm/kg, at least 260 mOsm/kg, at least 270 mOsm/kg, at least 280 mOsm/kg, at least 290 mOsm/kg, at least 300 mOsm/kg, at least 310 -128- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 mOsm/kg, at least 320 mOsm/kg, at least 330 mOsm/kg, at least 340 mOsm/kg, at least 350 mOsm/kg, or at least 360 mOsm/kg. In some embodiments, the pharmaceutical composition has an osmolality ranging from at least 275 mOsm/kg to at least 330 mOsm/kg. In some embodiments, the pharmaceutical composition has an osmolality of at least 279 mOsm/kg, at least 314 mOsm/kg, or at least 329 mOsm/kg. [0538] 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 at least about 300 mOsm/kg. In some embodiments, the pharmaceutical composition has an osmolarity of at least about 250 mOsm/kg, at least about 260 mOsm/kg, at least about 270 mOsm/kg, at least about 280 mOsm/kg, at least about 290 mOsm/kg, at least about 300 mOsm/kg, at least about 310 mOsm/kg, at least about 320 mOsm/kg, at least about 330 mOsm/kg, at least about 340 mOsm/kg, at least about 350 mOsm/kg, or at least about 360 mOsm/kg. In some embodiments, the pharmaceutical composition has an osmolality ranging from at least about 275 mOsm/kg to at least about 330 mOsm/kg. In some embodiments, the pharmaceutical composition has an osmolality of at least about 279 mOsm/kg, at least about 314 mOsm/kg, or at least about 329 mOsm/kg. [0539] 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. [0540] In some embodiments, the pharmaceutical composition has a viscosity ranging from at least 0.5 cP to at least 5 cP. For example, the pharmaceutical composition may have a viscosity ranging from at least 0.5 cP to at least 5 cP, at least 0.75 cP to at least 4.5 cP, at -129- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 least 1.0 cP to at least 4 cP, at least 1.2 cP to at least 3.5 cP, at least 1.3 cP to at least 3 cP, at least 1.4 cP to at least 2.5 cP, at least 1.5 cP to at least 2 cP, or at least 1.6 cP to at least 1.8 cP. In some embodiments, the pharmaceutical composition has a viscosity of at least 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 at least 1.4 cP or at least 1.6 cP. [0541] In some embodiments, the pharmaceutical composition has a viscosity ranging from at least about 0.5 cP to at least about 5 cP. For example, the pharmaceutical composition may have a viscosity ranging from at least about 0.5 cP to at least about 5 cP, at least about 0.75 cP to at least about 4.5 cP, at least about 1.0 cP to at least about 4 cP, at least about 1.2 cP to at least about 3.5 cP, at least about 1.3 cP to at least about 3 cP, at least about 1.4 cP to at least about 2.5 cP, at least about 1.5 cP to at least about 2 cP, or at least about 1.6 cP to at least about 1.8 cP. In some embodiments, the pharmaceutical composition has a viscosity of at least 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 at least about 1.4 cP or at least about 1.6 cP. [0542] 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. [0543] 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. -130- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0544] 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. [0545] 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, 110 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, or 200 mM. [0546] 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, 35mM, 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. [0547] 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. [0548] In some embodiments, the pharmaceutical composition comprises a surfactant, such as a sorbitan ester. [0549] In some embodiments, the pharmaceutical composition comprises a flavoring or scent, such as an aromatic oil. -131- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0550] 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%. [0551] In some embodiments, the pharmaceutical composition may comprise the non- naturally occurring melanocortin analog in an amount of at least 0.03 wt%, at least 0.05 wt%, at least 0.1 wt%, at least 0.15 wt%, at least 0.2 wt%, at least 0.25 wt%, at least 0.3 wt%, at least 0.35 wt%, at least 0.4 wt%, at least 0.45 wt%, at least 0.5 wt%, at least 0.55 wt%, at least 0.6 wt%, at least 0.65 wt%, at least 0.7 wt%, at least 0.75 wt%, at least 0.8 wt%, at least 0.85 wt%, at least 0.9 wt%, at least 0.95 wt%, or at least 1 wt%. [0552] In some embodiments, the pharmaceutical composition may comprise the non- naturally occurring melanocortin analog in an amount of at least about 0.03 wt%, at least about 0.05 wt%, at least about 0.1 wt%, at least about 0.15 wt%, at least about 0.2 wt%, at least about 0.25 wt%, at least about 0.3 wt%, at least about 0.35 wt%, at least about 0.4 wt%, at least about 0.45 wt%, at least about 0.5 wt%, at least about 0.55 wt%, at least about 0.6 wt%, at least about 0.65 wt%, at least about 0.7 wt%, at least about 0.75 wt%, at least about 0.8 wt%, at least about 0.85 wt%, at least about 0.9 wt%, at least about 0.95 wt%, or at least about 1 wt%. [0553] The non-naturally occurring melanocortin analogs of the present technology may be formulated for administration using any means known in the art, including orally, rectally, vaginally, ocularly, intranasally, topically, parenterally, or by injection. If administered by injection, the peptide injection may be intravenous (IV), subcutaneous (SC), intramuscular (IM), intraperitoneal (IP), intracerebroventricular (ICV), or other means known in the art. The non-naturally occurring melanocortin analog of the combination therapy may -132- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 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, anti-oxidants and other agents known in the art. In general, any route of administration by which the peptides are introduced across an epidermal layer of cells may be employed. Administration includes topical delivery. 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. [0554] In some embodiments, the pharmaceutical composition formulated for intranasal administration comprises a non-naturally occurring melanocortin analog at a concentration at 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 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. [0555] In some embodiments, the pharmaceutical composition is formulated for oral administration. For example, the pharmaceutical composition may be in the form of a tablet, capsule, lozenge, pill, sachet, or any other orally deliverable form know in the art. [0556] The 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 pharmaceutical composition includes a propellant, such as hydrofluoroalkane. [0557] In some embodiments, the pharmaceutical composition may be configured to be administered using a spray device or nasal inhaler. The spray device or nasal inhaler may be configured to deliver 1µg to 100µg per spray. In some embodiments, the spray -133- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 device or nasal inhaler may be configured to deliver 1µg to 100µg, 5µg to 90µg, 10µg to 80µg, 15µg to 70µg, 20µg to 60µg, 25µg, to 50µg, or 30µg to 40µg per spray. Combination Therapy [0558] In some embodiments, the present technology relates to a combination therapy comprising a first non-naturally occurring melanocortin analog and a second non-naturally occurring melanocortin analog. In some embodiments, the first non-naturally occurring melanocortin analog is a non-naturally occurring melanocortin analog agonist. The combination therapy may be useful in one or more methods of the present technology. The combination therapies may be more effective than the first non-naturally occurring melanocortin analog or a second non-naturally occurring melanocortin analog administered alone. [0559] In some embodiments, the first non-naturally occurring melanocortin analog is selected from the group consisting of a non-naturally occurring melanocortin analog of any one of Formulae (I)-(IG) to the subject. [0560] In some embodiments, the non-naturally occurring melanocortin analog is selected from the group consisting of MC4-NN2-0453 (16-(tetrazol-5-yl)hexadecanoyl-Oeg- Gly-Ser-Gln-His-Dap[bis(carboxymethyl)amino]acetyl-Nle-c[Glu-Hyp-dPhe-Arg-Trp-Lys]- NH2), LY2112688 (Ac-dArg-c[Cys-Glu-His-dPhe-Arg-Trp-Cys]-NH2), Melanotan-II (Ac-Nle- [Asp-His-dPhe-Arg-Trp-Lys]-NH2), Afamelanotide (Ac-Ser-Tyr-Ser-Nle-Glu-His-dPhe-Arg- Trp-Gly-Lys-Pro-Val-NH2), Bremelanotide (Ac-Nle-[Asp-His-dPhe-Arg-Trp-Lys]-OH, setmelanotide (Ac-Arg-[Cys-dAla-His-dPhe-Arg-Trp-Cys]-NH2), AZD2820, MK-0493 (N- [(1S)-1-[2-[1-[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carbonyl]piperidin-4- yl]-5-chlorophenyl]ethyl]acetamide), PF-00446687 ([(3S,4R)-1-tert-butyl-4-(2,4- difluorophenyl)pyrrolidin-3-yl]-[(3S,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-1- yl]methanone), RM-718, and LB54640 (N-[(3S,5S)-1-[(3S,4R)-1-tert-butyl-4-(4- chlorophenyl)pyrrolidine-3-carbonyl]-5-(morpholine-4-carbonyl)pyrrolidin-3-yl]-2-methyl-N- (4-methylcyclohexyl)propenamide). [0561] The second non-naturally occurring melanocortin analog and the first non- naturally occurring melanocortin analog may be administered concurrently, sequentially, or -134- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 cyclically. In some embodiments, the second non-naturally occurring melanocortin analog and a non-naturally occurring melanocortin agonist are administered concurrently, sequentially, or cyclically. In some embodiments, the second non-naturally occurring melanocortin analog and a non-naturally occurring melanocortin antagonist are administered concurrently, sequentially, or cyclically. [0562] In some embodiments, the second non-naturally occurring melanocortin analog and the first non-naturally occurring melanocortin analog are administered concurrently. In such embodiments, the second non-naturally occurring melanocortin analog and the first non-naturally occurring melanocortin analog may be administered concurrently but separately, such as in separate compositions (e.g., the first pharmaceutical composition and the second pharmaceutical composition). When the second non-naturally occurring melanocortin analog and the first non-naturally occurring melanocortin analog are administered concurrently but separately, the administration may be simultaneous or stepwise. Alternatively, the second non-naturally occurring melanocortin analog and the first non-naturally occurring melanocortin analog may be formulated in a single composition and may be administered as such. [0563] When the second non-naturally occurring melanocortin analog and the first non- naturally occurring melanocortin analog are administered to a subject concurrently, administration of the second non-naturally occurring melanocortin analog is started at the same time as administration of the first non-naturally occurring melanocortin analog. Thus, in a concurrent administration regimen, the subject may not have received any prior treatment with either the second non-naturally occurring melanocortin analog or the first non- naturally occurring melanocortin analog. [0564] Concurrent administration of the second non-naturally occurring melanocortin analog and the first non-naturally occurring melanocortin analog may include continued administration of both treatments until the desired effect is achieved. In some embodiments, concurrent administration includes beginning treatment with the second non-naturally occurring melanocortin analog and the first non-naturally occurring melanocortin analog at the same time and continuing administration of the second non-naturally occurring melanocortin analog for a full treatment cycle and the first non-naturally occurring -135- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 melanocortin analog for a full treatment cycle. In some embodiments, the full treatment cycle of the second non-naturally occurring melanocortin analog is longer than the full treatment cycle of the first non-naturally occurring melanocortin analog. In other embodiments, the full treatment cycle of the second non-naturally occurring melanocortin analog is shorter than the full treatment cycle of the first non-naturally occurring melanocortin analog. Accordingly, although concurrent administration includes beginning treatment with the second non- naturally occurring melanocortin analog and the first non-naturally occurring melanocortin analog at the same time, administration of the second non-naturally occurring melanocortin analog may be completed before or after administration of the first non-naturally occurring melanocortin analog. [0565] Further, when the first non-naturally occurring melanocortin analog and the second non-naturally occurring melanocortin analog are administered concurrently but separately, the second non-naturally occurring melanocortin analog and the non-naturally occurring analog may be administered simultaneously or stepwise. Concurrent stepwise administration may be useful for combination therapies in which the second non-naturally occurring melanocortin analog should be administered once a week and the first non- naturally occurring melanocortin analog should be administered daily, or with any other regimen where treatment is being carried out simultaneously with the second non-naturally occurring melanocortin analog and the first non-naturally occurring melanocortin analog, but the administration schedules differ. For example, in concurrent stepwise administration, the second non-naturally occurring melanocortin analog may be administered at one time point and the non-naturally melanocortin analog may be administered at a second time point. The time interval between the first time point and the second time point may be about 0.5-1 minutes, 2-3 minutes, 4-5 minutes, 6-8 minutes, 9-10 minutes, 12-15 minutes, 20-25 minutes, 30 to 60 minutes, 1 hour, 1-2 hours, 2-6 hours, 2-12 hours, 12-24 hours, 1-2 days, 2 days, 3 days, 4 days, 5 days, 6 days, or about 1 week, 2 weeks, 3 weeks, one month, or any period of time in between. In some embodiments, the second non-naturally occurring melanocortin analog and the first non-naturally occurring melanocortin analog are administered less than 15 minutes, less than 30 minutes, less than 45 minutes, less than 1 hour, less than 2 hours, less than 4 hours, less than 8 hours, less than 12 hours, less than -136- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 16 hours, less than 20 hours, less than 24 hours, less than 36 hours, or less than 48 hours apart. [0566] In some embodiments, the second non-naturally occurring melanocortin analog is administered once weekly and the first non-naturally occurring melanocortin analog is administered once, twice, or three times daily. Accordingly, the first non-naturally occurring melanocortin analog may be administered 1 day, 2 days, 3 days, 4 days, 5 days, and/or 6 days after the second non-naturally occurring melanocortin analog. In other embodiments, the second non-naturally occurring melanocortin analog is administered once weekly and the first non-naturally occurring melanocortin analog is administered once weekly. When both agents are administered on a weekly basis, the second non-naturally occurring melanocortin analog and the first non-naturally occurring melanocortin analog may be administered on the same day, 1 day apart, 2 days apart, 3 days apart, 4 days apart, 5 days apart, or 6 days apart. In still other embodiments, the second non-naturally occurring melanocortin analog is administered weekly and the first non-naturally occurring melanocortin analog is administered once every 2 weeks, once every 3 weeks, or once monthly. In such embodiments, the first non-naturally occurring melanocortin analog may be administered on the same day as the second non-naturally occurring melanocortin analog or on a different day than the second non-naturally occurring melanocortin analog once every 2 weeks, once every 3 weeks or once monthly. [0567] In some embodiments, the first non-naturally occurring melanocortin analog and/or the second non-naturally occurring melanocortin analog is present in a pharmaceutical composition of the present technology. The combination therapies of the present technology may comprise the first non-naturally occurring melanocortin analog and the second non-naturally occurring melanocortin analog as distinct compositions. For example, the second non-naturally occurring melanocortin analog may be present in a first pharmaceutical composition and the non-naturally occurring analog may be present in a second pharmaceutical composition. As will be described in more detail below, the first and second pharmaceutical compositions may be administered concurrently, sequentially, or cyclically. Alternatively, pharmaceutical combinations of the present technology may be -137- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 formulated as a single pharmaceutical composition comprising a first non-naturally occurring melanocortin analog and a second non-naturally occurring melanocortin analog. [0568] In some embodiments of the combination therapy, the second non-naturally occurring melanocortin analog is present in a first pharmaceutical composition and the first non-naturally occurring melanocortin analog is present in a second pharmaceutical composition. The second non-naturally occurring melanocortin analog may be formulated with one or more pharmaceutically acceptable carriers and/or excipients to form the first pharmaceutical composition. Similarly, the first non-naturally occurring melanocortin analog may be formulated with one or more pharmaceutically acceptable carriers and/or excipients to form the second pharmaceutical composition. In some embodiments, the first and the second pharmaceutical compositions are different. [0569] In some embodiments, the first pharmaceutical composition comprising the second non-naturally occurring melanocortin analog and the second pharmaceutical composition comprising the first non-naturally occurring melanocortin analog are administered concurrently. [0570] In other embodiments, the first pharmaceutical composition and the second pharmaceutical composition are administered sequentially. In sequential administration, the first pharmaceutical composition may be administered before the second pharmaceutical composition, after the second pharmaceutical composition, or both. Likewise, the second pharmaceutical composition may be administered before the first pharmaceutical composition, after the first pharmaceutical composition, or both. [0571] In still other embodiments, the first pharmaceutical composition and the second pharmaceutical composition may be administered cyclically. EXAMPLES [0572] 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 -138- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 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: Non-Naturally Occurring Melanocortin Analog Synthesis-Generic [0573] 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. [0574] 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. [0575] 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 solid- phase 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. [0576] 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 alpha- -139- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 amine 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 aminde 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)-α-[1-(9H-fluor-en-9-yl)-methoxyformamido]-2,4-dimethyloxybenzyl]-phenoxyacetic acid (Rink linker) via an amide linkage. [0577] 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: Non-Naturally Occurring Melanocortin Analog Synthesis-Protecting Groups [0578] 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. [0579] 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 -140- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 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. [0580] 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: Non-Naturally Occurring Melanocortin Analog Synthesis-Additional Modifications [0581] If necessary, the non-naturally occurring melanocortin analogs 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. [0582] 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-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H- -141- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 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-1H-benzotriazol- 1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TATU), 2-(2-oxo-1 (2H)-pyridyl)-1,1,3,3- tetramethyluronium tetrafluoroborate (TPTU), N,N′-dicyclohexylcarbodiimide/1- hydroxybenzotriazole (DCCl/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 [0001] The agonist and antagonist activity of exemplary non-naturally occurring melanocortin analogs at the melanocortin receptors (e.g., MC1R, 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 [0002] Compounds were delivered as powder (1 mg) or 10 mM solutions (100 μl) 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. Table 1. Cell lines Receptor Cell Line Reference agonist Reference t -142- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 MC5R CHO-K1 NDP-α-MSH N/A Compound [0003] 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-0230C) 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 [0004] Cyclic AMP (cAMP) Homogenous Time-Resolved Fluorescence (HTRF) assay for Gs coupled receptor: [0005] 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 KCl, 1.25 mM MgSO4, 124 mM NaCl, 25 mM HEPES, 13.3 mM Glucose, 1.25 mM KH2PO4, 1.45 mM CaCl2, 0.5 g/l BSA, supplemented with 1mM IBMX or 25μM Rolipram). [0006] Dose response curves were performed in parallel with the reference compounds. [0007] For agonist test (384well): 5 μl of cells were mixed with 5 μl 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. [0008] For antagonist test (384well): 5 μl of cells were mixed in the wells of an assay plate with 5 μl 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 -143- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 temperature, and fluorescence ratios were measured according to the manufacturer specification, with the HTRF kit. Quality Control for Compound Testing [0009] 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. [0010] Reference values thus obtained for the test were compared to historical values obtained from the same receptor and used to validate the experimental session. [0011] 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. [0012] 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 [0013] Group A included non-naturally occurring melanocortin analogs A1 to A4, all of which are cyclic peptides comprising the motif c[Asp-His-p(F)dPhe-Arg-Trp-Lys] (SEQ ID NO: 161). Group A melanocortin analogs also comprise Ala or dArg at the N-terminus and dVal-dPro or dTle-dPro at the C-terminus. Group A non-naturally occurring melanocortin analogs are provided in Table 2. Table 2. Group A non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula [0014] Group B included non-naturally occurring melanocortin analogs B1 to B10, all of which are cyclic peptides comprising the motif c[Asp-His-p(F)dPhe-Arg-Trp-Lys] (SEQ ID NO: 161). Group B melanocortin analogs also comprise Arg, Lys, dLys, His, or dHis at the -144- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 N-terminus and dVal-dPro or dTle-dPro at the C-terminus. Group B non-naturally occurring melanocortin analogs are provided in Table 3. Table 3. Group B non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analog NO 2 2 2 2 l of which are cyclic peptides comprising the motif c[Asp-His-p(F)dPhe-Arg-Trp-Lys] (SEQ ID NO: 161). Group C melanocortin analogs also comprise Nle at the N-terminus. Group C non-naturally occurring melanocortin analogs are provided in Table 4. Table 4. Group C non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula 2 2 2 2 -145- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro- C8 26 NH2 l of which are cyclic peptides comprising a derivative of the motif c[Asp-His-p(F)dPhe-Arg-Trp- Lys] (SEQ ID NO: 161). Derivatives of the motif of SEQ ID NO: 161 may include substitution of His with another amino acid, for example, Gln or dHis, substitution of Arg with another amino acid, for example, His, or substitution of Trp with another amino acid, for example, dNal(2’). Group D non-naturally occurring melanocortin analogs are provided in Table 5. Table 5. Group D non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analog NO H2 l of which are cyclic peptides comprising the motif c[Asp-His-dPhe-Arg-Trp-Lys] (SEQ ID NO: 164) or a derivative thereof. Derivatives of the motif of SEQ ID NO: 164 included in Group E melanocortin analogs include insertions of a Pro between Asp and His or between Trp and Lys. Group E non-naturally occurring melanocortin analogs are provided in Table 6. Table 6. Group E non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula [0018] Group F included non-naturally occurring melanocortin analogs F1 to F4, all of which are cyclic peptides comprising a derivative of the motif c[Asp-His-dPhe-Arg-Trp-Lys] (SEQ ID NO: 164). Derivatives of the motif of SEQ ID NO: 164 may include substitution of -146- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 His with another amino acid, for example, Gln, Pro or dHis, or substitution of Arg with another amino acid, for example, cisPro(guan) or transPro(guan). Group F non-naturally occurring melanocortin analogs are provided in Table 7. Table 7. Group F non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analog NO 2 2 s a cyclic peptide comprising a derivative of the motif c[Asp-His-dPhe-Arg-Trp-Lys] (SEQ ID NO: 164). The derivative of the motif of SEQ ID NO: 164 included in the Group G melanocortin analog includes at least one insertion between Asp and His. The Group G non-naturally occurring melanocortin analog is provided in Table 8. Table 8. Group G non-naturally occurring melanocortin analog Melanocortin SEQ ID Formula analo NO , l of which are cyclic peptides comprising the motif dAla-His-dPhe-Arg-Trp (SEQ ID NO: 163), or a derivative thereof. Derivatives of the motif of SEQ ID NO: 163 may include substitution of dAla with a similar amino acid, for example, Ala. Group H non-naturally occurring melanocortin analogs are provided in Table 9. Table 9. Group H non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula 2 -147- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 H2 39 Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 H2 of which are cyclic peptides comprising the motif His-p(Cl)dPhe-Arg-Trp (SEQ ID NO: 165). Group I melanocortin analogs also comprise Nle at the N-terminus. Group I non-naturally occurring melanocortin analogs are provided in Table 10. Table 10. Group I non-naturally occurring melanocortin analogs Melanocortin SEQ ID analog NO Formula 2 2 2 , l of which are cyclic peptides comprising the motif His-p(F)dPhe-Arg-Trp (SEQ ID NO: 166). Group J melanocortin analogs may be cyclized through a lactam bond between R2 and R7, where the amine-containing residue, e.g., Lys, Orn, Dap, or Dab, is present at either the R2 or R7 position and the carboxylic acid-containing residue, e.g., Asp or Glu, is present at the other position. Group J non-naturally occurring melanocortin analogs are provided in Table 11. -148- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Table 11. Group J non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analog NO 2 2 2 2 2 2 2 2 2 2 H2 all of which are cyclic peptides comprising the motif Asn-p(F)dPhe-Arg-Trp (SEQ ID NO: 167). Group K melanocortin analogs may be cyclized through a lactam bond between R2 and R7, where the amine-containing residue, e.g., Lys, Orn, or Dab, is present at either the R2 or R7 position and the carboxylic acid-containing residue, e.g., Asp or Glu, is present at the other position. Further, Group K melanocortin analogs may have a linear dVal-dPro C-terminus. Group K non-naturally occurring melanocortin analogs are provided in Table 12. Table 12. Group K non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula 2 2 2 2 -149- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 K5 182 Ac—Nle-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 K 184 Ac—Nle-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 2 2 2 H2 2 2 2 2 2 2 2 2 2 2 l of which are cyclic peptides comprising the motif Asn-p(F)dPhe-Arg-Trp (SEQ ID NO: 167). Group L melanocortin analogs may be cyclized through a lactam bond between R2 and R7, where the amine-containing residue, e.g., Lys, Orn, Dap, or Dab, is present at either the R2 or R7 position and the carboxylic acid-containing residue, e.g., Asp or Glu, is present at the other position. Further, Group L melanocortin analogs may not have a linear C-terminus. Group L non-naturally occurring melanocortin analogs are provided in Table 13. Table 13. Group L non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula -150- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 L4 216 Ac—Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]—NH2 L 207 Ac—Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]—NH2 all of which are cyclic peptides comprising the motif Pro-dPhe-Arg-Trp (SEQ ID NO: 168) or derivatives thereof and cyclized through a lactam bond between Lys at R2 and Glu R7. Derivative of the motif of SEQ ID NO: 168 may include substitution or deletion of Pro. Group M non-naturally occurring melanocortin analogs are provided in Table 14. Table 14. Group M non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analog NO , l of which are cyclic peptides comprising the motif His-dPhe-Arg-Trp (SEQ ID NO: 169). Group M melanocortin analogs may be cyclized through a lactam bond between R2 and R7, where the amine-containing residue, e.g., Lys, Orn, Dap, or Dab, is present at either the R2 or R7 position and the carboxylic acid-containing residue, e.g., Asp or Glu, is present at the other position. Group N non-naturally occurring melanocortin analogs are provided in Table 15. Table 15. Group N non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula -151- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 N4 193 Ac—Nle-c[Lys-His-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 N 194 Ac—Nle-c[Orn-His-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 nd O10, all of which are cyclic peptides comprising the motif His-p(F)dPhe-Arg-Trp-Orn (SEQ ID NO: 162), or a derivative thereof. Derivatives of SEQ ID NO: 162 may include substitution of Arg with a similar amino acid, for example, His. Group O non-naturally occurring melanocortin analogs are provided in Table 16. Table 16. Group O non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analog NO 2 2 , all of which are cyclic peptides comprising the motif Asn-dPhe-Arg-Trp (SEQ ID NO: 170). Group P melanocortin analogs may be cyclized through a lactam bond between R2 and R7, where the amine-containing residue, e.g., Lys, Orn, Dap, or Dab, is present at either the R2 or R7 position and the carboxylic acid-containing residue, e.g., Asp or Glu, is present at the other position. Further, Group P melanocortin analogs may have a linear C-terminus or dVal-dPro or dArg-dVal. Group P non-naturally occurring melanocortin analogs are provided in Table 17. Table 17. Group P non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula -152- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 P2 197 Ac—Nle-c[Lys-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 P 198 Ac—Nle-c[Lys-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 , all of which are cyclic peptides comprising the motif Asn-dPhe-Arg-Trp (SEQ ID NO: 170). Group Q melanocortin analogs may be cyclized through a lactam bond between R2 and R7, where the amine-containing residue, e.g., Lys, Orn, Dap, or Dab, is present at either the R2 or R7 position and the carboxylic acid-containing residue, e.g., Asp or Glu, is present at the other position. Further, Group Q melanocortin analogs may not have a linear C-terminus. Group Q non-naturally occurring melanocortin analogs are provided in Table 18. Table 18. Group Q non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula -153- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Q2 218 Ac—Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]—NH2 219 Ac—Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]—NH2 l of which are cyclic peptides comprising the motif Asn-p(Cl)dPhe-Arg-Trp (SEQ ID NO: 171) and are cyclized through a lactam bond between Glu or Lys R2 and Orn or Asp at R7. Group Q non-naturally occurring melanocortin analogs are provided in Table 19. Table 19. Group Q non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analog NO 2 H2 n 5 receptor [0031] Administration of some non-naturally occurring melanocortin analogs activated melanocortin 1 receptor (MC1R) and melanocortin 5 receptor (MC5R) activity, as measured by cAMP levels (Table 12). -154- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Table 12. Dose-response results of melanocortin analogs and control against the melanocortin 1 receptor (MC1R) and the melanocortin 5 receptor MC1R MC5R Compound Max Max n -155- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 23 C5 0.01 102.78 0.41 101.46 24 C6 0.00 99.42 0.02 102.04 -156- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 186 K8 0.01 102.58 0.02 102.53 187 K9 0.01 102.31 0.01 102.59 -157- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 222 Q6 0.77 102.92 0.46 103.63 207 L5 2.51 104.84 0.65 103.52 -158- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 189 I5 0.002 102.21 0.01 102.37 185 K7 0.36 103.32 1.53 104.01 g y g p ortin 4 receptor [0032] Administration of all the non-naturally occurring melanocortin analogs activated melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) activity, as measured by cAMP levels (Table 13). -159- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Table 13. Dose-response results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) in agonist mode MC3R MC4R Compound Max Max n -160- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 24 C6 0.33 87.59 0.24 100.29 25 C7 0.36 88.52 0.33 99.69 -161- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 187 K9 *** A *** A 179 K2 *** A *** A -162- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 207 L5 ** A *** A 213 L1 * A ** A -163- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 185 K7 ** B ** A 204 P6 ** B ** A ** = 1 nM to 100 nM * = > 100 nM A = > 85% Emax B = 50 - 85% Emax C = < 50% Emax Antagonist activity of melanocortin analogs on melanocortin 3 receptor and melanocortin 4 receptor -164- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0033] Administration of none of the non-naturally occurring melanocortin analogs substantially inhibited melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) activity, as measured by cAMP levels (Table 14). Table 14. Dose-response results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) in antagonist mode MC3R MC4R Com ound Max Max n -165- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 6 C1 >1000 nd >1000 nd 22 C4 >1000 nd >1000 nd -166- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 184 K6 — n.c. — - — n.c. — - 178 K1 — n.c. — - — n.c. — - -167- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 220 Q4 — n.c. — - — n.c. — - 221 Q5 — n.c. — - — n.c. — - -168- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 208 L6 — n.c. — - — n.c. — - 227 K10 — n.c. — - — n.c. — - n.c. = not calculated *** = < 1 nM ** = 1 nM to 100 nM * = > 100 nM -169- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 A = > 85% Emax B = 50 - 85% Emax C = < 50% Emax Comparison of agonist activity of O10 and similar melanocortin analogs [0034] To determine the impact that certain features of the melanocortin analogs of the present technology had on agonist activity at the different melanocortin receptors, the agonist activity of O10 was compared to the agonist activity of similar sequences. Specifically, O10 was compared to sequences with different lactam cyclization types, different residues at the R4 and R3 positions, and different C-terminal residues. The agonist activity of O10 and comparative sequences is provided in Table 15, below. Table 15. Agonist activity of O10 and melanocortin analogs with point mutations relative to O10 MC3R MC4R SEQ ID Max Max o -170- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-Nle-[Asp-His-p(Cl)dPhe- Arg-Trp-Lys]-dVal-dPro-NH2 147 0.220 43 0.609 75 on agonist activity, when the His-p(F)dPhe-Arg-Trp (SEQ ID NO: 166) is conserved. On the other hand, a substantial change in agonist activity on the MC3 receptor was observed when His was substituted for Pro (e.g., SEQ ID NO: 43 vs. SEQ ID NOs: 99 and 106). Additionally, substitution of the smaller p(F)dPhe residue with a larger p(Br)dPhe residue resulted in substantially decreased activation and potency on both MC3R and MC4R (e.g., SEQ ID NO: 43 vs. SEQ ID NO: 171). Residual binding of melanocortin analogs on melanocortin 1 receptor [0036] The residual binding of some of the non-naturally occurring melanocortin analogs was measured on the melanocortin 1 receptor (MC1R) by RLB assay. Among the non-naturally occurring melanocortin analogs, O10 had the lowest EC50 value at 0.19 nM (Table 16). Table 16. Dose-response binding results of melanocortin analogs and control against the melanocortin 1 receptor (MC1R) Synthetic Max Residual EC50 (nM)* Hill Top (%) -171- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Residual binding of melanocortin analogs on melanocortin 3 receptor [0037] The residual binding of some of the non-naturally occurring melanocortin analogs was measured on the melanocortin 3 receptor (MC3R) by RLB assay (Table 17). Table 17. Dose-response binding results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) Synthetic Max Residual EC50 (nM)* Hill Top (%) Pe tide Bindin % Coefficient Re [0038] The residual binding of some of the non-naturally occurring melanocortin analogs was measured on the melanocortin 4 receptor (MC4R) by RLB assay. Among the non-naturally occurring melanocortin analogs, O10 had the lowest EC50 value at 0.23 nM, respectively (Table 18). Table 18. Dose-response binding results of melanocortin analogs and control against the melanocortin 4 receptor (MC4R) Synthetic Max Residual EC50 (nM)* Hill Top (%) Re [0039] The residual binding of some of the non-naturally occurring melanocortin analogs was measured on the melanocortin 5 receptor (MC5R) by RLB assay. Among the non-naturally occurring melanocortin analogs, O10 had the lowest EC50 value at 0.19 nM (Table 19). -172- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Table 19. Dose-response binding results of melanocortin analogs and control against the melanocortin 5 receptor (MC5R) Synthetic Max Residual EC50 (nM)* Hill Top (%) Peptide Binding % Coefficient Ag [0040] The agonist activity of some of the non-naturally occurring melanocortin analogs was measured on GPR54 by Aequorin assay. Results from this assay are provided in Table 20. Table 20. Dose-response results of melanocortin analogs and control against GPR54 Synthetic Max EC50 (nM)* Hill Top (%) An [0041] The antagonist activity of some of the non-naturally occurring melanocortin analogs was measured on GPR54 by Aequorin assay. Results from this assay are provided in Table 21. Table 21. Dose-response results of melanocortin analogs and control against GPR54 Synthetic Max IC50 (nM)* Hill Top (%) Ag -173- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0042] The agonist activity of some of the non-naturally occurring melanocortin analogs was measured on QRFP by Aequorin assay. Results from this assay are provided in Table 22. Table 22. Dose-response results of melanocortin analogs and control against QRFP Synthetic Max EC50 (nM)* Hill Top (%) Peptide Activation % Coefficient Antagonist activity on QRFP [0043] The antagonist activity of some of the non-naturally occurring melanocortin analogs was measured on QRFP by Aequorin assay. Results from this assay are provided in Table 23. Table 23. Dose-response results of melanocortin analogs and control against QRFP Synthetic Max IC50 (nM)* Hill Top (%) Ag [0044] The agonist activity of some of the non-naturally occurring melanocortin analogs was measured on PrRP by Aequorin assay. Results from this assay are provided in Table 24. Table 24. Dose-response results of melanocortin analogs and control against PrRP Synthetic Max EC50 (nM)* Hill Top (%) -174- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 LY2112688 trifluoroacetate 2.33 >2000 - - An [0045] The antagonist activity of some of the non-naturally occurring melanocortin analogs was measured on PrRP by Aequorin assay. Results from this assay are provided in Table 25. Table 25. Dose-response results of melanocortin analogs and control against PrRP Synthetic Max IC50 (nM)* Hill Top (%) Ag [0046] The agonist activity of some of the non-naturally occurring melanocortin analogs was measured on NPFF2S by Aequorin assay. Results from this assay are provided in Table 26. Table 26. Dose-response results of melanocortin analogs and control against NPFF2S Synthetic Max EC50 (nM)* Hill Top (%) An [0047] The antagonist activity of some of the non-naturally occurring melanocortin analogs was measured on NPFF2S by Aequorin assay. Results from this assay are provided in Table 27. -175- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Table 27. Dose-response results of melanocortin analogs and control against NPFF2S Synthetic Max IC50 (nM)* Hill Top (%) Peptide Inhibition % Coefficient Ag [0048] The agonist activity of some of the non-naturally occurring melanocortin analogs was measured on NPY1 by cAMP assay. Results from this assay are provided in Table 28. Table 28. Dose-response results of melanocortin analogs and control against NPY1 Synthetic Max EC50 (nM)* Hill Top (%) An [0049] The antagonist activity of some of the non-naturally occurring melanocortin analogs was measured on NPY1 by cAMP assay. Results from this assay are provided in Table 29. Table 29. Dose-response results of melanocortin analogs and control against NPY1 Synthetic Max IC50 (nM)* Hill Top (%) Ag [0050] The agonist activity of some of the non-naturally occurring melanocortin analogs was measured on NPFF1 by cAMP assay. Results from this assay are provided in Table 30. -176- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Table 30. Dose-response results of melanocortin analogs and control against NPFF1 Synthetic Max EC50 (nM)* Hill Top (%) Peptide Activation % Coefficient An [0051] The antagonist activity of some of the non-naturally occurring melanocortin analogs was measured on NPFF1 by cAMP assay. Results from this assay are provided in Table 31. Table 31. Dose-response results of melanocortin analogs and control against NPFF1 Synthetic Max IC50 (nM)* Hill Top (%) Ex cortin Analogs Following Oral Administration to Rats and Cynomolgus Monkeys Study Objective [0052] The objective of this study is to determine the pharmacokinetics of non-naturally occurring melanocortin analogs of the present technology following oral gavage administration in male rats and single oral administration to non-naïve male cynomolgus monkeys. In rats, the test article will be monitored in plasma for up to 24 hours post each dose. Study design and sample collection will be conducted as outlined in Table 32 and Table 33. Table 32. Study Design Target T r t T r t -177- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 (mg/m L) -178- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 physiological Rat 3 E O10 10 10 1 PO saline . Dosage Sampling time points (hr) Group 4 * P: plasma C: cerebrospinal fluid *Sampled only for certain compounds [0053] Dose Solution Analysis Samples: After each dose preparation, remove approximately 0.5 mL aliquots from the formulations, transfer the aliquots into amber HPLC vials and stored at -60°C or lower until assayed in duplicate for dose validation. [0054] Disposition of Remaining Test Article Formulations: Remaining formulations will be stored at -60°C or lower. -179- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0055] Disposition of Remaining Test Article (dry powder or solid): Remaining test article will be stored at room temperature desiccated, and protected from light until shipment or discard. [0056] Animals will be fasted overnight through 4 hours post dosing. Vehicle and Formulation Preparation: [0057] Appropriate amount of test article will be accurately weighed and mixed with appropriate volume of vehicle to get a clear solution or suspension. [0058] Formulation samples will be removed from each of the formulation solutions, transferred into 1.5 mL of polypropylene microcentrifuge tubes and run dose validation by LC/UV or LC-MS/MS. [0059] Compounds to be assessed are outlined in Table 34. Table 34. Compounds Compound Animal MW Exact Purity Storage FW (g/mol) CF n Animal Specifications: Cynomolgus Monkeys [0060] Cynomolgus Monkey specifications are outlined in Table 35. Table 35. Cynomolgus Monkey Specifications Species Cynomolgus Monkeys -180- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 This is an acceptable species to support PK Justification for Species studies for compounds intended to use in e or al ff g e [0061] Environmental Conditions: Environment controls will be set to maintain a temperature range of 20-26°C, a relative humidity range of 40 to 70%, and a 12-hour light/12-hour dark cycle. The light/dark cycle may be interrupted for study-related activities. [0062] Housing: Animals will be group-housed (up to four animals/sex/cage) in polysulfone cages with certified aspen shaving bedding or corncob bedding during acclimation and study period. While animals may be individually housed after surgery or when there is special requirement in protocol, as well as, for behavioral or health reasons or due to cage mate death. -181- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0063] Diet and Feeding: Animals were offered certified rodent breeding and growth diet ad libitum every day, unless fasted for study procedures. Each lot of the diet is analyzed for nutrients, chemical contaminant and microorganisms, the results are reviewed and evaluated by veterinarians before provided to animals. [0064] Drinking Water: Autoclaved RO (reverses osmosis) water will be available to all animals, ad libum. [0065] Feed and Water Analyses: Autoclaved RO water will be provided ad libitum via water bottle. Water samples are periodically analyzed by a certified laboratory for specified microorganisms and environment contaminants. The diet is routinely analyzed by the manufacturer for specified microorganisms, nutritional components and environmental contaminants. [0066] Environmental Enrichment: Enrichment toys will be provided. [0067] Dose Administration: The dose volume will be determined by the animals' body weight collected on the morning of dosing day. Animal Specifications: Rats [0068] Rat specifications are outlined in Table 36. Table 36. Rat Specifications Species Rat in o -182- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 The number of animals used in this study is, in the judgment of the investigator involved, the is Observ [0069] Clinical Observations: All animals will be observed at dosing and each scheduled collection. All abnormalities will be recorded. [0070] Body Weight: All animals will be weighed on the dosing day prior to dosing to determine the dose volume to be administered. Sample Collection and Processing [0071] Blood Sample Collection and Process: At least 0.1 mL blood will be collected at each time point. All blood samples will be collected via jugular vein. All blood samples will be transferred into low binding EP tube with anticoagulant (0.5 M Potassium (K2) EDTA will be pre-added as a ratio of 50:1 for blood: anticoagulant), 0.05% Triton X-100 (e.g., 100uL Blood+2uL 2.5% Triton X-100) will be used for desorption the blood samples will be placed on wet ice. [0072] Blood samples will be centrifuged within 1hr of collection at 3,200 g 4°C for 10 minutes. Following centrifugation, plasma samples will be transferred into their respective pre-labeled low binding EP tube and immediately frozen over dry ice. The plasma samples will be stored lower than -60°C until bioanalysis. [0073] LC-MS/MS method development: [0074] A LC-MS/MS method for the quantitative determination of test compound in biological matrix will be developed. [0075] N in 1 cassette LC-MS/MS method may be developed for samples coming from different studies as long as these studies belong to the same sponsor. -183- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0076] Cassette administration assay could be performed if the mass difference (ΔMass) among different analytes is ≥4 Da. In this case, interference evaluation is not necessary. [0077] If ΔMass among different analytes is less than 4 Da, there is a potential risk that interference would occur during LC-MS/MS analysis. If such kind of cassette assay is still requested by client, interference among analytes will not be evaluated but the LC separation of those analytes by using a generic method will be attempted. [0078] Sample analysis: [0079] A calibration curve with at least 6 non-zero calibration standards will be applied for each batch including LLOQ. [0080] If sample number within a batch is ≤ 12, at least one set of standard curve separated with two parts through begin and end of the sequence should be included in the run and QCs are not required. The recommended injection order is C8, C6, C4, C2, study samples, C7, C5, C3, C1. [0081] If sample number within a batch is > 12, one standard curve and two sets of QCs with low, middle and high concentrations will be applied for bioanalysis. Meanwhile, QCs number should be more than 5% of study sample number. [0082] Samples, coming from one client with the same type of matrix in different studies, are allowed to be quantified in one analysis run by using the developed N in 1 cassette LC-MS/MS method. [0083] Acceptance criteria: [0084] (1) Linearity: At least 75% of the calibration standards should fall within ±20% of their nominal values for biofluid and within ±25% of their nominal values for tissue and feces samples. If the endpoints, such as LLOQ and ULOQ, on the calibration curve are eliminated, the calibration curve will be truncated. The truncated calibration curve should consist of at least 75% of the initial STDs. -184- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0085] (2) Accuracy: At least 67% of QCs should fall within ±20% of their nominal values for biofluid and within ±25% of their nominal values for tissue and feces samples. At least half of QCs at each concentration should be passed. [0086] (3) Specificity: The mass response of analyte in the double blank and blank should be ≤ 50% LLOQ. [0087] (4) Sensitivity: The LLOQ will be tried to target ≤ 3 ng/mL. Any adjustment of LLOQ will be informed to client in advance. [0088] (5) Carryover: The mean calculated carryover peak area in the double blanks or blanks immediately after the highest standard injection should be less than that of LLOQ. If the carryover couldn’t meet the criteria, the impact of the carryover on unknown samples should be re-evaluated according to the below procedure: [0089] Carryover should be re-evaluated based on absolute carryover. Absolute carryover is calculated by carryover contribution multiplies carryover impact, where the carryover contribution is calculated by the area ratio of the double blank or blank with the highest carryover (Area max of carryover blank) to the ULOQ with the minimum calculated value (Area min of ULOQ), and the carryover impact is calculated by the area ratio of one injection (Area of one injection) to the following injection (Area of the following injection). The absolute carryover should be below the acceptable accuracy of the studies (e.g., 20% or 25%). [0090] Carryover contribution = Areamax of carryover blank / Areamin of ULOQ Carryover impact = Area of one injection / Area of the following injection Absolute carryover = Carryover contribution * Carryover impact Data Analysis [0091] Plasma concentration versus time data for Compounds A-C in Rats and Cynomolgus Monkeys will be plotted in graph and analyzed by non-compartmental approaches. Related PK parameters will be calculated according to dosing route, e.g., Cl, Vdss and C0 for intravenous administration, Cmax, Tmax or %F for extravascular administration, and T½, AUC(0-t), AUC(0-inf), MRT(0-t), MRT(0-inf) for all routes. Preliminary plasma results after -185- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 24 hours for 60 mg/kg oral administration in Rats and 30mg/kg of Compound C (C2) in Cynomolgus Monkeys are shown in Table 37 and FIG.1. Table 37. Plasma Pharmacokinetic Results of Compound C after 24 hours 30 mg/kg PO plasma Cynomolgus Com- 60 mg/kg PO plasma Rat Data 24 h Monkeys data 24 h /2 ) 98 -2F) in Cynomolgus Monkeys was plotted in graphs and analyzed by non-compartmental approaches. Related PK parameters were calculated according to dosing route, e.g., Cl, Vdss and C0 for intravenous administration, Cmax, Tmax or %F for extravascular administration, and T½, AUC(0-t), AUC(0-inf), MRT(0-t), MRT(0-inf) for all routes. Preliminary plasma results after 24 hours of 3 mg/kg, 10 mg/kg, 30 mg/kg, or 60 mg/kg PO administration of Compound E (Ac- Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; O10 (SEQ ID NO: 43)) in Cynomolgus Monkeys are shown in Table 38 and FIG.20. Table 38. Plasma Pharmacokinetic Results of Compound E (O10) in Cynomolgus Monkeys after 24 hours AUC0- Dose Cmax AUC0 i f CE -186- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 30 8h - 1006 1041 3.27 3.66 4.75 14.2 E 248 2h 2.47 24h of administration of Compound E (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; O10), and in Rats are shown in Table 39 and Table 40. Graphs of plasma concentration and CSF concentration in Rats are shown in FIGS 3A-3C (IP, SC administration), FIGS.4A-4G (IP, SC administration), and FIGS.5A-5C (PO administration). [0094] Plasma and CSF concentrations over 24 hours after administration of Compound E (O10) or setmelanotide were also assessed. It was predicted that O10 will be efficacious for treating general obesity in part due to the PK values in plasma and CSF and the higher affinity for MC3R and MC4R relative to setmelanotide. Table 39. Plasma Pharmacokinetic Results of Compound E (O10) in Rats after 24 hours AUC0- AUC0- Dose Cmax AUM Table 40. CSF Pharmacokinetic Results of Compound E (O10) in Rats after 24 hours -187- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Admin AUC0- AUC0- Dose Cmax AUM Comp Route Tmax T1/2 last inf MRT0- MRT0- AUCE [0095] Dose proportionality of Compound E (O10) following a single administration via SC, IP, and PO in Rats is shown in Tables 41-43. Table 41. Dose Proportionality of Compound E in Rats after a single SC administration AUC Compoun Compare Doses Dose Cmax Cm x R ti AUC V l t tio 5 4 7 n Compou Compare Doses Dose Cmax Cmax AUC0-last a e . ose opo o a y o o pou as a e a s ge a s a on Compoun Compare Doses Dose Cmax Cmax AUC0-last AUC0-last -188- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Plasma Concentration [0096] Plasma pharmacokinetic measurements using 30 mg/kg were assessed in Cynomolgus monkey plasma up to 24 hours. Results are detailed in Table 44. Table 44: Pharmacokinetic Data Compound 30 mg/kg Name PO Cynomolgus Monkey [0097] The antagonist activity of exemplary non-naturally occurring melanocortin analogs at specific ion channels was measured using the Qube electrophysiological platform. The non-naturally occurring melanocortin analogs and specific ion channel targets are provided in Table 45. Table 45. Ion channel targets and melanocortin analogs Melanocortin Ion channel targets MW + Saly Condition [0098] The non-naturally occurring melanocortin analogs identified above were tested for antagonist activity at various ion channels at concentrations ranging from 0.1 mM to 30 mM. In each experiment and if applicable, the respective reference compounds were tested concurrently with the test compounds, and the data were compared with known historical values. hNav1.5 Sodium Channel Assay – Qube APC -189- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0099] Onset and steady state block of peak Nav1.5 current is measured using a pulse pattern, repeated every 5 sec, consisting of a hyperpolarizing pulse to -120mV for a 200ms duration, depolarization to -15mV amplitude for a 40ms duration, followed by step to 40mV for 200ms and finally a 100ms ramp (1.2 V/s) to a holding potential of -80mV. Peak current is measured during the step to -15mV. [0100] The parameters measured were difference between the peak inward current on stepping to -15mV (i.e., peak of the current) and the leak current. All data were filtered for seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition and the amount of block was assessed by dividing the Test compound current amplitude by the Control current amplitude. Control is the mean Nav1.5 current amplitude collected 10 seconds at the end of the vehicle control; Test Compound is the mean Nav1.5 current amplitude collected 10 seconds at the end of test concentration application for each concentration. hKv4.3/hKChIP2 Potassium Channel Assay – Qube APC [0101] After whole cell configuration is achieved, the cells are held at -80mV. Onset and steady state block of hKv4.3 current is measured using a pulse pattern from -80mV to 40mV amplitude for a 110ms duration, and finally a 100ms ramp (1.2 V/s) to -80mV. This paradigm is delivered once every 5s to monitor the current amplitude. [0102] The parameters measured were the maximum outward current evoked on stepping to 40mV from holding potential of -80mV. All data were filtered for seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition and the amount of block was assessed by dividing the Test compound current amplitude by the Control current amplitude. Control data is the mean Kv4.3/KChIP2 current amplitude collected 10 seconds at the end of the vehicle control period; Test compound data is the mean Kv4.3/KChIP2 current amplitude collected 10 seconds at the end of test concentration application for each concentration. hCav1.2 (L-type) CiPA Calcium Channel Assay – Qube APC [0103] Onset and steady state block of peak hCav1.2 current is measured using a pulse pattern, repeated every 15 sec. Cells were held at -80mV for a 50ms before stepping -190- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 to -90mV for 100ms to measure leak current and then stepped back to -80mV for 50ms, depolarization to 0mV amplitude for a 40ms duration, followed by step to 40mV for 200ms and finally a 100ms ramp (1.2 V/s) to a holding potential of -80 mV. Peak current is measured during the step to 0mV. Each concentration is applied for 5 minutes. [0104] The calcium current amplitude is calculated by measuring the difference between the peak inward current on stepping to 0mV or the peak inward current at the ramp (i.e. peak of the current) and the leak current. The calcium current is assessed in vehicle control conditions and at the end of each five (5) minute compound application. hNav1.5 Late Current Sodium Channel Assay – Qube APC [0105] Onset and steady state block of Late Nav1.5 current is measured using a pulse pattern, repeated every 5 sec, consisting of a hyperpolarizing pulse to -120mV for a 200ms duration, depolarization to -15mV amplitude for a 40ms duration, followed by step to 40mV for 200ms and finally a 100ms ramp (1.2 V/s) to a holding potential of -80mV. Late current is measured as charge current elicited during the ramp with 50nM ATXII. [0106] The parameters measured were the ramp current charge (AUC) evoked on ramping back to -80mV from 40mV test pulse in the presence of 50nM ATXII. All data were filtered for seal quality, seal drop, and current. The peak and ramp current amplitude was calculated before and after compound addition and the amount of current was assessed by dividing the Test compound current by the Control current. Control data is the mean hNav1.5 late current collected 15 seconds at the end of 50nM ATXII application (50nM ATXII control); Test compound data is the mean ramp hNav1.5 current collected 15 seconds at the end of test concentration application for each concentration. hERG Potassium Channel Assay - Qube APC [0107] After whole cell configuration is achieved, the cells are held at -80mV. Cells are held at this voltage for 50ms to measure the leak current, which is subtracted from the tail current on-line. The cells are depolarized to +40mV for 500ms and then to -80 mV over a 100ms ramp to elicit the hERG tail current. This paradigm is delivered once every 8s to monitor the current amplitude. All compounds were tested in the presence of 0.1% Pluronic F-68 Non-Ionic Surfactant and at approximately room temperature. -191- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0108] The parameters measured were the maximum tail current evoked ramping back to -80mV from the test pulse of 40mV. All data were filtered for seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition and the amount of block was assessed by dividing the Test compound current amplitude by the Control current amplitude. Control data is the mean hERG current amplitude collected for three pulses (24 seconds) at the end of the vehicle control; Test compound data is the mean hERG current amplitude collected for three pulses (24 seconds) at the end of test concentration application for each concentration. hKCNQ1/hminK Potassium Channel Assay – Qube APC [0109] After whole cell configuration is achieved, the cells are held at -80mV. KCNQ1/minK currents are evoked by a 1000ms pulse from -80mV to 60mV followed by a ramp from 60mV to -80mV over 115ms with the outward peak currents measured upon depolarization of the cell membrane. This paradigm is delivered once every 15s to monitor the current amplitude. [0110] The parameters measured were the maximum outward current evoked on stepping to +60mV from a holding potential of -80mV. All data were filtered for seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition and the amount of block was assessed by dividing the Test compound current amplitude by the Control current amplitude. Control data is the mean hKCNQ1/hminK current amplitude collected 30 seconds at the end of vehicle control period; Test compound data is the mean hKCNQ1/hminK current amplitude collected 30 seconds at the end of test concentration application for each concentration. hKir2.1 Potassium Channel Assay – Qube APC [0111] After whole cell configuration is achieved, the cells are held at -30mV. Kir2.1 currents are evoked by a single 500ms pulse to -120mV before returning to the holding potential of -30mV. This paradigm is delivered once every 20s to monitor the current amplitude. [0112] The parameters measured were the maximum inward current elicited on stepping to -120mV for 500ms from a holding potential of -30 mV. All data were filtered for -192- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition. Residual non-Kir2.1 current was eliminated via normalization to residual current after application of 100uM Barium Chloride. The amount of Test compound effect was then assessed by dividing the Test compound current amplitude by the Control current amplitude. Control data is the mean Kir2.1 current amplitude collected 40 seconds at the end of the vehicle control; Test compound data is the mean Kir2.1 current amplitude collected 30 seconds at the end of test concentration application for each concentration. Results [0113] Where presented, IC50 values were determined by a non-linear, least squares regression analysis. Reference standards were run as an integral part of each assay to ensure the validity of the results obtained. Results from the ion channel assessment of non- naturally occurring melanocortin analogs are provided in Table 46. Table 46. Dose-response results of melanocortin analogs and reference compounds against ion channels. Compound Ion channel target Max Estimated IC50 -193- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Example 6: Assessment of physical biological properties of non-naturally occurring melanocortin analogs [0114] Physical biological properties including solubility, in vitro absorption and in vitro metabolism of nine exemplary non-naturally occurring melanocortin analogs were assessed according to the following procedures. In each experiment and if applicable, the respective reference compound was tested concurrently with the test compounds, and the data were compared with known values. Stock solutions of the tested compounds were prepared at a concentration of 0.01M in DMSO. Solution Properties [0115] Solution properties of non-naturally occurring melanocortin analogs and reference compounds in various biological media were assessed according to the conditions provided in Table 47. Table 47. Assay conditions for in vitro absorption assessment Assay Technique Incubation Detection Method -194- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0116] Aqueous solubility (μM) was determined by comparing the peak area of the principal peak in a calibration standard (200 μM) containing organic solvent (methanol/water, 60/40, v/v) with the peak area of the corresponding peak in a buffer sample. In addition, chromatographic purity (%) was defined as the peak area of the principal peak relative to the total integrated peak area in the HPLC chromatogram of the calibration standard. A chromatogram of the calibration standard of each test compound, along with a UV/VIS spectrum with labeled absorbance maxima, was generated. [0117] A chromatogram of the test compound (200 μM) along with a UV/VIS spectrum with labeled absorbance maxima, was generated. Protein Binding [0118] The peak areas of the test compound in the buffer and test samples were used to calculate percent binding and recovery according to the following formulas: Protein binding(%) = ((Areap-Areab)/Areap) x 100 Recovery(%) = ((Areap-Areab)/Areac) x 100 where: Areap = peak area of analyte in protein matrix; Areab = peak area of analyte in buffer; and Areac = peak area of analyte in control sample. Partition Coefficient [0119] The total amount of compound was determined as the peak area of the principal peak in a calibration standard (100 μM) containing organic solvent (methanol/water, 60/40, v/v). The amount of compound in buffer was determined as the combined, volume-corrected, and weighted areas of the corresponding peaks in the aqueous phases of three organic- aqueous samples of different composition. An automated weighting system was used to ensure the preferred use of raw data from those samples with well quantifiable peak signals. The amount of compound in organic was calculated by subtraction. Subsequently, Log D was calculated as the Log10 of the amount of compound in the organic phase divided by the amount of compound in the aqueous phase. Half-Life Determination -195- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0120] At the end of the incubation at each of the time points, an equal volume of an organic mixture (acetonitrile/methanol, 50/50, v/v) was added to the incubation mixture. Samples were analyzed by HPLC-MS/MS and corresponding peak areas were recorded for each analyte. The ratio of precursor compound remaining after each time point relative to the amount present at time 0, expressed as percent, is reported as chemical stability. The half-life (T1/2) was estimated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) versus time, assuming first order kinetics. [0121] Results of the solubility assessment detailed above are provided in Tables 48- 51. Table 48. Protein binding of melanocortin analogs in plasma Compound Test Average % Average % Table 49. Half-life of melanocortin analogs in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) Compound Test Average Half-life (min) -196- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Propantheline 1.0E-6 >120 113.6 Chlorambucil 1.0E-6 - 20.0 Table 50. Aqueous solubility of melanocortin analogs in plasma (PBS), simulated gastric fluid (SGF), and simulated intestinal fluid (SIF) Compound Test Concentration (M) Average Solubility (mM) PB * F IF Table 51. Partition coefficient of melanocortin analogs and reference compounds Compound Test Concentration (M) Partition Coefficient* -197- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 *log D, n-octanol/PBS, pH 7.4 In Vitro Absorption [0122] In vitro absorption of non-naturally occurring melanocortin analogs was determined using permeability assays. Assay conditions are provided in Table 52. Table 52. Assay conditions for in vitro absorption assessment Assay Source pH Incubation Detection Method A-B rm bilit C -2 ll lin 65/74 0 nd 60 min HPLC-MS/MS [0123] The apparent permeability coefficient (Papp) of the test compound was calculated as follows: [0124] Papp(cm/s) = (VR*CR,end/Dt) x (1/A*(CD,mid-CR,mid) [0125] where VR is the volume of the receiver chamber; CR,end is the concentration of the test compound in the receiver chamber at the end time point; Δt is the incubation time; A is the surface area of the cell monolayer; CD,mid is the calculated mid-point concentration of the test compound in the donor side, which is the mean value of the donor concentration at time 0 minute and the donor concentration at the end time point; and CR,mid is the mid- point concentration of the test compound in the receiver side, which is one half of the receiver concentration at the end time point. Concentrations of the test compound were expressed as peak areas of the test compound. Recovery of the Test Compound from the Permeability Assay [0126] The recovery of the test compound was calculated as follows: [0127] Recovery(%) = ((VD*CD,end+VR*CR,end)/VD*CD0) x 100 [0128] where VD and VR are the volumes of the donor and receiver chambers, respectively; CD,end is the concentration of the test compound in the donor sample at the end time point; CR,end is the concentration of the test compound in the receiver sample at the end -198- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 time point; and CD0 is the concentration of the test compound in the donor sample at time zero. Concentrations of the test compound are expressed as peak areas of the test compound. Fluorescein assessment for Permeability assays [0129] Fluorescein was used as the cell monolayer integrity marker. Fluorescein permeability assessment (in the A-B direction at pH 7.4 on both sides) was performed after the permeability assay for the test compound. The cell monolayer that had a fluorescein permeability of less than 1.5 x 10-6 cm/s for Caco-2 and MDR1-MDCKII cells and 2.5 x 10-6 cm/s for MDCKII cells was considered intact, and the permeability result of the test compound from intact cell monolayer is reported. [0130] Results of the in vitro absorption assessments described above are provided in Table 53. Table 53. In vitro absorption of melanocortin analogs and reference compounds Compound Test A-B permeability B-A permeability y In Vitro Metabolism [0131] In vitro metabolism of non-naturally occurring melanocortin analogs was determined using the assay conditions provided in Table 54. Table 54. Assay conditions for in vitro metabolism assessment Assay Source Incubation Detection Method -199- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Intrinsic clearance Human liver microsomes 0, 15, 30, 45, and HPLC-MS/MS (0.1 mg/mL) 60 min, 37°C ng, was calculated by comparing the peak area of the compound at the time point relative to that at time-0. The half-life (T1/2) was estimated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) vs. time, assuming the first-order kinetics. The apparent intrinsic clearance (CLint, in μL/min/pmol, μL/min/mg or μL/min/Mcell) was calculated according to the following formula: CLint= 0.693/(T1/2*(mg protein/μL or million cells/μL or pmol CYP isoyme/μL)). [0133] Results from the intrinsic clearance assay are provided in Table 55. Table 55. In vitro metabolism of melanocortin analogs and reference compounds Compound Test Concentration (M) Half-life Clint (uL/mi/mg) Phys [0134] Physiochemical and Absorption, Distribution, Metabolism, and Excretion (ADME) properties of O10 were assessed (Tables A and B). O10 may be efficiently manufactured using standard solid-phase peptide synthesis (SPPS). B07, a melanocortin antagonist, has high structural homology to O10. B07 has been made in GMP batches up to 1 kg and it is amenable to efficient SPPS with high overall yields. Non-canonical residues and cyclic structure may restricts fermentation-based approaches, and peptide purification is performed using standard RP-HPLC techniques. [0135] O10 may be amenable to liquid-phase peptide synthesis (LPPS) for late-stage clinical and commercial manufacturing, offering potential for significant reductions in -200- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 manufacturing cost. It is anticipated that typical scale-up cost reductions (e.g., use of bulk residues, process optimization, captive manufacturing cost setups) will emerge. Table A: O10 Physicochemical Properties Calculated logD % unmodified, Aqueous solubility in PBS isoelectric Plasma Half-life in solution % Remaining after Half-life, Stability in s 0 ** SIF: simulated intestinal fluid Example 7: CYP Inhibition of Non-Naturally Occurring Melanocortin Analogs [0136] The inhibitory potential of exemplary non-naturally occurring melanocortin analogs was tested on seven human Cytochrome P450 (CYP) enzymes: CYP1A, CYP2B6, CYP2C19, CYPC8, CYP2C9, CYP2D6, and CYP3A. Exemplary melanocortin analogs O7 and O10 and comparator melanocortin analog TCMCB07 (Ac-Nle-c[Asp-Pro-dNal(2’)-Arg- Trp-Lys]-dVal-dPro-NH2; SEQ ID NO: 270) were tested at concentrations ranging from 0.1 mM to 100 mM for inhibition of the seven CYPs. The CYP inhibition assays were performed using human liver microsomes (HLM) and human recombinant CYP isozymes in 96-well plate format. Direct inhibition (e.g., zero-min incubation) and time-dependent (e.g., 30 min -201- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 preincubation) inhibition assays were performed. The results of the CYP inhibition assays of O7 and O10 at 10 mM are shown in Table 56 and the results of the comparator CYP inhibition assays including IC50 values at each of the CYP enzymes are shown in Table 57. Table 56. CYP Inhibition Studies of O10 Assay Substrate NADPH+/- O7 O10 µm 10µ -202- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Table 57. CYP Inhibition of TCMCB07 CYP Marker Substrate Isoform-Catalyzed TCMCB07 IC50 Values (µm) IC50 (Conc.) Reaction No Pre- 30-min Pre- Shift b [0137] Preliminary weight loss and food intake results in animals after administration of 3 mg/kg (3mg/kg) O10 for three or four days are shown in FIGS.6A (weight loss) and 6B (daily food intake). As shown in FIG. 6A, although animals administered 3 mg/kg O10 demonstrated weight loss compared to animals administered saline. Similarly, animals administered 3 mg/kg O10 had a decrease in daily food intake compared to animals administered saline (FIG.6B). Example 9: Body Weight, Complete Blood Count, Clinical Chemistry, and Food Intake in an Animal Model Objective [0001] The objective of this study was to evaluate the pharmacodynamic (PD) characteristics and effects on food intake, body composition, and clinical chemistry following administration of exemplary non-naturally occurring melanocortin analogs of the present technology. Non-naturally occurring melanocortin analogs were administered to Cynomolgus monkeys via two subcutaneous (s.c.) injections at different doses. Primate Specifications -203- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0002] Primate specifications are outlined in Table 58. Table 58: Primate Specifications Species: Cynomolgus monkey Sex and Number: Male, 6 Animal Husbandry [0003] Animals were supplied with unlimited Certified Monkey Diet for 72 hours after dosing on days 1, 8, and 11. Otherwise, the animals were supplied with Certified Monkey Diet twice a day. Animals received fruit daily as nutritional enrichment. [0004] Animals were supplied with fresh reverse-osmosis (RO) water using an automated watering system. Study Design [0005] Non-naturally occurring melanocortin analogs were each administered to a group of Cynomolgus monkeys (n=2 per group) via s.c. injections as outlined in Table 59. The start of treatment is designed as Day 1. The end time of dosing was recorded as 0h. Table 59. Group & Dosing Information 2nd 1st Dose D Dose Dose Route of o -204- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0006] General physical examinations were completed once in the acclimation period. Cage-side observations for general health and appearance, such as nausea and vomiting, were done every hour for 6 hours after dosing on Days 8 and 11. Otherwise, cage-side clinical observations were done once daily during the pre-study and after dosing period. [0007] Acclimatization Period (Day 1-7): Each animal was examined at least once during the acclimation period to determine suitability for the study. Body weight, clinical observations, and food intake observations were recorded daily. Measurement of initial body composition using Dual-Energy X-Ray Absorptiometry (DEXA) was recorded at least once during this time. Standard blood markers (e.g., glucose, insulin, HDL-c, LDL-c, triglycerides, total cholesterol, alanine aminotransferase, aspartate aminotransferase) were measured once. [0008] Treatment Phase (Days 8-49): Body weight was recorded twice a week, clinical observation and food intake were recorded once a day. Standard hematology and clinical chemistry readouts as above were conducted before dosing and at the conclusion of the study on day 49. DEXA measurements of body composition were conducted biweekly. Food intake measurement [0009] Food intake was observed at about 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 24 hours, 48 hours, and 72 hours after administration of saline or non- naturally occurring melanocortin analogs at 1 mg/kg and 3 mg/kg (Day 8 and Day 11) dosing. On Days 4-7, monkeys were acclimatized to a normal diet of two meals per day. On Day 8, the lower dose of the non-naturally occurring melanocortin analogs were administered, and observations continued through Day 10. On Day 11, the higher dose of the non-naturally occurring melanocortin analogs was administered, and observations continued through Day 13, the conclusion of the study. Blood collection [0010] Blood collection according to Table 60 was conducted for the following: clinical chemistry (Serum), hematology (whole blood). Whole blood was collected at each time point with syringe via the cephalic or saphenous veins into labeled polypropylene tubes. -205- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Table 60. Blood Sampling Animal Blood Minimum Volume Time Point Test Type Gr S m l T f Bl d S m les [0011] Clinical chemistry and hematology assessments were conducted, assessing the parameters outlined in Tables 61 and 62. Table 61: Clinical Chemistry Parameter Abbreviation Unit Al i ALB L -206- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Parameter Abbreviation Unit Red blood cell count RBC 1012/L [0012] Body weight was assessed in male Cynomolgus monkeys having diet-induced obesity of age 14-19 years old (n=6). Monkeys were subcutaneously injected with O10 at 1 mg/kg and 3 mg/kg. Monkeys were fasted overnight before dosing. Body weight was measured on days 1, 8, and 15 and percent change in body weight was calculated. Results are shown in Tables 63 and 64, respectively. Table 63: Body Weight (kg) Group Animal ID -207- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 3mg/kg, SC, two doses, n=2 4 14.48 14.32 14.44 Group Animal No. Day 1 Day 8 Day 15 [0013] Complete blood count (CBC) was assessed on days 1, 8, and 12. Results are detailed in Tables 65-70. -208- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 Table 65: Complete Blood Count Day 1 (Part 1) Table 66: Complete Blood Count Day 1 (Part 2) -209- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 Table 67: Complete Blood Count Day 8 (Part 1) Table 68: Complete Blood Count Day 8 (Part 2) -210- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 Table 69: Complete Blood Count Day 12 (Part 1) Table 70: Complete Blood Count Day 12 (Part 2) -211- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 Clinical Chemistry [0014] Clinical chemistry, including triglycerides, creatine kinase, lactate dehydrogenase, alanine amino transferase, aspartate amino transferase, bilirubin, alkaline phosphatase, total protein, albumin, globulin, glucose, urea nitrogen, creatine, urea acid, and C-reactive protein was assessed in monkey serum on days 1, 8 (2h), and 11 (2h). Results of each measurement are outlined in Tables 71-76. -212- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 Table 71: Clinical Chemistry Day 1 (Part 1) Table 72: Clinical Chemistry Day 1 (Part 2) -213- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 Table 73: Clinical Chemistry Day 8 (Part 1) Table 74: Clinical Chemistry Day 8 (Part 2) -214- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 Table 75: Clinical Chemistry Day 12 (Part 1) Table 76: Clinical Chemistry Day 12 (Part 2) Food Intake [0015] Food intake (g) was assessed in monkeys on days 2, 3, 4, 9, 10, 11, and 13-15. Results are detailed in Table 77. -215- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 Table 77: Food Intake . . . . . . . . . [0016] Food intake was also assessed on days 1, 8, and 12 at 0.5-, 1-, 1.5-, 2-, 3-, 4-, 24-, 48-, and 72-hours post-dose. Results are detailed in Tables 78 and 79. -216- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 Table 78: Food intake Days 1 and 8 , Table 79: Food Intake Day 12 doses, n=2 -217- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 Example 10: Acute Food Intake [0138] Food intake was assessed in 6 diet-induced obese Cynomolgus monkeys (n=6). Monkeys were first administered saline on day 1 (D1) and food intake was measured (FIGS. 7A-7D). On day 8 and day 12, monkeys were administered 1 mg/kg, O10 (Group 2; n=2), (FIGS. 8A-8H). Monkeys were fasted overnight prior to administration. Food was administered 2 hours after each dose and intake was measured at 0.5-, 1-, 1.5-, 2-, 3-, 4-, 24-, 48-, and 72-hours after dosing. Group 2 monkeys demonstrated a decrease in food intake relative to saline dosing (FIGS.9A and 9B). Example 11: Caloric Intake, Body Weight, and Body Composition Food Intake and Body Composition in Monkeys [0139] Changes in caloric intake and body weight were assessed in diet-induced obese Cynomolgus monkeys (n=6). Monkeys were orally administered O10 (MC3R/MC4R coagonist) once daily. One day 15, dosing changed to 15/mg/kg administered twice daily, and dosing was maintained until at least day 28 and monkeys were assessed until at least day 35. Control monkeys were administered saline. Daily caloric intake (FIGS. 10A), cumulative caloric intake (FIGS. 10B), percent change in caloric consumption, relative to baseline (FIGS.10C), and caloric intake per body weight were measured in addition to food intake (also see FIGS. 11A-11R; Tables 80-98). Cumulative caloric intake and percent change in caloric intake, relative to baseline, were each reduced in the monkeys administered O10, relative to those administered saline. [0140] Food preference towards a lower-fat diet in the monkeys administered O10 was also observed, where O10-treated monkeys consumed 50% more reduced-fat feed and 20% less high-fat feed on average compared to monkeys administered saline (FIGS.11A-11R). [0141] Body composition was assessed, including body weight (kg), body height (m), BMI (kg/m2), whole body bone mineral content (g), trunk bone mineral content (g), bone density (g/cm2), trunk fat mass (g), trunk fat mass (%), trunk muscle mass (g), trunk muscle mass (%), fat mass (g), fat mass (%), muscle mass (g), muscle mass (%), and lean mass (%) (Tables 99-104) (FIGS. 13A-13N). Diet-induced obese monkeys administered O10 showed a 7.5% weight loss in 5 weeks, relative to baseline -218- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 Table 80: Animal Pre-screening and Day 1 Food Intake , T 10mg/kg (Day 1-8), -219- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 y , T bl 82 D 57 F d I t k on Day 15), BID -220- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 Table 83: Days 8-10 Food Intake T QD -221- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 y , T bl 85 D 14 F d I t k . . . T 10mg/kg (Day 1- SD 34.05088 62.89411 25.36378 34.61016 45.74607 45.70314 -222- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 , Table 87: Da s 17 and 18 Food Intake 15mg/kg (Started on Day 15), BID T 15mg/kg (Started on Day 15), BID SD 25.96755 57.27054 40.21774 33.32081 43.72036 64.86716 -223- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 Table 89: Days 21 and 22 Food Intake 5mg/g (Sared on ay 5), S 3.86 5.063 .5 6 36.36 8.559 .83366 T Day 15), BID -224- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 Table 91: Days 26 and 27 Food Intake mg/g ( are on ay ), T 15mg/kg (Started on Day 15), BID -225- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 Table 93: Day 30 Food Intake T . . . . . . -226- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 Table 95: Days 5-10 Food Intake (Calorie) T . . . . -227- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 Table 97: Days 15-22 Food Intake (Calorie) , . . . . . . . . Table 98: Days 24-30 Food Intake (Calorie) BID SD 308.3572522 332.830924 328.5675853 317.5290018 321.5047862 275.3078471 262.1208391 -228- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 Table 99: Body Composition at Baseline (Part 1) 15), BID SD Table 100: Body Composition at Baseline (Part 2) QD SD 10.99736982 792.642236 10.69439969 1412.54931 9.726611141 1560.134243 9.127144584 -229- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 , Table 101: Body Composition Day 29 (Part 1) 15), BID SD 2.39911554 0.03642507 7.46423249 61.5495561 26.3972401 0.07098378 1072.03211 -230- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 Table 102: Body Composition Day 29 (Part 2) 15), BID SD 12.7292618 866.349319 12.3416197 1417.4723 10.5881251 1620.04201 9.9040825 -231- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 Table 103: Body Composition Change (Part 1) Table 104: Body Composition Change (Part 2) -232- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 -233- 146316.8034.WO00\181226204.17
Docket No.: 146316.8023.WO00 [0142] By day 8, the body weight change relative to baseline was most reduced in the monkeys administered O10, compared to monkeys administered saline (FIGS. 12A-12M) (Tables 105 and 106). Monkeys were administered O10 orally for 36 days and abstained from dosing until day 43. From days 43-50, monkeys were subcutaneously administered O10, with dosing discontinued after day 36 or 50 (FIG.12F, 12G, 12I, 12K). A decrease in percent change in body weight was observed in monkeys administered O10, relative to saline. Following dosing discontinuation, body weight was maintained and did not rebound during the day 50-71 observations (FIGS.12H-12J). Table 105: Body Weight (kg) (Day 1-22) Day 1 Day 8 Day 15 Day 22 Day 29 Table 106: Body Weight (Percent Change) Gr Anim l M r m nt y 8 , , , lso assessed (FIGS.14A-14D; Tables 107-118). Blood levels chemistry levels were unchanged -234- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 by day 29 from baseline in monkeys orally administered O10 relative to those administered saline. Cage side observations showed no signs of gastric distress (assessed by stool changes) or nausea (assessed by food refusal). Table 107: Clinical Chemistry Day 1 (Part A) Clinical Glu Alanine Aspartate Alkaline Gamma- Total Total Trigly Chemis cos Aminotran Aminotransf Phospha glutamyl Biliru Prote cerid ol 71 5 41 9 .6 80 3 Table 108: Clinical Chemistry Day 1 (Part B) Clinical (Total) Alb High density Low density Lactate Cre Urea Creatin e -235- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 um mmol Day 1 mmol/L g/L mmol/L mmol/L U/L ol/L /L U/L M 75 95 3 62 5 33 6 56 4 Table 109: Clinical Chemistry Day 15 (Part A) Clinical Meas Glu Alanine Aspartate Alkaline Gamma- Total Total Trigl Chemi urem cos Aminotran Aminotrans Phos ha lutam l Biliru Prot ceri o 5 5 7 3 5 -236- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 O10, p.o., n=8 69 45 Table 110: Clinical Chemistry Day 15 (Part B) Clinica l Mea (Total) Alb High density Low density Lactate Cre Urea Creati e .5 54 2 4 26 7 -237- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 QD 15mg/ k Table 111: Clinical Chemistry Day 29 (Part A) Clinical Meas Glu Alanine Aspartate Alkaline Gamma- Total Total Trigl Chemi urem cos Aminotran Aminotrans Phospha glutamyl Biliru Prot yceri o 7 5 9 9 6 5 8 3 -238- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 Table 112: Clinical Chemistry Day 29 (Part B) Clinica l Mea (Total) Alb High density Low density Lactate Cre Urea Creati Ch i Ch l i li t i li t i D hd ti Nit i e 82 5 79 1 63 5 04 4 -239- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 Table 113: Complete Blood Count Day 1 (Part A) Mea n T t a e u V .7 5 0 5 4 .1 5 5 9 8 1 2 6 0 2 1 Table 114: Complete Blood Count Day 1 (Part B) CB Measu Neutr Lymph Mono Eosin Baso Neutr Lymph Mono Eosin Baso t hil t t hil hil hil t t hil hils A 0 0 -240- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 QD, n=8 1 11 7 11 2 7 0 0 0 Table 115: Complete Blood Count Day 15 (Part A) Mean corpu n el V 21 5 09 7 -241- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 Grou 14.78 5.676 123.2 42.12 74.13 21.72 292.3 14.08 512.3 9.887 p 2 Mean 25 25 5 5 75 5 75 75 75 5 O10 241 4 1 14 4 47 1 2 1 91 7 25 5 Table 116: Complete Blood Count Day 15 (Part B) Meas Lymp Lymp urem Neutr hocyt Mono Eosin Baso Neutr hocyt Mono Eosin Baso A 05 53 2 12 5 35 5 -242- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 /kg (Day 9-14) Table 117: Complete Blood Count Day 29 (Part A) MCH WBC RBC HGB HCT MCV MCH C RDW PLT MPV 91 5 53 6 13 5 39 6 -243- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 Table 118: Complete Blood Count Day 29 (Part B) Meas Lymp Lymp urem Neutr hocyt Mono Eosin Baso Neutr hocyt Mono Eosin Baso s A 25 46 1 0 0 40 5 [0144] Changes in pigmentation were observed in the monkeys orally administered O10, where, at high doses of O10, a tanning effect was observed. The tanning effect comprised skin darkening without hyperpigmentation (e.g., an uneven distribution of melanin) compared to baseline. Notably, the tanning effect was only seen in typically sun- exposed skin, with no observation of ectopic tanning (e.g., palms, gums, etc.). Monkeys -244- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 were never exposed to sunlight. Pigmentation resolved back to baseline levels rapidly after treatment was discontinued. [0145] The slope of the O10 weight loss curve (FIG.12I) suggests that a lower dose of O10 may be employed for the same efficacy. This suggests presence of a therapeutic window between weight loss and pigmentation (i.e., tanning effect). Combinations with weight loss agents may permit usage of lower doses of both agents, limiting side effects, and increasing therapeutic window further. Food Intake and Body Composition in Rats [0146] Normalized cumulative food consumption (FIG. 11Q), and percent change in body weight (FIG. 12L) were assessed in rats administered the following MC4R selective agonists: Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 48; A07D), Ac- Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 106; O7) and Ac-Nle- c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 62; O11) (n=5) or MC3R/MC4R co-agonist O10 compared to saline controls (n=4). For each treatment group, rats were subcutaneously administered 0.5 mg/kg of A07D, O7, O10, or O11 for days 1-7 and 1 mg/kg for days 8-17. O11 and O7 did not appear to influence food consumption as a percent of food consumption in saline-treated rats, relative to O10 (FIG.11Q). At 17 days, O10 treated rats gained only about 0.64% of their body weight compared to saline, which gained about 8.98% body weight (**) (FIG.12L). O10-treated rats gained less weight than O7-treated rats (****), A07D-treated rats (*), and O11-treated rats (p=.066). O10, an MC3R/MC4R coagonist, also exhibited a stronger influence on caloric consumption, as measures by cumulative food consumption) than the MC4R selective agonists. However, both the MC4R selective agonists and the MC3R/MC4R coagonists were each more effective in reducing body weight relative to saline controls. Example 12: Cardiac Effects [0017] Changes in cardiac effects were assessed in rats subcutaneously administered O10 at either 0.5 mg/kg, 1 mg/kg, or 3 mg/kg. Control rats were administered saline. Animal specifications are outlined in Table 119. Table 119: Animal Specifications -245- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 Species Sprague-Dawley (SD) Rats A [0018] 6-7 week old male SD rats were obtained and housed in a controlled environment (target conditions: temperature 20 to 24°C, relative humidity 30 to 70%). Temperature and relative humidity was monitored daily. An electronic time-controlled lighting system was used to provide a 12-hour light/12-hour dark cycle. Rats were housed in plastic cages. Enrichment toys were provided. During the housing and study period, the rats were fed with normal chow and fresh water, ad libitum. Animal Acclimation [0019] After arrival, the animals acclimated to environment for at least 5 days. Study Design [0020] Before the experiment, the weight of each animal was measured and rats were be separated into different groups based on weight, with 3 rats per group (Table 120). Table 120: Study Groups Dosag Volum Concentr Frequ Monito Numbe ti y le -246- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 [0021] After acclimatization, animals were anesthetized with urethane as well as subjected to femoral vein for drug injection and carotid common artery to measure blood pressure. Meanwhile, electrocardiogram (ECG) was detected by subcutaneous puncture needle electrodes. The body temperature of the rats was maintained at about 37°C during assessments and experimentation. The blood pressure (BP) and ECG was recorded for 15 minutes before administration and for 3 hours after administration continuously for each rat. Readouts [0022] Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were recorded with blood pressure measurements. [0023] QRS, ST, QT, P wave, T wave, and HR were assessed with ECG measurements. [0024] Recording duration occurred from -15 min (pre-dose) to 180 min (after dosing). Blood Collection [0025] After recording, animals were euthanized with CO2 immediately and blood was collected for in vitro analysis, including plasma corticosterone by ELISA Kit. Data Processing and Analysis [0026] All values were expressed as mean ± SEM. The significances of the differences among groups and within groups was evaluated by one-way ANOVA followed by Dunnett’s test using Graph Pad statistic software. A p value of less than 0.05 was considered statistically significant. Results for the BP analysis are shown for all groups in Tables 121- 123 and for groups 1 and 5-7 in FIGS.15A-15C. ECG results are shown in Tables 124-128. Table 121: Blood Pressure Analysis (Part 1) Animal SBP(mmHg) mi -247- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 G6: Mean 107 111 110 108 111 108 110 107 110 O10 1 k SEM 1 1 2 1 2 5 4 4 3 Table 122: Blood Pressure Analysis (Part 2) Animal DBP(mmHg) Group Measureme 0mi 5mi 15mi 30mi 60mi 90mi 120mi 150mi 180mi Table 123: Blood Pressure Analysis (Part 3) Animal HR(BPM) Gr M r m mi -248- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 Table 124: ECG Results (Part 1) Animal Heart Rate (BPM) Group Measureme 0mi 5mi 15mi 30mi 60mi 90mi 120mi 150mi 180mi Animal PR Interval (s) Group Measurem 15mi 30mi 60mi 90mi 120mi 150mi 180mi 3 2 0 8 0 1 3 9 1 1 Animal QRS Interval (s) mi -249- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 Mean 0.015 0.015 0.015 0.016 0.016 0.016 0.017 0.016 0.016 3 7 8 7 6 7 0 7 5 1 2 1 1 2 2 1 2 1 02 1 6 1 6 0 6 0 0 Animal QTc (s) Group Measurem 15mi 30mi 60mi 90mi 120mi 150mi 180mi 1 4 0 5 1 0 3 6 7 5 Group ST Height -250- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 Animal Measurem 0min 5min 15mi 30mi 60mi 90mi 120mi 150mi 180mi ent n n n n n n n 4 6 7 1 2 9 9 3 3 4 [0027] No significant changes in systolic blood pressure (SBP) (FIG. 15A), diastolic blood pressure (DBP) (FIG. 15B), nor heart rate (HR) (FIG. 15C) were observed in rats administered O10 at any dose, relative to controls. Comparably, setmelanotide-treated animals showed at some doses, there were changes in QTc, suggesting altered cardiac repolarization (FIGS.16A-16D). [0028] Normalized heart rate (HR), QTc, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), QT interval, QRS interval, and RR interval were also assessed in male cynomolgus monkeys orally administered 3 mg/kg, 10 mg/kg, 30 mg/kg, or 60 mg/kg O10 (FIGS. 17A-17H). Relative to control cynomolgus monkeys administered saline, no significant cardiac effects were observed in monkeys administered O10 at any dose. In contrast, monkeys administered setmelanotide experienced an increase in SBP, DBP, and MBP, relative to monkeys administered saline. This increase was also observed during the dark cycle (“lights off” FIGS. 17C-17H). No increase in these parameters were observed at any time point in monkeys administered O10, relative to those administered saline. -251- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 Example 13: Assessing Off-Target Binding of O10 [0147] O10 was assessed for interaction with RFamide receptors, which are hypothesized to cause cardiac activation in MC4R-targeting small molecules and peptides (Table 129). Table 129: O10 Assessment for RFamide Receptor Binding Antagonist mode, IC50 (nM) Agonist mode, EC50 (nM) F 0 [0148] Generally, O10 did not agonize or antagonize RFamide receptors up to 1000 nM (top concentration tested), 1000x-100,000x above their respective EC50s on MC4R. Additionally, no hERG inhibition observed from O10 at concentrations up to 30 µM. [0149] O10 was next screened for binding against a panel of 87 receptors and channels at 10 µM. Results showing an inhibition or stimulation higher than 50% were considered to represent significant effects of the test compounds. O10 only showed >50% inhibition of control on melanocortin receptors (FIG. 18). O10 was shown to have minimal inhibition at 10 µM for cytochrome P450 (CYP) enzymes (Table 130 and Table 131). O10 showed no meaningful impact on CYP induction or inhibition at physiologically relevant concentrations, demonstrating minimal drug-drug interactions. Table 130: Assessing Time Dependent CYP Inhibition O10 -252- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 4.0 1A HLM, phenacetin substrate - NADPH -253- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 0.5 2C9 HLM diclofenac substrate Table 131: Assessing O10 and CYP Induction mRNA Fold Induction of Hepatocytes with Different Treatments: Mean -254- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 1 3.1 20.4 3.4 (1.97, 5.31) (17.6, 23.2) (3.42, 3.55) 0.8 30.7 B6; Rifampicin (10 µM) for CYP3A4. Example 14: Assessing Adipose Tissue Effects of O10 [0150] To assess adipose tissue effects from O10 administration, fat tissue was harvested from diet-induced obese cynomolgus monkeys orally administered 10 mg/kg O10 or saline control. O10-treated monkeys showed (1) smaller lipid droplets, (2) darker, dense staining likely attributed to higher mitochondrial concentrations, and (3) increased vascularization, relative to saline controls (FIG. 19; H&E staining, 200x), consistent with beige/brown adipocytes. This suggests that O10 administration may stimulate metabolic remodeling through adipose tissue browning, which in turn may increase metabolic rate and calorie burn and may improve insulin sensitivity. Example 15: Assessing absorption, distribution, metabolism, and excretion of non- naturally occurring melanocortin analogs [0151] Non-naturally occurring melanocortin analogs of the present technology, O10 and C2, were assessed for solution properties, in vitro absorption, and in vitro metabolism for absorption, distribution, metabolism, and excretion (ADME) properties. Various ADME outcomes are outlined in Table 132. Aqueous Solubility [0152] Aqueous solubility (μM) was determined by comparing the peak area of the principal peak in a calibration standard (200 μM) containing organic solvent (methanol/water, 60/40, v/v) with the peak area of the corresponding peak in a buffer sample. Additionally, chromatographic purity (%) was defined as the peak area of the principal peak relative to the total integrated peak area in the HPLC chromatogram of the calibration standard. A -255- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 chromatogram of the calibration standard of each test compound, along with a UV/VIS spectrum with labeled absorbance maxima, was generated. HPLC-UV Screen [0153] A chromatogram of the test compound (200 μM) along with a UV/VIS spectrum with labeled absorbance maxima, was generated. Protein Binding [0154] The peak areas of the test compound in the buffer and test samples were used to calculate percent binding and recovery according to the following formulas: Protein binding (%)= (Areap−AreabAreap)∗100 Recovery (%)=((Areap+Areab)/Areac)∗100 where: Areap = Peak area of analyte in protein matrix Areab = Peak area of analyte in buffer Areac = Peak area of analyte in control sample Partition Coefficient [0155] The total amount of compound was determined as the peak area of the principal peak in a calibration standard (100 μM) containing organic solvent (methanol/water, 60/40, v/v). The amount of compound in buffer was determined as the combined, volume-corrected, and weighted areas of the corresponding peaks in the aqueous phases of three organic- aqueous samples of different composition. An automated weighting system was used to ensure the preferred use of raw data from those samples with well quantifiable peak signals. The amount of compound in organic was calculated by subtraction. Subsequently, LogD was calculated as the Log10 of the amount of compound in the organic phase divided by the amount of compound in the aqueous phase. Half-Life Determination [0156] At the end of the incubation at each of the time points, an equal volume of an organic mixture (acetonitrile/methanol, 50/50, v/v) was added to the incubation mixture. -256- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 Samples were analyzed by HPLC-MS/MS and corresponding peak areas were recorded for each analyte. The ratio of precursor compound remaining after each time point relative to the amount present at time 0, expressed as percent, is reported as chemical stability. The half-life (T1/2) was estimated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) versus time, assuming first-order kinetics. ADME-Tox: In Vitro Absorption Permeability [0157] The apparent permeability coefficient (Papp) of the test compound was calculated as follows: Papp(cm/s)=(VR⋅CR,end/Δt)⋅(1/A*(CD,mid−CR,mid)) where: VR is the volume of the receiver chamber. CR,end is the concentration of the test compound in the receiver chamber at the end time point. Δt is the incubation time. A is the surface area of the cell monolayer. CD,mid is the calculated mid-point concentration of the test compound in the donor side, which is the mean value of the donor concentration at time 0 minute and the donor concentration at the end time point. CR,mid is the mid-point concentration of the test compound in the receiver side, which is one half of the receiver concentration at the end time point. Concentrations of the test compound were expressed as peak areas of the test Recovery of the Test Compound from the Permeability Assay [0158] The recovery of the test compound was calculated as follows: Recovery (%)=((VD⋅CD,end+VR⋅CR,end)/(VD⋅CD0))∗100 where: VD and VR are the volumes of the donor and receiver chambers, respectively. -257- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 CD,end is the concentration of the test compound in the donor sample at the end time point. CR,end is the concentration of the test compound in the receiver sample at the end time point. CD0 is the concentration of the test compound in the donor sample at time zero. Concentrations of the test compound are expressed as peak areas of the test compound. Fluorescein Assessment for Permeability Assays [0159] Fluorescein was used as the cell monolayer integrity marker. Fluorescein permeability assessment (in the A-B direction at pH 7.4 on both sides) was performed after the permeability assay for the test compound. The cell monolayer that had a fluorescein permeability of less than 1.5 x 10-6 cm/s for Caco-2 and MDR1-MDCKII cells and 2.5 x 10-6 cm/s for MDCKII cells was considered intact, and the permeability result of the test compound from intact cell monolayer is reported. ADME-Tox: In Vitro Metabolism Intrinsic Clearance (microsomes, S9, cryopreserved hepatocytes, recombinant CYP, recombinant UGT) [0160] Metabolic stability, expressed as percent of the parent compound remaining, was calculated by comparing the peak area of the compound at the time point relative to that at time-0. The half-life (T1/2) was estimated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) vs. time, assuming first-order kinetics. The apparent intrinsic clearance (CLint, in μL/min/pmol, μL/min/mg or μL/min/Mcell) was calculated according to the following formula: CLint = 0.693/(T1/2*(mg protein/μL or million cells/μL or pmol CYP isoyme/μL)) -258- 146316.8034.WO00\181226204.17 Docket No.: 146316.8023.WO00 Table 132: ADME Assessment of Non-Naturally Occurring Analogs and Reference Compounds -259- 146316.8034.WO00\181226204.17
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Docket No.: 146316.8034.WO00 Example 16: Comparing O10 and Setmelanotide [0161] As shown in the examples provided herein, the non-naturally occurring melanocortin analogs of the present technology out-perform setmelanotide across numerous metrics. First, compared to setmelanotide, O10 is (1) about 408x (x, times) more potent on MC3R, (2) about 120x more potent on MC4R, and (3) has superior PK parameters as shown in at least rats, where the CSF half-life of O10 is about 2x longer, the plasma half-life is about 3x longer, the CSF AUC is about 1.5x higher, and the plasma AUC is 4.5x higher (also see Table 133 and Table 134) compared to setmelanotide. Table 133: cAMP Signaling Assay – Agonist Mode; EC50 (nM) Setmelanotide O10 Table 134: 10mg/kg SC (rat) PK Parameters Setmelanotide O10 PK M F M M F M [0162] Second, as shown by at least the drug exposure over the EC50 analyses, O10 is present at efficacious doses in CSF for periods of time longer than setmelanotide, O10 remains present in the CSF at concentrations higher than the EC50. It is predicted that O10 will be more efficacious for general obesity (e.g., obesity not caused by genetic factors related to the melanocortin system) due to higher affinity for -267- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 MC3R and MC4R and PK values in plasma and CSF (as shown in the rat) compared to setmelanotide. [0163] Third, as shown in at least the non-human primate studies, O10 reduces food intake in a single dose via 1 and 3 mg/kg SC injection in DIO cynomolgus monkeys, whereas setmelanotide did not affect food intake in 39-week toxicity study via 3 mg/kg/day SC injection in standard BMI cynomolgus monkeys. It is predicted that the 10 and 30 mg/kg oral administration doses of O10 will be efficacious considering the PK data and superior potency of O10 on MC3R and MC4R activation (Table 135). Table 135: PL parameters O1030 mg/kg, oral administration in monkeys PK Mean SD CV (%) Paramet [0164] The oral PK results suggest that O10 will also be efficacious at 10 and 30 mg/kg PO administration. As shown in the working examples, the plasma PKs of a 1 mg/kg SC injection of O10 to an oral 10 mg/kg and 30 mg/kg administration of O10 were above the EC50. Food intake may thus be reduced following oral administration of O10. -268- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Example 17: in vitro Pharmacology of Non-Naturally Occurring Melanocortin Analogs [0165] Eighty-seven binding and enzyme and uptake assays were performed on O10 to determine in vitro pharmacology properties of the three melanocortin analogs. In each assay, the compounds were tested at a concentration of 10 µM, and, if applicable, a reference compound was tested concurrently with the test compounds (i.e., O10). Each assay was performed according to known protocols, typically at a volume of 200 µL in a 96-well plate. Exemplary protocols for two binding assays are provided below and may be adapted by the skilled artisan for different receptors. Human neurokinin NK1 receptor (agonist radioligand) binding assay [0166] Cells membrane homogenates (about 50 μg) were incubated for 30 min at 22°C with 0.05 nM [125I]-substance P LYS3 in the absence or presence of the test compound (i.e., O10) in a buffer containing 50 mM Tris-HCl (pH 7.4), 5 mM MnCl2, 0.2% BSA and 40 μg/ml bacitracin. Nonspecific binding was then determined in the presence of 1 μM [Sar9,Met(O2)11]-substance P. [0167] Following incubation, the samples were filtered rapidly under vacuum through glass fiber filters (GF/B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). The filters were dried then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). Results are shown in Table 78 and expressed as a percent inhibition of the control radioligand specific binding. [0168] The standard reference compound, [Sar9,Met(O2)11]-substance P, was tested in each experiment at several concentrations to obtain a competition curve from which its IC50 was calculated. Human neuropeptide Y1 receptor (agonist radioligand) binding assay [0169] Cells membrane homogenates (32 μg protein) were incubated for 120 min at 37°C with 0.025 nM [125I]peptide YY in the absence or presence of the test compound (i.e., O10) in a buffer containing 50 mM Hepes/NaOH (pH 7.4), 1 mM MnCl2, 2.5 nM CaCl2, 0.025% NaN3 and 0.3% BSA. Nonspecific binding was then determined in the presence of 1 μM NPY. -269- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0170] Following incubation, the samples were filtered rapidly under vacuum through glass fiber filters (GF/B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester. The filters were dried then counted for radioactivity in a scintillation counter using a scintillation cocktail. Results are expressed as a percent inhibition of the control radioligand specific binding. [0171] The standard reference compound, NPY, was tested in each experiment at several concentrations to obtain a competition curve from which its IC50 was calculated. Assay Results [0172] Compound binding was calculated as a % inhibition of the binding of a ligand specific for each target and compound enzyme inhibition effect was calculated as a % inhibition of control enzyme activity. [0173] O10 was tested at 1.0E-05 M (Table 136). Compound binding was calculated as a % inhibition of the binding of a ligand specific for each target. Table 136: O10 Binding Assay 1.0E-05 M [0174] Compound enzyme inhibition effect was calculated as a % inhibition of control enzyme activity (FIGS.21-23) (Table 137 and Table 138). Table 137: In Vitro Pharmacology: Binding Assays – Test Compound Results -270- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Compound Test % Inhibition of Control Specific Binding Concentration 1st 2nd Mean -271- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Compound Test % Inhibition of Control Specific Binding Concentration 1st 2nd Mean -272- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Compound Test % Inhibition of Control Specific Binding Concentration 1st 2nd Mean -273- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Compound Test % Inhibition of Control Specific Binding Concentration 1st 2nd Mean -274- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Compound Test % Inhibition of Control Specific Binding Concentration 1st 2nd Mean -275- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Compound Test % Inhibition of Control Specific Binding Concentration 1st 2nd Mean Table 138: In Vitro Pharmacology: Binding Assays Reference Compound Results Compound IC50(M) Ki(M) nH Sodium Channel Site2 (Non-selective) Rat Ion Channel Batrachotoxin Mass -276- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Compound IC50(M) Ki(M) nH alpha1B (h) (antagonist radioligand) -277- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Compound IC50(M) Ki(M) nH D2S(h) (agonist radioligand) -278- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Compound IC50(M) Ki(M) nH MAO-A (antagonist radioligand) -279- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Compound IC50(M) Ki(M) nH RARalpha (h) (agonist radioligand) -280- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Compound IC50(M) Ki(M) nH Ca2+ channel (L verapamil site) (phenylalkylamine) (antagonist radioligand) [0029] O10 was first screened for binding against a panel of 87 receptors and channels at 10 µM. MC1 and MC4 showed >50% inhibition of control O10 (MC1 (agonist radioligand): 97.4%; MC4(h) (agonist radioligand): 100.4%) (FIGS.21-23). [0030] Enzyme inhibition and uptake was also assessed for O10 (FIG.23) (Table 139 and Table 140). Table 139: In Vitro Pharmacology: Enzyme and Uptake Assays – Test Compound Results -281- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Compound Test % Inhibition of Control Values Concentration 1st 2nd Mean Table 140: In Vitro Pharmacology: Enzyme and Uptake Assays – Reference Compound Results Compound IC50(M) nH -282- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Compound IC50(M) nH PDE3A (h) [0175] Results showing an inhibition (or stimulation for assays run in basal conditions) higher than 50% are considered to represent significant effects of the test compounds. 50% is the most common cut-off value for further investigation (determination of IC50 or EC50 values from concentration-response curves) that we would recommend. [0176] Results showing an inhibition (or stimulation) between 25% and 50% are indicative of weak to moderate effects (in most assays, they should be confirmed by further testing as they are within a range where more inter-experimental variability can occur). [0177] Results showing an inhibition (or stimulation) lower than 25% are not considered significant and mostly attributable to variability of the signal around the control level. [0178] Low to moderate negative values have no real meaning and are attributable to variability of the signal around the control level. High negative values (≥ 50%) that -283- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 are sometimes obtained with high concentrations of test compounds are generally attributable to nonspecific effects of the test compounds in the assays. On rare occasion they could suggest an allosteric effect of the test compound. [0179] Additional details of the experimental conditions and assays used are shown in Tables 141 and 142. Table 141: In Vitro Pharmacology: Binding Assays Assay Source Ligand Conc. Kd Non Specific Incuba- Detection tion Method on on on on on on on -284- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Assay Source Ligand Conc. Kd Non Specific Incuba- Detection tion Method on on on on on on on on on on on on -285- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Assay Source Ligand Conc. Kd Non Specific Incuba- Detection tion Method on on on on on on on on on on on on -286- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Assay Source Ligand Conc. Kd Non Specific Incuba- Detection tion Method on on on on on on on on on on on -287- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Assay Source Ligand Conc. Kd Non Specific Incuba- Detection tion Method on on on on on on on on on on -288- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Assay Source Ligand Conc. Kd Non Specific Incuba- Detection tion Method on on on on on -289- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Assay Source Ligand Conc. Kd Non Specific Incuba- Detection tion Method on on on on on on on on -290- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Assay Source Ligand Conc. Kd Non Specific Incuba- Detection tion Method on on on on on Assay Source Substrate/ Incubation Measured Detection n -291- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Assay Source Substrate/ Incubation Measured Detection Stimulus/ Component Method n n y y n n y -292- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Assay Source Substrate/ Incubation Measured Detection Stimulus/ Component Method y y y [0180] The results demonstrate the highly selective binding of O10 on the melanocortin 1 and melanocortin 4 receptors. O10 had 97.4% binding inhibition of the control, and on MC4R, with 100.4% binding inhibition of the control. O10 also did not exhibit significant binding activity at any other receptor. Additional Embodiments [0181] Various embodiments of the present technology are set forth below in paragraphs [0182] to [0367]: [0182] 1. A method of reducing body weight and/or fat mass in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I): X1-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4 (I), wherein: -293- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1 is selected from the group consisting of Nle, Arg, dArg, aspartic acid (Asp), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2 is selected from the group consisting of Asp, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), Lys, ornithine (Orn), D-cysteine (dCys), Ala, D-alanine (dAla), proline (Pro), glutamic acid (Glu), and phenylalanine (Phe); R3 is absent or selected from the group consisting of His, dHis, Pro, Phe, asparagine Asn, and glutamine (Gln); R4 is selected from the group consisting of D-phenylalanine (dPhe), Pro, para- fluoro-D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5 is selected from the group consisting of Arg, His, cis-4-guanidyl-proline (cisPro(guan)), and trans-4-guanidyl-proline (transPro(guan)); R6 is selected from the group consisting of dPhe, tryptophan (Trp), and 2’-D- naphthylalanine (dNal(2’)); R7 is selected from the group consisting of Arg, Pro, ornithine (Orn), cysteine (Cys), Glu, Asp, and lysine (Lys); R8 is absent, Lys, or Trp; R9 is absent or Lys; Y1 is absent or selected from the group consisting of dArg, D-valine (dVal), D- proline (dPro), and D-tert-leucine (dTle); Y2 is absent or selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, 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 R2 and R7 when R2 is dCys, R4 is p(Cl)dPhe, and R7 is Cys; -294- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 a lactam bridge between R2 and R7 when R1 is Dap, Dab, Orn, or Lys, and R7 is Glu or Asp; a lactam bridge between R1 or R2 and any one of R7-R9 when R1 or R2 is Asp, R4 is dPhe, or p(F)dPhe, and any one of R7-R9 is Lys; and a lactam bridge between R2 and R7 when R2 is Asp or Glu and R7 is Orn, provided that: when R3 is Pro, then R4 is dPhe and either (i) X1 and Y3 are both present; or (ii) R2 is Lys and R7 is Glu; when R4 is p(Cl)dPhe, then R3 is His or Asn and the non-naturally occurring melanocortin analog is not cyclized through a lactam bond between Asp at R2 and Lys at R7, wherein when R3 is His, then R2 is not Dap and when R3 is Asn then either (i) R2 is Glu, R7 is Orn and R1 is Nle; or (ii) R2 is Lys and R7 is Asp; when R2 or R3 is Phe, then R4 is Pro and R6 is dPhe; when R3 is His and R1 is Glu or Asp, then R2 is Ala, dAla, or Pro, R5 is Arg, and Y1-Y2 is dVal-dPro, wherein when R2 is Ala, then R1 is Nle and when R2 is dAla; and when R3 is absent or Asn, then R1 is Arg, R2 is Lys or Dap, R4 is dPhe or p(F)dPhe, and R7 is Glu. [0183] 2. Use of a non-naturally occurring melanocortin analog for reducing body weight and/or fat mass in a subject in need thereof, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0184] 3. Use of a non-naturally occurring melanocortin analog for reducing body weight and/or fat mass in a subject in need thereof, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0185] 4. A method of reducing body weight and/or fat mass in an obese subject, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0186] 5. Use of a non-naturally occurring melanocortin analog for reducing body weight and/or fat mass in an obese subject, comprising administering a non- -295- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0187] 6. The method or the use of any one of embodiments 2-5, wherein the method or the use further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject. [0188] 7. The method or the use of embodiment 6, wherein the lean mass is lean muscle mass. [0189] 8. The method or the use of any one of embodiments 2-7, wherein the method or the use further comprises treating, preventing, or reducing glucose intolerance and/or diabetes mellitus in the subject. [0190] 9. A method of treating, preventing, or reducing hyperplasia in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0191] 10. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing hyperplasia in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I). [0192] 11. A method of treating, preventing, or reducing hypothalamic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0193] 12. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing hypothalamic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I). [0194] 13. The method or the use of embodiment 11 or 12, wherein the hypothalamic obesity comprises congenital hypothalamic damage, damage from tumors, or damage from trauma. [0195] 14. A method of treating, preventing, or reducing a proopiomelanocortin (POMC) deficiency in a subject in need thereof, comprising -296- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I). [0196] 15. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing a POMC deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I). [0197] 16. A method of treating, preventing, or reducing a leptin deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0198] 17. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing a leptin deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I). [0199] 18. A method of treating, preventing, or reducing a syndromic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0200] 19. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing a syndromic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I). [0201] 20. The method or the use of embodiment 18 or 19, wherein the syndromic obesity is selected from the group consisting of Prader–Willi syndrome, Wilms tumor, Aniridia, Genitourinary, Range of Developmental Delays (WAGR) syndrome, Bardet-Biedl syndrome, Fragile X syndrome, Cohen syndrome, Proprotein Convertase Subtilisin/Kexin Type 1 (PCSK1) deficiency, Alstrom syndrome, MC4 haploinsufficiency, 17p11.2 deletion syndrome, and 2q37 deletion syndrome. [0202] 21. A method of treating, preventing, or reducing non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering a non- -297- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0203] 22. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing NASH in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0204] 23. A method of treating, preventing, or reducing hyperinsulinism in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0205] 24. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing hyperinsulinism in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I). [0206] 25. A method of treating, preventing, or reducing a cardiovascular disease in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0207] 26. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing a cardiovascular disease in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0208] 27. The method or the use of embodiment 25 of 451, wherein the cardiovascular disease comprises a stroke or a heart attack. [0209] 28. A method of treating, preventing, or reducing osteoarthritis in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0210] 29. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing osteoarthritis in a subject in need thereof, comprising -298- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I). [0211] 30. A method of treating, preventing, or reducing a cancer in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0212] 31. Use of non-naturally occurring melanocortin analog for treating, preventing, or reducing a cancer in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0213] 32. The method or the use of embodiment 30 or 31, wherein the method or the use further comprises reducing a risk of the cancer. [0214] 33. A method of treating, preventing, or reducing erectile dysfunction in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0215] 34. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing erectile dysfunction in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I). [0216] 35. A method of treating, preventing, or reducing body weight gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0217] 36. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing body weight gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0218] 37. A method of maintaining body weight after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring -299- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0219] 38. Use of a non-naturally occurring melanocortin analog for maintaining body weight after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I). [0220] 39. A method of treating, preventing, or reducing fat mass gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0221] 40. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing fat mass gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0222] 41. A method of treating, preventing, or reducing glucose intolerance and/or diabetes mellitus in a subject in need thereof, comprising administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0223] 42. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing glucose intolerance and/or diabetes mellitus in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). [0224] 43. The method or the use of embodiment 41 or 42, wherein the method or the use further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject. [0225] 44. The method or the use of embodiment 43, wherein the lean mass is lean muscle mass. [0226] 45. The method or the use of any one of embodiments 1-44, wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); -300- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 R1 is selected from the group consisting of Nle, Arg, dArg, aspartic acid (Asp), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2 is selected from the group consisting of Asp, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), Lys, ornithine (Orn), D-cysteine (dCys), Ala, D-alanine (dAla), proline (Pro), glutamic acid (Glu), and phenylalanine (Phe); R3 is absent or selected from the group consisting of His, dHis, Pro, Phe, asparagine Asn, and glutamine (Gln); R4 is selected from the group consisting of D-phenylalanine (dPhe), Pro, para- fluoro-D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5 is selected from the group consisting of Arg, His, cis-4-guanidyl-proline (cisPro(guan)), and trans-4-guanidyl-proline (transPro(guan)); R6 is selected from the group consisting of dPhe, tryptophan (Trp), and 2’-D- naphthylalanine (dNal(2’)); R7 is selected from the group consisting of Arg, Pro, ornithine (Orn), cysteine (Cys), Glu, Asp, and lysine (Lys); R8 is absent, Lys, or Trp; R9 is absent or Lys; Y1 is absent or selected from the group consisting of dArg, D-valine (dVal), D- proline (dPro), and D-tert-leucine (dTle); Y2 is absent or selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, 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 R2 and R7 when R2 is dCys, R4 is p(Cl)dPhe, and R7 is Cys; a lactam bridge between R2 and R7 when R1 is Dap, Dab, Orn, or Lys, and R7 is Glu or Asp; -301- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 a lactam bridge between R1 or R2 and any one of R7-R9 when R1 or R2 is Asp, R4 is dPhe, or p(F)dPhe, and any one of R7-R9 is Lys; and a lactam bridge between R2 and R7 when R2 is Asp or Glu and R7 is Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 49); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 51); His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 52); dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 53); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 54); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 55); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 57); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c[dCys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 59); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 61); Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c[Asp-Phe-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 64); Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 66); Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 68) Ac-Nle-c[dCys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 70); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 71); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 73); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 74); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 75); -302- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 76); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 77); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 78); Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 79); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 80); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 81); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 82); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 83); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 84); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 85); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 86); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 87); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 88); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 89); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 90); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 91); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 92); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 93); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 104); Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 106); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 94); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 118); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 119); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 95); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 120); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 121); -303- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 122); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 123); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 107); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 108); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 109); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 110); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 111); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 112); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 113); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 114); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 115); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 116); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 117); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 96); Ac-Nle-c[Asp-Pro-dPhe-Arg-dTrp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 97); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 99); Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 124); Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 125); Ac-Nle-c[Dap-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 281); Ac-Nle-c[Dab-Pro-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 282); Ac-Nle-c[Lys-Pro-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 283); Ac-Nle-c[Lys-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 284); Ac-Nle-c[Orn-Pro-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 285); Ac-Nle-c[Orn-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 286); Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 287); Ac-Nle-c[Dap-Pro-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 288); -304- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-Nle-c[Dab-Pro-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 289); Ac-Nle-c[Lys-Pro-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 290); Ac-Nle-c[Orn-Pro-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 291); Ac-Nle-c[Orn-Pro-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 292); Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 293); Ac-dArg-c[Orn-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 294); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 100); Ac-Nle-c[Asp-Pro-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 103); Ac-Nle-c[Asp-Pro-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 98); Ac-Nle-c[Dap-Pro-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 295); Ac-Nle-c[Dab-Pro-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 296); Ac-Nle-c[Lys-Pro-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 297); Ac-Nle-c[Lys-Pro-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 298); Ac-Nle-c[Orn-Pro-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 299); Ac-Nle-c[Orn-Pro-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 300); Ac-Nle-c[Glu-Pro-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 301); Ac-Nle-c[Glu-Pro-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 105); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 271); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-NH2 (SEQ ID NO: 272); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 273); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 274); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 275); Ac-dArg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 131); Ac-Arg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 132); Ac-Lys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 133); Ac-dLys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 134); -305- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-His-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 135); Ac-dHis-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 136); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 126); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 127); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 128); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 141); Ac-dArg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 143); Ac-Arg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 144); Ac-Lys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 151); Ac-dLys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 145); Ac-His-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 152); Ac-dHis-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 146); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 302); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 303); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 139); Ac-Nle-c[Asp-Phe-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 149); Ac-Ala-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 130); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 137); Ac-Nle-c[Asp-His-p(Cl)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 138); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 140); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 129); Ac-Ala-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 142); Ac-Nle-c[Asp-dHis-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 148); Ac-Nle-c[Asp-Gln-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 150); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 147); -306- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-Nle-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 304); Ac-Nle-c[Dab-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 305); Ac-Nle-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 306); Ac-Nle-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 307); Ac-Nle-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 308); Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 309); Ac-Arg-c[Dap-Asn-p(Cl)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 310); Ac-Arg-c[Dab-Asn-p(Cl)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 311); Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 312); Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 313); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 314); Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 315); Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 316); Ac-Arg-c[Dab-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 317); Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 318); Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 319); Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 320); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 321); Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 322); Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 323); Ac-Nle-c[Dap-His-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 324); Ac-Nle-c[Dap-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 325); Ac-Nle-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 326); Ac-Nle-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 327); Ac-Arg-c[Dap-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 328); Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 157); -307- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 155); Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 154); Ac-Nle-c[Asp-Phe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 153); Ac-Nle-c[Asp-Phe-Phe-Pro-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 156); Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 276); Ac-Nle-c[Asp-Ala-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 277); Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 159); Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 160); Ac-Arg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 278); Ac-dArg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 279); Ac-Nle-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 280); Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 158); Ac-Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]-dArg-dVal-NH2 (SEQ ID NO: 329); Ac-Arg-c[Glu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 330); Ac-Nle-c[Glu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 331); Ac-Arg-c[Glu-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 332); Ac-Nle-c[Glu-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 333); Ac-Arg-c[Lys-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 334); Ac-Nle-c[Lys-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 335); Ac-Nle-c[Lys-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 336); Ac-Arg-c[Glu-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 337); Ac-Nle-c[Glu-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 338); Ac-Nle-c[Lys-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 339); and Ac-Arg-c[Lys-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 340), wherein c represents cyclization via a lactam or disulfide bond. -308- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0227] 46. The method or the use of any one of embodiments 1-45, wherein the sequence of Formula (I) is a sequence of Formula (IA): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4 (IA), wherein: X1 is absent or is selected from the group consisting of Nle, Arg, and dArg; R1 is selected from the group consisting of Nle, Arg, dArg, Asp, Ala, Lys, dLys, His, and dHis; R2 is selected from the group consisting of Asp, Ala, dAla, Dab, Dap, Lys, Orn, Pro, and Glu R3 is absent or selected from the group consisting of His, dHis, Asn, Pro, and Gln; R4 is dPhe or p(F)dPhe; R5 is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6 is Trp or dNal(2’); R7 is selected from the group consisting of Pro, Orn, Glu, Asp, and Lys; R8 is absent or Lys; Y1 is absent or selected from the group consisting of dArg, dVal, dPro, and dTle; Y2 is absent or selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, 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 lactam bridge between R2 and R7 when R2 is Dap, Dab, Orn, or Lys, and R7 is Glu or Asp; a lactam bridge between R1 or R2 and R7 or R8 when R1 or R2 is Asp and R7 or R8 is Lys; and a lactam bridge between R2 and R7 when R2 is Asp or Glu and R7 is Orn. -309- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0228] 47. The method or the use of any one of embodiments 1-46, wherein the sequence of Formula (I) is a sequence of Formula (IA(i)): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4 (IA(i)), wherein: X1 is absent or Nle; R1 is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; R2 is selected from the group consisting of Dab, Dap, Lys, Orn, Asp and Glu; R3 is absent or selected from the group consisting of His, dHis, Pro, and Gln; R4 is dPhe or p(F)dPhe; R5 is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6 is Trp or dNal(2’); R7 is selected from the group consisting of Orn, Glu, Asp, and Lys; Y1 is absent or selected from the group consisting of dArg, dVal, dPro, and dTle; Y2 is absent or selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, dVal, or dPro; Y4 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Asp or Glu at R2 and Orn or Lys at R7; or a lactam bridge between Dap, Dab, Orn, or Lys at R2, and Glu or Asp at R7. [0229] 48. The method or the use of any one of embodiments 1-45, wherein the sequence of Formula (I) is a sequence of Formula (IB): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4 (IB), wherein: X1 is absent or Nle; -310- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 R1 is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; R2 is selected from the group consisting of Asp, Dap, Dab, Lys, Orn, and Glu; R3 is His; R4 is p(F)dPhe; R5 is Arg; R6 is Trp; R7 is selected from the group consisting of Orn, Glu, Asp, and Lys; Y1 is selected from the group consisting of dVal, dPro, and dTle; Y2 is selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, dVal, or dPro; Y4 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Asp or Glu at R2 and Orn or Lys at R7; or a lactam bridge between Dap, Dab, Orn, or Lys at R2, and Glu or Asp at R7. [0230] 49. The method or the use of any one of embodiments 1-45, wherein the sequence of Formula (I) is a sequence of Formula (IC): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3 (IC), wherein: X1 is absent or norleucine (Nle); R1 is Nle or Asp; R2 is selected from the group consisting of Asp, Dap, Dab, Lys, Orn, Glu, and Pro; R3 is selected from the group consisting of His, dHis, Pro, and Gln; R4 is dPhe; -311- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 R5 is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6 is Trp; R7 is selected from the group consisting of Orn, Glu, Asp, Orn, Lys, and Pro; R8 is absent or Lys; Y1 is dVal or dPro; Y2 is dVal or dPro; Y3 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R1 or R2 and R7 or R8 when R1 or R2 is Asp and R7 or R8 is Lys; a lactam bridge between R2 and R7 when R2 is Dap, Dab, Orn, or Lys, and R7 is Glu or Asp; and a lactam bridge between R2 and R7 when R2 is Asp or Glu and R7 is Orn. [0231] 50. The method or the use of any one of embodiments 1-45, wherein the sequence of Formula (I) is a sequence of Formula (ID): R1-R2-R3-R4-R5-R6-R7-Y1-Y2 (ID), wherein: R1 is selected from Nle, Arg, and dArg; R2 is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3 is absent or selected from the group consisting of Pro, Asn, and His; R4 is selected from dPhe, p(F)dPhe, and p(Cl)dPhe; R5 is Arg; R6 is Trp; R7 is selected from the group consisting of Glu, Asp, Lys, and Orn; Y1 is absent, dVal, or dArg; -312- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Y2 is absent, dPro, or dVal; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between Glu or Asp at R2 and Orn at R7; a lactam bridge between Glu at R2 and Lys at R7; a lactam bridge between Asp at R2, Asn at R3, and Lys at R7; and a lactam bridge between Dap, Dab, Orn, or Lys at R2 and Glu or Asp at R7. [0232] 51. The method or the use of any one of embodiments 1-45, wherein the sequence of Formula (I) is a sequence of Formula (IE): R1-R2-R3-R4-R5-R6-R7-Y1-Y2 (IE), wherein: R1 is Nle or Arg; R2 is selected from the group consisting of Dab, Lys, Orn, and Glu; R3 is Asn or His; R4 is p(Cl)dPhe; R5 is Arg; R6 is Trp; R7 is selected from the group consisting of Glu, Asp, Lys, and Orn; Y1 is absent or dVal; Y2 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Glu at R2 and Orn or Lys at R7; or a lactam bridge between Dab, Orn, or Lys at R2 and Glu or Asp at R7 [0233] 52. The method or the use of any one of embodiments 1-45, wherein the sequence of Formula (I) is a sequence of Formula (IF): R1-R2-R3-R4-R5-R6-R7-Y1-Y2 (IF), -313- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 wherein: R1 is selected from Nle, Arg, and dArg; R2 is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3 is absent, Asn, or His; R4 is p(F)dPhe; R5 is Arg; R6 is Trp; R7 is selected from the group consisting of Glu, Asp, Lys, and Orn; Y1 is absent or dVal; Y2 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between Glu or Asp at R2 and Orn at R7; a lactam bridge between Glu at R2 and Lys at R7; a lactam bridge between Asp at R2, Asn at R3, and Lys at R7; and a lactam bridge between Dap, Dab, Orn, or Lys at R2 and Glu or Asp at R7. [0234] 53. The method or the use of any one of embodiments 1-45, wherein the sequence of Formula (I) is a sequence of Formula (IG): R1-R2-R3-R4-R5-R6-R7-Y1-Y2 (IG), wherein: R1 is Nle or Arg; R2 is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3 is selected from the group consisting of Pro, Asn, and His; R4 is dPhe; R5 is Arg; R6 is Trp; -314- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 R7 is selected from the group consisting of Glu, Asp, Lys, and Orn; Y1 is absent, dVal, or dArg; Y2 is absent, dPro, or dVal; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between Glu or Asp at R2 and Orn at R7; a lactam bridge between Glu at R2 and Lys at R7; a lactam bridge between Asp at R2, Asn at R3, and Lys at R7; and a lactam bridge between Dap, Dab, Orn, or Lys at R2 and Glu or Asp at R7. [0235] 54. The method or the use of any one of embodiments 1-53, wherein the N-terminus is modified by an acyl group. [0236] 55. The method or the use of embodiment 54, wherein the acyl group is acetyl group. [0237] 56. The method or the use of any one of embodiments 1-55, wherein the N-terminus is modified by an amide group. [0238] 57. The method or the use of any one of embodiments 1-56, wherein R3 is His. [0239] 58. The method or the use of any one of embodiments 1-57, wherein the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R2 and Lys at R7. [0240] 59. The method or the use of any one of embodiments 1-58, wherein R4 is p(F)dPhe or dPhe. [0241] 60. The method or the use of any one of embodiments 1-59, wherein R1 is selected from Nle, Ala, Arg, dArg, Lys, dLys, His, and dHis and R4 is p(F)dPhe. [0242] 61. The method or the use of any one of embodiments 1-60, wherein Y1 is dVal and Y2 is dPro. -315- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0243] 62. The method or the use of any one of embodiments 1-61, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 3); Ac—dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 4); Ac—Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 14); Ac—Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 15); Ac—Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 16); Ac—dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 17); Ac—His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 18); and Ac—dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 19), wherein c represents cyclization through R2 and R7 via a lactam bond. [0244] 63. The method or the use of any one of embodiments 1-60, wherein Y1 is dTle and Y2 is dPro. [0245] 64. The method or the use of any one of embodiments 1-60 and 63, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 7); Ac—dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 8); Ac—Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 24); Ac—Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 27); Ac—Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 28); Ac—dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 29); Ac—His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 30); and Ac—dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 31), wherein c represents cyclization through R2 and R7 via a lactam bond. -316- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0246] 65. The method or the use of any one of 1-56, wherein R1 is Nle and R4 is dPhe. [0247] 66. The method or the use of embodiment any one of embodiments 1- 59 and 65, wherein the sequence according to any one of Formulae (I)-(IG) is: Ac—Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal—NH2 (SEQ ID NO: 33); or Ac—Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 42), wherein c represents cyclization through R2 and R7 via a lactam bond. [0248] 67. The method or the use of any one of embodiments 1-59, wherein R1 is Nle and R4 is p(F)dPhe. [0249] 68. The method or the use of embodiment any one of embodiments 1- 59 and 67, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal—NH2 (SEQ ID NO: 6); Ac—Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 20); Ac—Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro—NH2 (SEQ ID NO: 22); Ac—Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro—NH2 (SEQ ID NO: 23); Ac—Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 25); and Ac—Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro—NH2 (SEQ ID NO: 26), wherein c represents cyclization through R2 and R7 via a lactam bond. [0250] 69. The method or the use of any one of embodiments 1-59, wherein R1 is Nle and R4 is dPhe or p(F)dPhe. [0251] 70. The method or the use of embodiment any one of embodiments 1- 59 and 69, wherein R5 is Arg, transPro(guan), or cisPro(guan). [0252] 71. The method or the use of embodiment any one of embodiments 1- 59, 69, and 70, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: -317- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac—Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 21); Ac—Nle-c[Asp-His-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 46); and Ac—Nle-c[Asp-His-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 47), wherein c represents cyclization through R2 and R7 via a lactam bond. [0253] 72. The method or the use of any one of embodiments 1-59, wherein R6 is dNal(2’). [0254] 73. The method or the use of embodiment any one of embodiments 1- 59 and 72, wherein the sequence according to any one of Formulae (I)-(IG) is: Ac—Nle- c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro—NH2 (SEQ ID NO: 5), wherein c represents cyclization through R2 and R7 via a lactam bond. [0255] 74. The method or the use of any one of embodiments 1-59, wherein the non-naturally occurring melanocortin analog is cyclized through R2 and R7 via a bond other than a lactam bond between Asp at and Lys. [0256] 75. The method or the use of any one of embodiments 1-59 and 74, wherein the sequence of any one of Formulae (I)-(IG) is cyclized through a lactam bond between Asp or Glu at R2 and Orn at R7 or Glu at R2 and Lys at R7. [0257] 76. The method or the use of embodiment any one of embodiments 1- 59, 74, and 75, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 43); Ac—Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 44); Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac—Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 11); Ac—Nle-c[Glu-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 12); Ac—Nle-c[Asp-His-dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 201); Ac—Nle-c[Glu-His-dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 203); Ac—Nle-c[Glu-His-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 202); -318- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac—Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 183); and Ac—Nle-c[Glu-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 252), wherein c represents cyclization through R2 and R7 via a lactam bond. [0258] 77. The method or the use of any one of embodiments 1-59 and 74, wherein the sequence of any one of Formulae (I)-(IG) is cyclized through a lactam bond between Dap, Dab, Orn, or Lys at R2 and Asp or Glu at R7. [0259] 78. The method or the use of embodiment any one of embodiments 1- 59, 74, and 77, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Nle-c[Dap-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 172); Ac—Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 173); Ac—Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 174); Ac—Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 175); Ac—Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 176); Ac—Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 177); Ac—Nle-c[Lys-His-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 188); Ac—Nle-c[Lys-His-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 189); Ac—Nle-c[Dap-His-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 190); Ac—Nle-c[Dab-His-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 191); Ac—Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 192); Ac—Nle-c[Lys-His-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 193); Ac—Nle-c[Orn-His-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 194); Ac—Nle-c[Orn-His-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 195); Ac—Arg-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 242); Ac—Arg-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 243); Ac—Arg-c[Orn-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 244); Ac—dArg-c[Orn-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 245); -319- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac—dArg-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 246); Ac—Nle-c[Dab-His-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 248); Ac—Nle-c[Orn-His-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 249); and Ac—Nle-c[Orn-His-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 250), wherein c represents cyclization through R2 and R7 via a lactam bond. [0260] 79. The method or the use of any one of embodiments 1-59 and 74, wherein the sequence of any one of Formulae (I)-(IG) is cyclized through a lactam bond between dCys at R2 and Cys at R7. [0261] 80. The method or the use of embodiment any one of embodiments 1- 59, 74, and 79, wherein the sequence according to any one of Formulae (I)-(IG) is: Ac— Nle-c[dCys-His-p(Cl)dPhe-Arg-Trp-Cys]-dVal-dPro—NH2 (SEQ ID NO: 5), wherein c represents cyclization through R2 and R7 via a disulfide bond. [0262] 81. The method or the use of any one of embodiments 1-59 and 74, wherein the sequence of any one of Formulae (I)-(IG) is cyclized through a lactam bond between Asp at R2 and Lys at R8. [0263] 82. The method or the use of embodiment any one of embodiments 1- 59, 74, and 81, wherein the sequence according to any one of Formulae (I)-(IG) is: Ac— Nle-c[Asp-His-dPhe-Arg-Trp-Pro-Lys]-dVal-dPro—NH2 (SEQ ID NO: 35), wherein c represents cyclization through R2 and R8 via a lactam bond. [0264] 83. The method or the use of any one of embodiments 1-59 and 74, wherein the sequence of any one of Formulae (I)-(IG) is cyclized through a lactam bond between Asp at R1 and Lys at R7. [0265] 84. The method or the use of embodiment any one of embodiments 1- 59, 74, and 83, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 38); Ac—Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 39); Ac—dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 40); and Ac—Nle-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 41), -320- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 wherein c represents cyclization through R1 and R7 via a lactam bond. [0266] 85. The method or the use of embodiment any one of embodiments 1- 59, 74, and 83, wherein the sequence according to any one of Formulae (I)-(IG) is: Ac- Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 13), wherein c represents cyclization through R1 and R7 via a lactam bond. [0267] 86. The method or the use of any one of embodiments 1-56, wherein R3 is Asn. [0268] 87. The method or the use of any one of embodiments 1-56 and 86, wherein the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp or Glu at R2 and Lys or Orn at R7. [0269] 88. The method or the use of any one of embodiments 1-56, 86, and 87, wherein Y1 is dVal and Y2 is dPro. [0270] 89. The method or the use of any one of embodiments 1-56 and 86- 88, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Nle-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 184); Ac—Nle-c[Asp-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 185); Ac—Nle-c[Glu-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 186); Ac—Nle-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 187); Ac—Nle-c[Asp-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 204); Ac—Nle-c[Glu-Asn-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 205); Ac—Nle-c[Glu-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 206); Ac—Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 231); Ac—Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 232); Ac—Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 233); Ac—Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 234); Ac—Arg-c[Glu-Asn-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 240); Ac—Arg-c[Glu-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 241); -321- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac—Nle-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 253); and Ac—Arg-c[Asp-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 261), wherein c represents cyclization through R2 and R7 via a lactam bond. [0271] 90. The method or the use of any one of embodiments 1-56, 86, and 87, wherein Y1-Y4 are absent. [0272] 91. The method or the use of any one of embodiments 1-56, 86, 87, and 90, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]—NH2 (SEQ ID NO: 213); Ac—Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Orn]—NH2 (SEQ ID NO: 214); Ac—Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Lys]—NH2 (SEQ ID NO: 215); Ac—Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]—NH2 (SEQ ID NO: 216); Ac—Arg-c[Asp-Asn-dPhe-Arg-Trp-Lys]—NH2 (SEQ ID NO: 223); Ac—Arg-c[Asp-Asn-dPhe-Arg-Trp-Orn]—NH2 (SEQ ID NO: 224); Ac—Arg-c[Glu-Asn-dPhe-Arg-Trp-Lys]—NH2 (SEQ ID NO: 225); and Ac—Arg-c[Glu-Asn-dPhe-Arg-Trp-Orn]—NH2 (SEQ ID NO: 226), wherein c represents cyclization through R2 and R7 via a lactam bond. [0273] 92. The method or the use of any one of embodiments 1-56 and 86, wherein the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Dap, Dab, Lys, or Orn at R2 and Asp or Glu at R7. [0274] 93. The method or the use of any one of embodiments 1-56, 86, and 92, wherein Y1 is dVal and Y2 is dPro. [0275] 94. The method or the use of any one of embodiments 1-56, 86, 892, and 93, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Nle-c[Dab-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 178); Ac—Nle-c[Lys-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 179); Ac—Nle-c[Lys-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 180); -322- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac—Nle-c[Orn-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 181); Ac—Nle-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 182); Ac—Nle-c[Dab-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 196); Ac—Nle-c[Lys-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 197); Ac—Nle-c[Lys-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 198); Ac—Nle-c[Orn-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 199); Ac—Nle-c[Orn-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 200); Ac—Arg-c[Dab-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 227); Ac—Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 228); Ac—Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 229); Ac—Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 230); Ac—Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 235); Ac—Arg-c[Lys-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 236); Ac—Arg-c[Lys-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 237); Ac—Arg-c[Orn-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 238); Ac—Arg-c[Orn-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 239); Ac—Nle-c[Dap-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 247); Ac—Nle-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 251); Ac—Nle-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 255); Ac—Arg-c[Dap-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 257); Ac—Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 258); Ac—Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 259); Ac—Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 260); and Ac—Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dArg-dVal—NH2 (SEQ ID NO: 262), wherein c represents cyclization through R2 and R7 via a lactam bond. -323- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0276] 95. The method or the use of any one of embodiments 1-56, 86, and 92, wherein Y1-Y4 are absent. [0277] 96. The method or the use of any one of embodiments 1-56, 86, 92, and 95, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 207); Ac—Arg-c[Dap-Asn-p(F)dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 208); Ac—Arg-c[Dab-Asn-p(F)dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 209); Ac—Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 210); Ac—Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 211); Ac—Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 212); Ac—Arg-c[Orn-Asn-dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 217); Ac—Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 218); Ac—Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 219); Ac—Arg-c[Lys-Asn-dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 220); Ac—Arg-c[Lys-Asn-dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 221); Ac—Arg-c[Orn-Asn-dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 222); and Ac—Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 256), wherein c represents cyclization through R2 and R7 via a lactam bond. [0278] 97. The method or the use of embodiment any one of embodiments 1- 56, wherein R3 is absent or selected from dHis, Gln and Pro and R4 is dPhe or p(F)dPhe. [0279] 98. The method or the use of embodiment any one of embodiments 1- 56 and 97, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 9); Ac—Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro—NH2 (SEQ ID NO: 10); Ac—Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 32); -324- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac—Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 36); Ac—Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 37); Ac—Nle-c[Lys-Pro-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 254); and Ac—Arg-c[Lys-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 263), wherein c represents cyclization through R2 and R7 via a lactam bond. [0280] 99. The method or the use of any one of embodiments 1-56, wherein the sequence according to any one of Formulae (I)-(IG) is: Ac-Nle-c[Asp-Phe-Phe-Pro- His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 34), wherein c represents cyclization through R1 and R9 via a lactam bond. [0281] 100. The method or the use of any one of embodiments 1-99, wherein the non-naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 2-47 and 172-263. [0282] 101. The method or the use of any one of embodiments 1-100, wherein the non-naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 3-10, 14-33, 35-47, 172-187, 190-247, 254, 255, 257, 258, and 260-263. [0283] 102. The method or the use of any one of embodiments 1-100, wherein the non-naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 3-10, 14-33, 36, 37, 42-47, 172-187, 190-247, 254, 255, 257, 258, and 260-263. [0284] 103. The method or the use of any one of embodiments 1-100, wherein the non-naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 3-8, 14-31, 43, 44, 172-187, 207-216, 227-234, 242-247, 257, 258, and 263. [0285] 104. The method or the use of any one of embodiments 1-100, wherein the non-naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 10, 13, 33, 35-37, 42, 45-47, 190-206, 217-226, 235-241, 254, 255, and 260-262. [0286] 105. The method or the use of any one of embodiments 1-100, wherein the non-naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 172-263. -325- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0287] 106. The method or the use of any one of embodiments 1-100, wherein the non-naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 188, 189, 248-250, 252, 253, 256, and 259. [0288] 107. The method or the use of any one of embodiments 1-100, wherein the non-naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 172-187, 207-216, 227-234, 242-247, 257, 258, and 263. [0289] 108. The method or the use of any one of embodiments 1-100, wherein the non-naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 190-206, 217-226, 235-241, 254, 255, and 260-262. [0290] 109. The method or the use of any one of embodiments 1-98, wherein the non-naturally occurring melanocortin analog is a first non-naturally occurring melanocortin analog, and the method further comprises administering a second non- naturally occurring melanocortin analog selected from the group consisting of MC4- NN2-0453, LY2112688, Melanotan-II, Afamelanotide, Bremelanotide, AZD2820, MK- 0493, PF-00446687, setmelanotide, RM-718, and LB54640. [0291] 110. The method or the use of embodiment 109, wherein the first non- naturally occurring melanocortin analog is administered before the second non-naturally occurring melanocortin analog. [0292] 111. The method or the use of embodiment 109, wherein the first non- naturally occurring melanocortin analog is administered after the second non-naturally occurring melanocortin analog. [0293] 112. The method or the use of embodiment 109, wherein the first non- naturally occurring melanocortin analog and the second non-naturally occurring melanocortin analog are administered simultaneously. [0294] 113. The method or the use of any one of embodiments 109-112, wherein the first non-naturally occurring melanocortin analog and the second non- naturally occurring melanocortin analog are present in a single pharmaceutical composition. [0295] 114. The method or the use of any one of embodiments 109-112, wherein the first non-naturally occurring melanocortin analog is present in a first -326- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 pharmaceutical composition and the second non-naturally occurring melanocortin analog is present in a second pharmaceutical composition. [0296] 115. The method or the use of any one of embodiments 109-114, wherein the non-naturally occurring melanocortin analog is selected from the group consisting of MC4-NN2-0453, LY2112688, Melanotan-II, Afamelanotide, Bremelanotide, AZD2820, MK-0493, PF-00446687, setmelanotide, RM-718, and LB54640. [0297] 116. The method or the use of any one of embodiments 109-115, wherein the MC4-NN2-0453 is administered at a dose of about 0.03, 0.06, 0.15, 0.30, 0.60, 1.00, or 1.50 mg/kg. [0298] 117. The method or the use of any one of embodiments 109-116, wherein the MC4-NN2-0453 is administered at one or more doses of about 0.75, 1.5, 3.0, or 5.0 mg/day. [0299] 118. The method or the use of any one of embodiments 109-116, wherein the LY2112688 is administered at one or more doses of about 0.45 mg or 1.0 mg. [0300] 119. The method or the use of any one of embodiments 109-116, wherein the LY2112688 is administered at a dose of about 0.5 mg/kg/day. [0301] 120. The method or the use of any one of embodiments 109-116, wherein the Melanotan-II is administered at a dose of about 0.01 mg/kg. [0302] 121. The method or the use of embodiment 120, wherein the dose is escalated by 0.005 mg/kg increments to a 0.03 mg/kg dose or to a 0.025 mg/kg dose. [0303] 122. The method or the use of any one of embodiments 109-116, wherein the Melanotan-II is administered at a dose of about 0.025 mg/kg, or about 0.03 mg/kg. [0304] 123. The method or the use of any one of embodiments 109-116, wherein the Afamelanotide is administered at a one or more doses of about 0.08 mg/kg to about 0.21 mg/kg. [0305] 124. The method or the use of any one of embodiments 109-116, wherein the Afamelanotide is administered at a one or more doses of about 16 mg. -327- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0306] 125. The method or the use of embodiment 124, wherein the Afamelanotide is administered using a subcutaneous implant. [0307] 126. The method or the use of any one of embodiments 109-116, wherein the Bremelanotide is administered at a dose of about 1.75 mg, 4.0 mg, or 6.0 mg. [0308] 127. The method or the use of any one of embodiments 109-116, wherein the Bremelanotide is administered at a dose of at least about 7.0 mg or at least about 10 mg. [0309] 128. The method or the use of embodiment 127, wherein the Bremelanotide is administered intranasally. [0310] 129. The method or the use of any one of embodiments 109-116, wherein the MK-0493 is administered at a dose of about 10 mg or about 30 mg. [0311] 130. The method of any one of embodiments 109-116, wherein the MK- 0493 is administered at a dose of about 1 mg/kg to about 4 mg//kg. [0312] 131. The method or the use of any one of embodiments 109-116, wherein the MK-0493 is administered at a dose of about 2 mg/kg, about 6 mg/kg, or about 20 mg/kg. [0313] 132. The method or the use of any one of embodiments 109-116, wherein the PF-00446687 is administered at one or more doses of about 200 mg, 175 mg, 125 mg, 100 mg, or 20 mg. [0314] 133. The method or the use of any one of embodiments 109-116, wherein the setmelanotide is administered at one or more doses of about 0.5 mg, 1.0 mg, 2.0 mg, or 3.0 mg. [0315] 134. The method or the use of embodiment 133, wherein the setmelanotide is administered at two or more doses. [0316] 135. The method or the use of embodiment 134, wherein a second dose of the two or more doses is greater than a first dose of the two or more doses. [0317] 136. The method or the use of any one of embodiments 133-135, wherein the setmelanotide is administered daily. -328- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0318] 137. The method or the use of any one of embodiments 1-115, wherein the 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. [0319] 138. The method or the use of embodiment 137, wherein 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. [0320] 139. The method or the use of any one of embodiments 1-138, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily. [0321] 140. The method or the use of any one of embodiments 1-139, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily. [0322] 141. The method or the use of any one of embodiments 1-140, wherein the concentration of the non-naturally occurring melanocortin analog in the plasma or a tissue of the subject is at least about 5 ng/mL to at least about 2000 ng/mL about 24 hours after administration of the non-naturally occurring melanocortin analog. [0323] 142. The method or the use of any one of embodiments 1-141, wherein the non-naturally occurring melanocortin analog is administered to the subject until the concentration of the non-naturally occurring melanocortin analog in the plasma or a tissue of the subject is at least about 5 ng/mL to at least about 2000 ng/mL after administration of the non-naturally occurring melanocortin analog. [0324] 143. The method or the use of embodiment 141 or 142, wherein concentration is at least about 5 ng/mL after administration of the non-naturally occurring melanocortin analog. [0325] 144. The method or the use of embodiment 141 or 142, wherein concentration is at least about 10 ng/mL after administration of the non-naturally occurring melanocortin analog. [0326] 145. The method or the use of embodiment 141 or 142, wherein concentration is at least about 50 ng/mL after administration of the non-naturally occurring melanocortin analog. -329- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0327] 146. The method or the use of embodiment 141 or 142, wherein concentration is at least about 100 ng/mL after administration of the non-naturally occurring melanocortin analog. [0328] 147. The method or the use of embodiment 141 or 142, wherein concentration is at least about 200 ng/mL after administration of the non-naturally occurring melanocortin analog. [0329] 148. The method or the use of embodiment 141 or 142, wherein concentration is at least about 300 ng/mL after administration of the non-naturally occurring melanocortin analog. [0330] 149. The method or the use of embodiment 141 or 142, wherein concentration is at least about 400 ng/mL after administration of the non-naturally occurring melanocortin analog. [0331] 150. The method or the use of embodiment 141 or 142, wherein concentration is at least about 500 ng/mL after administration of the non-naturally occurring melanocortin analog. [0332] 151. The method or the use of embodiment 141 or 142, wherein concentration is at least about 750 ng/mL after administration of the non-naturally occurring melanocortin analog. [0333] 152. The method or the use of embodiment 141 or 142, wherein concentration is at least about 1000 ng/mL after administration of the non-naturally occurring melanocortin analog. [0334] 153. The method or the use of embodiment 141 or 142, wherein concentration is at least about 1500 ng/mL after administration of the non-naturally occurring melanocortin analog. [0335] 154. The method or the use of embodiment 141 or 142, wherein concentration is at least about 2000 ng/mL after administration of the non-naturally occurring melanocortin analog. [0336] 155. The method or the use of any one of embodiments 141-154, wherein the concentration is a maximum concentration (Cmax). -330- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0337] 156. The method or the use of any one of embodiments 22-155, wherein the non-naturally occurring melanocortin analog is administered as a single dosage unit. [0338] 157. The method or the use of any one of embodiments 1-155, wherein the non-naturally occurring melanocortin analog dose is administered as multiple dosage units. [0339] 158. The method or the use of embodiment 157, wherein the multiple dosage units individually comprise about 2.5 mg/mL to about 100 mg/mL of the non- naturally occurring melanocortin analog. [0340] 159. The method or the use of embodiment 158, wherein the multiple dosage units individually comprise about 2.5 mg/mL to about 10 mg/mL of the non- naturally occurring melanocortin analog. [0341] 160. The method or the use of embodiment 157, wherein the multiple dosage units individually comprise about 6 mg/mL of the non-naturally occurring melanocortin analog. [0342] 161. The method or the use of embodiment 157, wherein the non- naturally occurring melanocortin analog is administered as about 5 dosage units to about 10 dosage units. [0343] 162. The method or the use of embodiment 157, wherein the non- naturally occurring melanocortin analog is administered as 5 dosage units. [0344] 163. The method or the use of embodiment 157, wherein the non- naturally occurring melanocortin analog is administered as 10 dosage units. [0345] 164. The method or the use of any one of embodiments 1-163, wherein the dosage unit is a capsule. [0346] 165. The method or the use of embodiment 164, wherein the capsule comprises the non-naturally occurring melanocortin analog suspended in a saline solution. [0347] 166. The method or the use of embodiment 165, wherein the saline solution is about 100% saline. [0348] 167. The method or the use of embodiment 165, wherein the saline solution is about 95% saline. -331- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0349] 168. The method or the use of embodiment 165, wherein the saline solution is about 90% saline. [0350] 169. The method or the use of embodiment 167 or 168, wherein the saline solution comprises dimethyl sulfoxide (DMSO). [0351] 170. The method of the use of any one of embodiments 1-169, wherein the subject has an addiction or is susceptible to an addiction. [0352] 171. The method or the use of any one of embodiments 1-170, wherein the subject has used or is using one or more addictive substances. [0353] 172. The method or the use of any one of embodiments 1-171, wherein the subject has pain or is susceptible to pain. [0354] 173. The method or the use of any one of embodiments 1-172, wherein the subject has used or is using a medication to treat an addiction. [0355] 174. The method or the use of embodiment 173, wherein the medication is a rescue medication. [0356] 175. The method or the use of any one of embodiments 171 or 173, wherein a frequency or an amount of the addictive substance or a rescue medication is reduced during or after administration of the non-naturally occurring melanocortin analog. [0357] 176. The method or the use of embodiment 174 or 175, wherein the rescue medication is selected from the group consisting of an opioid agonist, an opioid antagonist, and a non-opioid medication. [0358] 177. The method or the use of embodiment 171, 173, or 175, wherein the addictive substance is selected from the group consisting of a prescription medication, a substance in an over-the-counter medication, a recreational substance, or an illegal substance. [0359] 178. The method or the use of embodiment 177, wherein the addictive substance is selected from the group consisting of an opioid, a painkillers, a stimulant, a narcotic, alcohol, a barbiturate, sedatives, marijuana, cannabis, tetrahydrocannabinol (THC), cannabidiol (CBD), or an inhalant. -332- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 [0360] 179. The method or the use of embodiment 178, wherein the opioid is selected from the group consisting of morphine, heroin, codeine, oxycodone, hydrocodone, and fentanyl. [0361] 180. The method or the use of embodiment 178, wherein the stimulant is selected from the group consisting of caffeine, nicotine, methamphetamine, cocaine, and amphetamine. [0362] 181. The method or the use of embodiment 178, wherein the barbiturate is selected from the group consisting of phenobarbital, methohexital, butalbital, pentobarbital, primidone, and amobarbital. [0363] 182. The method or the use of embodiment 178, wherein the sedative is selected from the group consisting of a tranquilizer, xylazine, eszopiclone, zaleplon, zolpidem, and zopiclone. [0364] 183. The method or the use of embodiment 178, wherein the inhalant is selected from the group consisting of an aerosol, a butane, freon, helium, nitrous oxide, propane, and a nitrite. [0365] 184. The method or the use of embodiment 180, wherein the nicotine comprises nicotine in a tobacco chew, a nicotine pouch, or a smoking device. [0366] 185. The method or the use of embodiment 184, wherein the smoking device is selected from the group consisting of cigarettes, electronic cigarettes, cigars, and vape products. [0367] 186. The method or the use of any one of embodiments 1-185, wherein the subject has or had an opioid use disorder or an alcohol use disorder. [0368] From the foregoing, it will be appreciated that specific embodiments of the present technology have been described herein for purposes of illustration, but that various modifications may be made without deviating from the scope of the present technology. Accordingly, the present technology is not limited except as by the appended claims. -333- 146316.8034.WO00\181226204.17

Claims

Docket No.: 146316.8034.WO00 CLAIMS I/We claim: 1. A method of reducing body weight and/or fat mass in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I): X1-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4 (I), wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1 is selected from the group consisting of Nle, Arg, dArg, aspartic acid (Asp), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2 is selected from the group consisting of Asp, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), Lys, ornithine (Orn), D-cysteine (dCys), Ala, D-alanine (dAla), proline (Pro), glutamic acid (Glu), and phenylalanine (Phe); R3 is absent or selected from the group consisting of His, dHis, Pro, Phe, asparagine Asn, and glutamine (Gln); R4 is selected from the group consisting of D-phenylalanine (dPhe), Pro, para- fluoro-D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5 is selected from the group consisting of Arg, His, cis-4-guanidyl-proline (cisPro(guan)), and trans-4-guanidyl-proline (transPro(guan)); R6 is selected from the group consisting of dPhe, tryptophan (Trp), and 2’-D- naphthylalanine (dNal(2’)); R7 is selected from the group consisting of Arg, Pro, ornithine (Orn), cysteine (Cys), Glu, Asp, and lysine (Lys); R8 is absent, Lys, or Trp; R9 is absent or Lys; -334- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Y1 is absent or selected from the group consisting of dArg, D-valine (dVal), D- proline (dPro), and D-tert-leucine (dTle); Y2 is absent or selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, 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 R2 and R7 when R2 is dCys, R4 is p(Cl)dPhe, and R7 is Cys; a lactam bridge between R2 and R7 when R1 is Dap, Dab, Orn, or Lys, and R7 is Glu or Asp; a lactam bridge between R1 or R2 and any one of R7-R9 when R1 or R2 is Asp, R4 is dPhe, or p(F)dPhe, and any one of R7-R9 is Lys; and a lactam bridge between R2 and R7 when R2 is Asp or Glu and R7 is Orn, provided that: when R3 is Pro, then R4 is dPhe and either (i) X1 and Y3 are both present; or (ii) R2 is Lys and R7 is Glu; when R4 is p(Cl)dPhe, then R3 is His or Asn and the non-naturally occurring melanocortin analog is not cyclized through a lactam bond between Asp at R2 and Lys at R7, wherein when R3 is His, then R2 is not Dap and when R3 is Asn then either (i) R2 is Glu, R7 is Orn and R1 is Nle; or (ii) R2 is Lys and R7 is Asp; when R2 or R3 is Phe, then R4 is Pro and R6 is dPhe; when R3 is His and R1 is Glu or Asp, then R2 is Ala, dAla, or Pro, R5 is Arg, and Y1-Y2 is dVal-dPro, wherein when R2 is Ala, then R1 is Nle and when R2 is dAla; and when R3 is absent or Asn, then R1 is Arg, R2 is Lys or Dap, R4 is dPhe or p(F)dPhe, and R7 is Glu. 2. Use of a non-naturally occurring melanocortin analog for reducing body weight and/or fat mass in a subject in need thereof, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). -335- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 3. Use of a non-naturally occurring melanocortin analog for reducing body weight and/or fat mass in a subject in need thereof, the non-naturally occurring . 4. A method of reducing body weight and/or fat mass in an obese subject, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 5. Use of a non-naturally occurring melanocortin analog for reducing body weight and/or fat mass in an obese subject, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 6. The method or the use of any one of claims 2-5, wherein the method or the use further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject. 7. The method or the use of claim 6, wherein the lean mass is lean muscle mass. 8. The method or the use of any one of claims 2-7, wherein the method or the use further comprises treating, preventing, or reducing glucose intolerance and/or diabetes mellitus in the subject. 9. A method of treating, preventing, or reducing hyperplasia in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 10. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing hyperplasia in a subject in need thereof, comprising -336- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I). 11. A method of treating, preventing, or reducing hypothalamic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 12. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing hypothalamic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I). 13. The method or the use of claim 11 or 12, wherein the hypothalamic obesity comprises congenital hypothalamic damage, damage from tumors, or damage from trauma. 14. A method of treating, preventing, or reducing a proopiomelanocortin (POMC) deficiency in a subject in need thereof, comprising administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 15. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing a POMC deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I). 16. A method of treating, preventing, or reducing a leptin deficiency in a subject in need thereof, comprising administering a non-naturally occurring -337- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 17. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing a leptin deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I). 18. A method of treating, preventing, or reducing a syndromic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 19. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing a syndromic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I). 20. The method or the use of claim 18 or 19, wherein the syndromic obesity is selected from the group consisting of Prader–Willi syndrome, Wilms tumor, Aniridia, Genitourinary, Range of Developmental Delays (WAGR) syndrome, Bardet-Biedl syndrome, Fragile X syndrome, Cohen syndrome, Proprotein Convertase Subtilisin/Kexin Type 1 (PCSK1) deficiency, Alstrom syndrome, MC4 haploinsufficiency, 17p11.2 deletion syndrome, and 2q37 deletion syndrome. 21. A method of treating, preventing, or reducing non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 22. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing NASH in a subject in need thereof, comprising administering a -338- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 23. A method of treating, preventing, or reducing hyperinsulinism in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 24. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing hyperinsulinism in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I). 25. A method of treating, preventing, or reducing a cardiovascular disease in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 26. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing a cardiovascular disease in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 27. The method or the use of claim 25 of 451, wherein the cardiovascular disease comprises a stroke or a heart attack. 28. A method of treating, preventing, or reducing osteoarthritis in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 29. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing osteoarthritis in a subject in need thereof, comprising -339- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I). 30. A method of treating, preventing, or reducing a cancer in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 31. Use of non-naturally occurring melanocortin analog for treating, preventing, or reducing a cancer in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 32. The method or the use of claim 30 or 31, wherein the method or the use further comprises reducing a risk of the cancer. 33. A method of treating, preventing, or reducing erectile dysfunction in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 34. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing erectile dysfunction in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I). 35. A method of treating, preventing, or reducing body weight gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 36. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing body weight gain after a weight loss in a subject in need thereof, -340- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 37. A method of maintaining body weight after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 38. Use of a non-naturally occurring melanocortin analog for maintaining body weight after a weight loss in a subject in need thereof, comprising administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 39. A method of treating, preventing, or reducing fat mass gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 40. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing fat mass gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 41. A method of treating, preventing, or reducing glucose intolerance and/or diabetes mellitus in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 42. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing glucose intolerance and/or diabetes mellitus in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the -341- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). 43. The method or the use of claim 41 or 42, wherein the method or the use further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject. 44. The method or the use of claim 43, wherein the lean mass is lean muscle mass. 45. The method or the use of any one of claims 1-44, wherein: X1 is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1 is selected from the group consisting of Nle, Arg, dArg, aspartic acid (Asp), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2 is selected from the group consisting of Asp, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), Lys, ornithine (Orn), D-cysteine (dCys), Ala, D-alanine (dAla), proline (Pro), glutamic acid (Glu), and phenylalanine (Phe); R3 is absent or selected from the group consisting of His, dHis, Pro, Phe, asparagine Asn, and glutamine (Gln); R4 is selected from the group consisting of D-phenylalanine (dPhe), Pro, para- fluoro-D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5 is selected from the group consisting of Arg, His, cis-4-guanidyl-proline (cisPro(guan)), and trans-4-guanidyl-proline (transPro(guan)); R6 is selected from the group consisting of dPhe, tryptophan (Trp), and 2’-D- naphthylalanine (dNal(2’)); R7 is selected from the group consisting of Arg, Pro, ornithine (Orn), cysteine (Cys), Glu, Asp, and lysine (Lys); R8 is absent, Lys, or Trp; R9 is absent or Lys; -342- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Y1 is absent or selected from the group consisting of dArg, D-valine (dVal), D- proline (dPro), and D-tert-leucine (dTle); Y2 is absent or selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, 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 R2 and R7 when R2 is dCys, R4 is p(Cl)dPhe, and R7 is Cys; a lactam bridge between R2 and R7 when R1 is Dap, Dab, Orn, or Lys, and R7 is Glu or Asp; a lactam bridge between R1 or R2 and any one of R7-R9 when R1 or R2 is Asp, R4 is dPhe, or p(F)dPhe, and any one of R7-R9 is Lys; and a lactam bridge between R2 and R7 when R2 is Asp or Glu and R7 is Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 49); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 51); His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 52); dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 53); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 54); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 55); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 57); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c[dCys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 59); -343- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 61); Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c[Asp-Phe-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 64); Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 66); Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 68) Ac-Nle-c[dCys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 70); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 71); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 73); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 74); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 75); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 76); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 77); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 78); Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 79); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 80); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 81); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 82); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 83); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 84); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 85); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 86); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 87); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 88); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 89); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 90); -344- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 91); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 92); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 93); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 104); Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 106); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 94); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 118); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 119); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 95); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 120); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 121); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 122); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 123); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 107); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 108); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 109); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 110); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 111); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 112); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 113); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 114); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 115); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 116); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 117); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 96); Ac-Nle-c[Asp-Pro-dPhe-Arg-dTrp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 97); -345- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 99); Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 124); Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 125); Ac-Nle-c[Dap-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 281); Ac-Nle-c[Dab-Pro-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 282); Ac-Nle-c[Lys-Pro-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 283); Ac-Nle-c[Lys-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 284); Ac-Nle-c[Orn-Pro-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 285); Ac-Nle-c[Orn-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 286); Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 287); Ac-Nle-c[Dap-Pro-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 288); Ac-Nle-c[Dab-Pro-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 289); Ac-Nle-c[Lys-Pro-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 290); Ac-Nle-c[Orn-Pro-dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 291); Ac-Nle-c[Orn-Pro-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 292); Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 293); Ac-dArg-c[Orn-Pro-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 294); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 100); Ac-Nle-c[Asp-Pro-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 103); Ac-Nle-c[Asp-Pro-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 98); Ac-Nle-c[Dap-Pro-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 295); Ac-Nle-c[Dab-Pro-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 296); Ac-Nle-c[Lys-Pro-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 297); Ac-Nle-c[Lys-Pro-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 298); Ac-Nle-c[Orn-Pro-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 299); Ac-Nle-c[Orn-Pro-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 300); -346- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-Nle-c[Glu-Pro-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 301); Ac-Nle-c[Glu-Pro-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 105); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 271); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-NH2 (SEQ ID NO: 272); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 273); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 274); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 275); Ac-dArg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 131); Ac-Arg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 132); Ac-Lys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 133); Ac-dLys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 134); Ac-His-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 135); Ac-dHis-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 136); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 126); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 127); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 128); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 141); Ac-dArg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 143); Ac-Arg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 144); Ac-Lys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 151); Ac-dLys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 145); Ac-His-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 152); Ac-dHis-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 146); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 302); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 303); -347- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 139); Ac-Nle-c[Asp-Phe-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 149); Ac-Ala-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 130); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 137); Ac-Nle-c[Asp-His-p(Cl)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 138); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 140); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 129); Ac-Ala-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 142); Ac-Nle-c[Asp-dHis-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 148); Ac-Nle-c[Asp-Gln-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 150); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 147); Ac-Nle-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 304); Ac-Nle-c[Dab-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 305); Ac-Nle-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 306); Ac-Nle-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 307); Ac-Nle-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 308); Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 309); Ac-Arg-c[Dap-Asn-p(Cl)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 310); Ac-Arg-c[Dab-Asn-p(Cl)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 311); Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Glu]-NH2 (SEQ ID NO: 312); Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Asp]-NH2 (SEQ ID NO: 313); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 314); Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 315); Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Orn]-NH2 (SEQ ID NO: 316); Ac-Arg-c[Dab-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 317); Ac-Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 318); -348- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro-NH2 (SEQ ID NO: 319); Ac-Arg-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 320); Ac-Arg-c[Asp-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 321); Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 322); Ac-Arg-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 323); Ac-Nle-c[Dap-His-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 324); Ac-Nle-c[Dap-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 325); Ac-Nle-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 326); Ac-Nle-c[Orn-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 327); Ac-Arg-c[Dap-Asn-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 328); Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 157); Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 155); Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 154); Ac-Nle-c[Asp-Phe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 153); Ac-Nle-c[Asp-Phe-Phe-Pro-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 156); Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 276); Ac-Nle-c[Asp-Ala-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 277); Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 159); Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 160); Ac-Arg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 278); Ac-dArg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 279); Ac-Nle-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 280); Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 158); Ac-Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]-dArg-dVal-NH2 (SEQ ID NO: 329); Ac-Arg-c[Glu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 330); -349- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac-Nle-c[Glu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 331); Ac-Arg-c[Glu-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 332); Ac-Nle-c[Glu-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 333); Ac-Arg-c[Lys-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 334); Ac-Nle-c[Lys-dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 335); Ac-Nle-c[Lys-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 336); Ac-Arg-c[Glu-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 337); Ac-Nle-c[Glu-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 338); Ac-Nle-c[Lys-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 339); and Ac-Arg-c[Lys-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro-NH2 (SEQ ID NO: 340), wherein c represents cyclization via a lactam or disulfide bond. 46. The method or the use of any one of claims 1-45, wherein the sequence of Formula (I) is a sequence of Formula (IA): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4 (IA), wherein: X1 is absent or is selected from the group consisting of Nle, Arg, and dArg; R1 is selected from the group consisting of Nle, Arg, dArg, Asp, Ala, Lys, dLys, His, and dHis; R2 is selected from the group consisting of Asp, Ala, dAla, Dab, Dap, Lys, Orn, Pro, and Glu R3 is absent or selected from the group consisting of His, dHis, Asn, Pro, and Gln; R4 is dPhe or p(F)dPhe; R5 is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6 is Trp or dNal(2’); -350- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 R7 is selected from the group consisting of Pro, Orn, Glu, Asp, and Lys; R8 is absent or Lys; Y1 is absent or selected from the group consisting of dArg, dVal, dPro, and dTle; Y2 is absent or selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, 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 lactam bridge between R2 and R7 when R2 is Dap, Dab, Orn, or Lys, and R7 is Glu or Asp; a lactam bridge between R1 or R2 and R7 or R8 when R1 or R2 is Asp and R7 or R8 is Lys; and a lactam bridge between R2 and R7 when R2 is Asp or Glu and R7 is Orn. 47. The method or the use of any one of claims 1-46, wherein the sequence of Formula (I) is a sequence of Formula (IA(i)): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4 (IA(i)), wherein: X1 is absent or Nle; R1 is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; R2 is selected from the group consisting of Dab, Dap, Lys, Orn, Asp and Glu; R3 is absent or selected from the group consisting of His, dHis, Pro, and Gln; R4 is dPhe or p(F)dPhe; R5 is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6 is Trp or dNal(2’); R7 is selected from the group consisting of Orn, Glu, Asp, and Lys; -351- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Y1 is absent or selected from the group consisting of dArg, dVal, dPro, and dTle; Y2 is absent or selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, dVal, or dPro; Y4 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Asp or Glu at R2 and Orn or Lys at R7; or a lactam bridge between Dap, Dab, Orn, or Lys at R2, and Glu or Asp at R7. 48. The method or the use of any one of claims 1-45, wherein the sequence of Formula (I) is a sequence of Formula (IB): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4 (IB), wherein: X1 is absent or Nle; R1 is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; R2 is selected from the group consisting of Asp, Dap, Dab, Lys, Orn, and Glu; R3 is His; R4 is p(F)dPhe; R5 is Arg; R6 is Trp; R7 is selected from the group consisting of Orn, Glu, Asp, and Lys; Y1 is selected from the group consisting of dVal, dPro, and dTle; Y2 is selected from the group consisting of dVal, dPro, and dTle; Y3 is absent, dVal, or dPro; Y4 is absent or dPro; and -352- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Asp or Glu at R2 and Orn or Lys at R7; or a lactam bridge between Dap, Dab, Orn, or Lys at R2, and Glu or Asp at R7. 49. The method or the use of any one of claims 1-45, wherein the sequence of Formula (I) is a sequence of Formula (IC): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3 (IC), wherein: X1 is absent or norleucine (Nle); R1 is Nle or Asp; R2 is selected from the group consisting of Asp, Dap, Dab, Lys, Orn, Glu, and Pro; R3 is selected from the group consisting of His, dHis, Pro, and Gln; R4 is dPhe; R5 is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6 is Trp; R7 is selected from the group consisting of Orn, Glu, Asp, Orn, Lys, and Pro; R8 is absent or Lys; Y1 is dVal or dPro; Y2 is dVal or dPro; Y3 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R1 or R2 and R7 or R8 when R1 or R2 is Asp and R7 or R8 is Lys; -353- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 a lactam bridge between R2 and R7 when R2 is Dap, Dab, Orn, or Lys, and R7 is Glu or Asp; and a lactam bridge between R2 and R7 when R2 is Asp or Glu and R7 is Orn. 50. The method or the use of any one of claims 1-45, wherein the sequence of Formula (I) is a sequence of Formula (ID): R1-R2-R3-R4-R5-R6-R7-Y1-Y2 (ID), wherein: R1 is selected from Nle, Arg, and dArg; R2 is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3 is absent or selected from the group consisting of Pro, Asn, and His; R4 is selected from dPhe, p(F)dPhe, and p(Cl)dPhe; R5 is Arg; R6 is Trp; R7 is selected from the group consisting of Glu, Asp, Lys, and Orn; Y1 is absent, dVal, or dArg; Y2 is absent, dPro, or dVal; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between Glu or Asp at R2 and Orn at R7; a lactam bridge between Glu at R2 and Lys at R7; a lactam bridge between Asp at R2, Asn at R3, and Lys at R7; and a lactam bridge between Dap, Dab, Orn, or Lys at R2 and Glu or Asp at R7. 51. The method or the use of any one of claims 1-45, wherein the sequence of Formula (I) is a sequence of Formula (IE): -354- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 R1-R2-R3-R4-R5-R6-R7-Y1-Y2 (IE), wherein: R1 is Nle or Arg; R2 is selected from the group consisting of Dab, Lys, Orn, and Glu; R3 is Asn or His; R4 is p(Cl)dPhe; R5 is Arg; R6 is Trp; R7 is selected from the group consisting of Glu, Asp, Lys, and Orn; Y1 is absent or dVal; Y2 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through: a lactam bridge between Glu at R2 and Orn or Lys at R7; or a lactam bridge between Dab, Orn, or Lys at R2 and Glu or Asp at R7 52. The method or the use of any one of claims 1-45, wherein the sequence of Formula (I) is a sequence of Formula (IF): R1-R2-R3-R4-R5-R6-R7-Y1-Y2 (IF), wherein: R1 is selected from Nle, Arg, and dArg; R2 is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3 is absent, Asn, or His; R4 is p(F)dPhe; R5 is Arg; R6 is Trp; R7 is selected from the group consisting of Glu, Asp, Lys, and Orn; -355- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Y1 is absent or dVal; Y2 is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between Glu or Asp at R2 and Orn at R7; a lactam bridge between Glu at R2 and Lys at R7; a lactam bridge between Asp at R2, Asn at R3, and Lys at R7; and a lactam bridge between Dap, Dab, Orn, or Lys at R2 and Glu or Asp at R7. 53. The method or the use of any one of claims 1-45, wherein the sequence of Formula (I) is a sequence of Formula (IG): R1-R2-R3-R4-R5-R6-R7-Y1-Y2 (IG), wherein: R1 is Nle or Arg; R2 is selected from the group consisting of Dap, Dab, Lys, Orn, Asp and Glu; R3 is selected from the group consisting of Pro, Asn, and His; R4 is dPhe; R5 is Arg; R6 is Trp; R7 is selected from the group consisting of Glu, Asp, Lys, and Orn; Y1 is absent, dVal, or dArg; Y2 is absent, dPro, or dVal; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between Glu or Asp at R2 and Orn at R7; a lactam bridge between Glu at R2 and Lys at R7; -356- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 a lactam bridge between Asp at R2, Asn at R3, and Lys at R7; and a lactam bridge between Dap, Dab, Orn, or Lys at R2 and Glu or Asp at R7. 54. The method or the use of any one of claims 1-53, wherein the N-terminus is modified by an acyl group. 55. The method or the use of claim 54, wherein the acyl group is acetyl group. 56. The method or the use of any one of claims 1-55, wherein the N-terminus is modified by an amide group. 57. The method or the use of any one of claims 1-56, wherein R3 is His. 58. The method or the use of any one of claims 1-57, wherein the non- naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R2 and Lys at R7. 59. The method or the use of any one of claims 1-58, wherein R4 is p(F)dPhe or dPhe. 60. The method or the use of any one of claims 1-59, wherein R1 is selected from Nle, Ala, Arg, dArg, Lys, dLys, His, and dHis and R4 is p(F)dPhe. 61. The method or the use of any one of claims 1-60, wherein Y1 is dVal and Y2 is dPro. 62. The method or the use of any one of claims 1-61, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 3); Ac—dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 4); Ac—Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 14); -357- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac—Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 15); Ac—Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 16); Ac—dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 17); Ac—His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 18); and Ac—dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 19), wherein c represents cyclization through R2 and R7 via a lactam bond. 63. The method or the use of any one of claims 1-60, wherein Y1 is dTle and Y2 is dPro. 64. The method or the use of any one of claims 1-60 and 63, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 7); Ac—dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 8); Ac—Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 24); Ac—Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 27); Ac—Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 28); Ac—dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 29); Ac—His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 30); and Ac—dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 31), wherein c represents cyclization through R2 and R7 via a lactam bond. 65. The method or the use of any one of 1-56, wherein R1 is Nle and R4 is dPhe. 66. The method or the use of claim any one of claims 1-59 and 65, wherein the sequence according to any one of Formulae (I)-(IG) is: Ac—Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal—NH2 (SEQ ID NO: 33); or -358- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac—Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 42), wherein c represents cyclization through R2 and R7 via a lactam bond. 67. The method or the use of any one of claims 1-59, wherein R1 is Nle and R4 is p(F)dPhe. 68. The method or the use of claim any one of claims 1-59 and 67, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal—NH2 (SEQ ID NO: 6); Ac—Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 20); Ac—Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro—NH2 (SEQ ID NO: 22); Ac—Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro—NH2 (SEQ ID NO: 23); Ac—Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 25); and Ac—Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro—NH2 (SEQ ID NO: 26), wherein c represents cyclization through R2 and R7 via a lactam bond. 69. The method or the use of any one of claims 1-59, wherein R1 is Nle and R4 is dPhe or p(F)dPhe. 70. The method or the use of claim any one of claims 1-59 and 69, wherein R5 is Arg, transPro(guan), or cisPro(guan). 71. The method or the use of claim any one of claims 1-59, 69, and 70, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 21); -359- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac—Nle-c[Asp-His-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 46); and Ac—Nle-c[Asp-His-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 47), wherein c represents cyclization through R2 and R7 via a lactam bond. 72. The method or the use of any one of claims 1-59, wherein R6 is dNal(2’). 73. The method or the use of claim any one of claims 1-59 and 72, wherein the sequence according to any one of Formulae (I)-(IG) is: Ac—Nle-c[Asp-His- p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro—NH2 (SEQ ID NO: 5), wherein c represents cyclization through R2 and R7 via a lactam bond. 74. The method or the use of any one of claims 1-59, wherein the non- naturally occurring melanocortin analog is cyclized through R2 and R7 via a bond other than a lactam bond between Asp at and Lys. 75. The method or the use of any one of claims 1-59 and 74, wherein the sequence of any one of Formulae (I)-(IG) is cyclized through a lactam bond between Asp or Glu at R2 and Orn at R7 or Glu at R2 and Lys at R7. 76. The method or the use of claim any one of claims 1-59, 74, and 75, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 43); Ac—Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 44); Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac—Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 11); Ac—Nle-c[Glu-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 12); Ac—Nle-c[Asp-His-dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 201); Ac—Nle-c[Glu-His-dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 203); -360- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac—Nle-c[Glu-His-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 202); Ac—Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 183); and Ac—Nle-c[Glu-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 252), wherein c represents cyclization through R2 and R7 via a lactam bond. 77. The method or the use of any one of claims 1-59 and 74, wherein the sequence of any one of Formulae (I)-(IG) is cyclized through a lactam bond between Dap, Dab, Orn, or Lys at R2 and Asp or Glu at R7. 78. The method or the use of claim any one of claims 1-59, 74, and 77, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Nle-c[Dap-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 172); Ac—Nle-c[Dab-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 173); Ac—Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 174); Ac—Nle-c[Lys-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 175); Ac—Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 176); Ac—Nle-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 177); Ac—Nle-c[Lys-His-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 188); Ac—Nle-c[Lys-His-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 189); Ac—Nle-c[Dap-His-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 190); Ac—Nle-c[Dab-His-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 191); Ac—Nle-c[Lys-His-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 192); Ac—Nle-c[Lys-His-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 193); Ac—Nle-c[Orn-His-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 194); Ac—Nle-c[Orn-His-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 195); Ac—Arg-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 242); Ac—Arg-c[Orn-His-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 243); -361- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac—Arg-c[Orn-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 244); Ac—dArg-c[Orn-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 245); Ac—dArg-c[Lys-His-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 246); Ac—Nle-c[Dab-His-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 248); Ac—Nle-c[Orn-His-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 249); and Ac—Nle-c[Orn-His-p(Cl)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 250), wherein c represents cyclization through R2 and R7 via a lactam bond. 79. The method or the use of any one of claims 1-59 and 74, wherein the sequence of any one of Formulae (I)-(IG) is cyclized through a lactam bond between dCys at R2 and Cys at R7. 80. The method or the use of claim any one of claims 1-59, 74, and 79, wherein the sequence according to any one of Formulae (I)-(IG) is: Ac—Nle-c[dCys- His-p(Cl)dPhe-Arg-Trp-Cys]-dVal-dPro—NH2 (SEQ ID NO: 5), wherein c represents cyclization through R2 and R7 via a disulfide bond. 81. The method or the use of any one of claims 1-59 and 74, wherein the sequence of any one of Formulae (I)-(IG) is cyclized through a lactam bond between Asp at R2 and Lys at R8. 82. The method or the use of claim any one of claims 1-59, 74, and 81, wherein the sequence according to any one of Formulae (I)-(IG) is: Ac—Nle-c[Asp-His- dPhe-Arg-Trp-Pro-Lys]-dVal-dPro—NH2 (SEQ ID NO: 35), wherein c represents cyclization through R2 and R8 via a lactam bond. 83. The method or the use of any one of claims 1-59 and 74, wherein the sequence of any one of Formulae (I)-(IG) is cyclized through a lactam bond between Asp at R1 and Lys at R7. -362- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 84. The method or the use of claim any one of claims 1-59, 74, and 83, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 38); Ac—Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 39); Ac—dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 40); and Ac—Nle-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 41), wherein c represents cyclization through R1 and R7 via a lactam bond. 85. The method or the use of claim any one of claims 1-59, 74, and 83, wherein the sequence according to any one of Formulae (I)-(IG) is: Ac-Nle-c[Asp-Pro- His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 13), wherein c represents cyclization through R1 and R7 via a lactam bond. 86. The method or the use of any one of claims 1-56, wherein R3 is Asn. 87. The method or the use of any one of claims 1-56 and 86, wherein the non- naturally occurring melanocortin analog is cyclized through a lactam bond between Asp or Glu at R2 and Lys or Orn at R7. 88. The method or the use of any one of claims 1-56, 86, and 87, wherein Y1 is dVal and Y2 is dPro. 89. The method or the use of any one of claims 1-56 and 86-88, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Nle-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 184); Ac—Nle-c[Asp-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 185); Ac—Nle-c[Glu-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 186); Ac—Nle-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 187); -363- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac—Nle-c[Asp-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 204); Ac—Nle-c[Glu-Asn-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 205); Ac—Nle-c[Glu-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 206); Ac—Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 231); Ac—Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 232); Ac—Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 233); Ac—Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 234); Ac—Arg-c[Glu-Asn-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 240); Ac—Arg-c[Glu-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 241); Ac—Nle-c[Glu-Asn-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 253); and Ac—Arg-c[Asp-Asn-dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 261), wherein c represents cyclization through R2 and R7 via a lactam bond. 90. The method or the use of any one of claims 1-56, 86, and 87, wherein Y1- Y4 are absent. 91. The method or the use of any one of claims 1-56, 86, 87, and 90, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Lys]—NH2 (SEQ ID NO: 213); Ac—Arg-c[Asp-Asn-p(F)dPhe-Arg-Trp-Orn]—NH2 (SEQ ID NO: 214); Ac—Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Lys]—NH2 (SEQ ID NO: 215); Ac—Arg-c[Glu-Asn-p(F)dPhe-Arg-Trp-Orn]—NH2 (SEQ ID NO: 216); Ac—Arg-c[Asp-Asn-dPhe-Arg-Trp-Lys]—NH2 (SEQ ID NO: 223); Ac—Arg-c[Asp-Asn-dPhe-Arg-Trp-Orn]—NH2 (SEQ ID NO: 224); Ac—Arg-c[Glu-Asn-dPhe-Arg-Trp-Lys]—NH2 (SEQ ID NO: 225); and Ac—Arg-c[Glu-Asn-dPhe-Arg-Trp-Orn]—NH2 (SEQ ID NO: 226), -364- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 wherein c represents cyclization through R2 and R7 via a lactam bond. 92. The method or the use of any one of claims 1-56 and 86, wherein the non- naturally occurring melanocortin analog is cyclized through a lactam bond between Dap, Dab, Lys, or Orn at R2 and Asp or Glu at R7. 93. The method or the use of any one of claims 1-56, 86, and 92, wherein Y1 is dVal and Y2 is dPro. 94. The method or the use of any one of claims 1-56, 86, 892, and 93, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Nle-c[Dab-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 178); Ac—Nle-c[Lys-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 179); Ac—Nle-c[Lys-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 180); Ac—Nle-c[Orn-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 181); Ac—Nle-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 182); Ac—Nle-c[Dab-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 196); Ac—Nle-c[Lys-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 197); Ac—Nle-c[Lys-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 198); Ac—Nle-c[Orn-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 199); Ac—Nle-c[Orn-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 200); Ac—Arg-c[Dab-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 227); Ac—Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 228); Ac—Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 229); Ac—Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 230); Ac—Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 235); Ac—Arg-c[Lys-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 236); -365- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac—Arg-c[Lys-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 237); Ac—Arg-c[Orn-Asn-dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 238); Ac—Arg-c[Orn-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 239); Ac—Nle-c[Dap-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 247); Ac—Nle-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 251); Ac—Nle-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 255); Ac—Arg-c[Dap-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 257); Ac—Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 258); Ac—Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]-dVal-dPro—NH2 (SEQ ID NO: 259); Ac—Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 260); and Ac—Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]-dArg-dVal—NH2 (SEQ ID NO: 262), wherein c represents cyclization through R2 and R7 via a lactam bond. 95. The method or the use of any one of claims 1-56, 86, and 92, wherein Y1- Y4 are absent. 96. The method or the use of any one of claims 1-56, 86, 92, and 95, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 207); Ac—Arg-c[Dap-Asn-p(F)dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 208); Ac—Arg-c[Dab-Asn-p(F)dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 209); Ac—Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 210); Ac—Arg-c[Lys-Asn-p(F)dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 211); Ac—Arg-c[Orn-Asn-p(F)dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 212); Ac—Arg-c[Orn-Asn-dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 217); Ac—Arg-c[Dap-Asn-dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 218); -366- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 Ac—Arg-c[Dab-Asn-dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 219); Ac—Arg-c[Lys-Asn-dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 220); Ac—Arg-c[Lys-Asn-dPhe-Arg-Trp-Glu]—NH2 (SEQ ID NO: 221); Ac—Arg-c[Orn-Asn-dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 222); and Ac—Arg-c[Lys-Asn-p(Cl)dPhe-Arg-Trp-Asp]—NH2 (SEQ ID NO: 256), wherein c represents cyclization through R2 and R7 via a lactam bond. 97. The method or the use of claim any one of claims 1-56, wherein R3 is absent or selected from dHis, Gln and Pro and R4 is dPhe or p(F)dPhe. 98. The method or the use of claim any one of claims 1-56 and 97, wherein the sequence according to any one of Formulae (I)-(IG) is selected from the group consisting of: Ac—Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 9); Ac—Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro—NH2 (SEQ ID NO: 10); Ac—Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 32); Ac—Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 36); Ac—Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 37); Ac—Nle-c[Lys-Pro-dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 254); and Ac—Arg-c[Lys-p(F)dPhe-Arg-Trp-Glu]-dVal-dPro—NH2 (SEQ ID NO: 263), wherein c represents cyclization through R2 and R7 via a lactam bond. 99. The method or the use of any one of claims 1-56, wherein the sequence according to any one of Formulae (I)-(IG) is: Ac-Nle-c[Asp-Phe-Phe-Pro-His-dPhe-Arg- Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 34), wherein c represents cyclization through R1 and R9 via a lactam bond. -367- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 100. The method or the use of any one of claims 1-99, wherein the non- naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 2-47 and 172-263. 101. The method or the use of any one of claims 1-100, wherein the non- naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 3-10, 14-33, 35-47, 172-187, 190-247, 254, 255, 257, 258, and 260-263. 102. The method or the use of any one of claims 1-100, wherein the non- naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 3-10, 14-33, 36, 37, 42-47, 172-187, 190-247, 254, 255, 257, 258, and 260-263. 103. The method or the use of any one of claims 1-100, wherein the non- naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 3-8, 14-31, 43, 44, 172-187, 207-216, 227-234, 242-247, 257, 258, and 263. 104. The method or the use of any one of claims 1-100, wherein the non- naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 10, 13, 33, 35-37, 42, 45-47, 190-206, 217-226, 235-241, 254, 255, and 260-262. 105. The method or the use of any one of claims 1-100, wherein the non- naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 172-263. 106. The method or the use of any one of claims 1-100, wherein the non- naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 188, 189, 248-250, 252, 253, 256, and 259. 107. The method or the use of any one of claims 1-100, wherein the non- naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 172-187, 207-216, 227-234, 242-247, 257, 258, and 263. -368- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 108. The method or the use of any one of claims 1-100, wherein the non- naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 190-206, 217-226, 235-241, 254, 255, and 260-262. 109. The method or the use of any one of claims 1-98, wherein the non- naturally occurring melanocortin analog is a first non-naturally occurring melanocortin analog, and the method further comprises administering a second non-naturally occurring melanocortin analog selected from the group consisting of MC4-NN2-0453, LY2112688, Melanotan-II, Afamelanotide, Bremelanotide, AZD2820, MK-0493, PF- 00446687, setmelanotide, RM-718, and LB54640. 110. The method or the use of claim 109, wherein the first non-naturally occurring melanocortin analog is administered before the second non-naturally occurring melanocortin analog. 111. The method or the use of claim 109, wherein the first non-naturally occurring melanocortin analog is administered after the second non-naturally occurring melanocortin analog. 112. The method or the use of claim 109, wherein the first non-naturally occurring melanocortin analog and the second non-naturally occurring melanocortin analog are administered simultaneously. 113. The method or the use of any one of claims 109-112, wherein the first non-naturally occurring melanocortin analog and the second non-naturally occurring melanocortin analog are present in a single pharmaceutical composition. 114. The method or the use of any one of claims 109-112, wherein the first non-naturally occurring melanocortin analog is present in a first pharmaceutical -369- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 composition and the second non-naturally occurring melanocortin analog is present in a second pharmaceutical composition. 115. The method or the use of any one of claims 109-114, wherein the non- naturally occurring melanocortin analog is selected from the group consisting of MC4- NN2-0453, LY2112688, Melanotan-II, Afamelanotide, Bremelanotide, AZD2820, MK- 0493, PF-00446687, setmelanotide, RM-718, and LB54640. 116. The method or the use of any one of claims 109-115, wherein the MC4- NN2-0453 is administered at a dose of about 0.03, 0.06, 0.15, 0.30, 0.60, 1.00, or 1.50 mg/kg. 117. The method or the use of any one of claims 109-116, wherein the MC4- NN2-0453 is administered at one or more doses of about 0.75, 1.5, 3.0, or 5.0 mg/day. 118. The method or the use of any one of claims 109-116, wherein the LY2112688 is administered at one or more doses of about 0.45 mg or 1.0 mg. 119. The method or the use of any one of claims 109-116, wherein the LY2112688 is administered at a dose of about 0.5 mg/kg/day. 120. The method or the use of any one of claims 109-116, wherein the Melanotan-II is administered at a dose of about 0.01 mg/kg. 121. The method or the use of claim 120, wherein the dose is escalated by 0.005 mg/kg increments to a 0.03 mg/kg dose or to a 0.025 mg/kg dose. 122. The method or the use of any one of claims 109-116, wherein the Melanotan-II is administered at a dose of about 0.025 mg/kg, or about 0.03 mg/kg. 123. The method or the use of any one of claims 109-116, wherein the Afamelanotide is administered at a one or more doses of about 0.08 mg/kg to about 0.21 mg/kg. -370- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 124. The method or the use of any one of claims 109-116, wherein the Afamelanotide is administered at a one or more doses of about 16 mg. 125. The method or the use of claim 124, wherein the Afamelanotide is administered using a subcutaneous implant. 126. The method or the use of any one of claims 109-116, wherein the Bremelanotide is administered at a dose of about 1.75 mg, 4.0 mg, or 6.0 mg. 127. The method or the use of any one of claims 109-116, wherein the Bremelanotide is administered at a dose of at least about 7.0 mg or at least about 10 mg. 128. The method or the use of claim 127, wherein the Bremelanotide is administered intranasally. 129. The method or the use of any one of claims 109-116, wherein the MK- 0493 is administered at a dose of about 10 mg or about 30 mg. 130. The method of any one of claims 109-116, wherein the MK-0493 is administered at a dose of about 1 mg/kg to about 4 mg//kg. 131. The method or the use of any one of claims 109-116, wherein the MK- 0493 is administered at a dose of about 2 mg/kg, about 6 mg/kg, or about 20 mg/kg. 132. The method or the use of any one of claims 109-116, wherein the PF- 00446687 is administered at one or more doses of about 200 mg, 175 mg, 125 mg, 100 mg, or 20 mg. 133. The method or the use of any one of claims 109-116, wherein the setmelanotide is administered at one or more doses of about 0.5 mg, 1.0 mg, 2.0 mg, or 3.0 mg. -371- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 134. The method or the use of claim 133, wherein the setmelanotide is administered at two or more doses. 135. The method or the use of claim 134, wherein a second dose of the two or more doses is greater than a first dose of the two or more doses. 136. The method or the use of any one of claims 133-135, wherein the setmelanotide is administered daily. 137. The method or the use of any one of claims 1-115, wherein the 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. 138. The method or the use of claim 137, wherein 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. 139. The method or the use of any one of claims 1-138, wherein the non- naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily. 140. The method or the use of any one of claims 1-139, wherein the non- naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily. 141. The method or the use of any one of claims 1-140, wherein the concentration of the non-naturally occurring melanocortin analog in the plasma or a tissue of the subject is at least about 5 ng/mL to at least about 2000 ng/mL about 24 hours after administration of the non-naturally occurring melanocortin analog. 142. The method or the use of any one of claims 1-141, wherein the non- naturally occurring melanocortin analog is administered to the subject until the concentration of the non-naturally occurring melanocortin analog in the plasma or a -372- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 tissue of the subject is at least about 5 ng/mL to at least about 2000 ng/mL after administration of the non-naturally occurring melanocortin analog. 143. The method or the use of claim 141 or 142, wherein concentration is at least about 5 ng/mL after administration of the non-naturally occurring melanocortin analog. 144. The method or the use of claim 141 or 142, wherein concentration is at least about 10 ng/mL after administration of the non-naturally occurring melanocortin analog. 145. The method or the use of claim 141 or 142, wherein concentration is at least about 50 ng/mL after administration of the non-naturally occurring melanocortin analog. 146. The method or the use of claim 141 or 142, wherein concentration is at least about 100 ng/mL after administration of the non-naturally occurring melanocortin analog. 147. The method or the use of claim 141 or 142, wherein concentration is at least about 200 ng/mL after administration of the non-naturally occurring melanocortin analog. 148. The method or the use of claim 141 or 142, wherein concentration is at least about 300 ng/mL after administration of the non-naturally occurring melanocortin analog. 149. The method or the use of claim 141 or 142, wherein concentration is at least about 400 ng/mL after administration of the non-naturally occurring melanocortin analog. -373- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 150. The method or the use of claim 141 or 142, wherein concentration is at least about 500 ng/mL after administration of the non-naturally occurring melanocortin analog. 151. The method or the use of claim 141 or 142, wherein concentration is at least about 750 ng/mL after administration of the non-naturally occurring melanocortin analog. 152. The method or the use of claim 141 or 142, wherein concentration is at least about 1000 ng/mL after administration of the non-naturally occurring melanocortin analog. 153. The method or the use of claim 141 or 142, wherein concentration is at least about 1500 ng/mL after administration of the non-naturally occurring melanocortin analog. 154. The method or the use of claim 141 or 142, wherein concentration is at least about 2000 ng/mL after administration of the non-naturally occurring melanocortin analog. 155. The method or the use of any one of claims 141-154, wherein the concentration is a maximum concentration (Cmax). 156. The method or the use of any one of claims 22-155, wherein the non- naturally occurring melanocortin analog is administered as a single dosage unit. 157. The method or the use of any one of claims 1-155, wherein the non- naturally occurring melanocortin analog dose is administered as multiple dosage units. 158. The method or the use of claim 157, wherein the multiple dosage units individually comprise about 2.5 mg/mL to about 100 mg/mL of the non-naturally occurring melanocortin analog. -374- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 159. The method or the use of claim 158, wherein the multiple dosage units individually comprise about 2.5 mg/mL to about 10 mg/mL of the non-naturally occurring melanocortin analog. 160. The method or the use of claim 157, wherein the multiple dosage units individually comprise about 6 mg/mL of the non-naturally occurring melanocortin analog. 161. The method or the use of claim 157, wherein the non-naturally occurring melanocortin analog is administered as about 5 dosage units to about 10 dosage units. 162. The method or the use of claim 157, wherein the non-naturally occurring melanocortin analog is administered as 5 dosage units. 163. The method or the use of claim 157, wherein the non-naturally occurring melanocortin analog is administered as 10 dosage units. 164. The method or the use of any one of claims 1-163, wherein the dosage unit is a capsule. 165. The method or the use of claim 164, wherein the capsule comprises the non-naturally occurring melanocortin analog suspended in a saline solution. 166. The method or the use of claim 165, wherein the saline solution is about 100% saline. 167. The method or the use of claim 165, wherein the saline solution is about 95% saline. 168. The method or the use of claim 165, wherein the saline solution is about 90% saline. -375- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 169. The method or the use of claim 167 or 168, wherein the saline solution comprises dimethyl sulfoxide (DMSO). 170. The method of the use of any one of claims 1-169, wherein the subject has an addiction or is susceptible to an addiction. 171. The method or the use of any one of claims 1-170, wherein the subject has used or is using one or more addictive substances. 172. The method or the use of any one of claims 1-171, wherein the subject has pain or is susceptible to pain. 173. The method or the use of any one of claims 1-172, wherein the subject has used or is using a medication to treat an addiction. 174. The method or the use of claim 173, wherein the medication is a rescue medication. 175. The method or the use of any one of claims 171 or 173, wherein a frequency or an amount of the addictive substance or a rescue medication is reduced during or after administration of the non-naturally occurring melanocortin analog. 176. The method or the use of claim 174 or 175, wherein the rescue medication is selected from the group consisting of an opioid agonist, an opioid antagonist, and a non-opioid medication. 177. The method or the use of claim 171, 173, or 175, wherein the addictive substance is selected from the group consisting of a prescription medication, a substance in an over-the-counter medication, a recreational substance, or an illegal substance. 178. The method or the use of claim 177, wherein the addictive substance is selected from the group consisting of an opioid, a painkillers, a stimulant, a narcotic, -376- 146316.8034.WO00\181226204.17 Docket No.: 146316.8034.WO00 alcohol, a barbiturate, sedatives, marijuana, cannabis, tetrahydrocannabinol (THC), cannabidiol (CBD), or an inhalant. 179. The method or the use of claim 178, wherein the opioid is selected from the group consisting of morphine, heroin, codeine, oxycodone, hydrocodone, and fentanyl. 180. The method or the use of claim 178, wherein the stimulant is selected from the group consisting of caffeine, nicotine, methamphetamine, cocaine, and amphetamine. 181. The method or the use of claim 178, wherein the barbiturate is selected from the group consisting of phenobarbital, methohexital, butalbital, pentobarbital, primidone, and amobarbital. 182. The method or the use of claim 178, wherein the sedative is selected from the group consisting of a tranquilizer, xylazine, eszopiclone, zaleplon, zolpidem, and zopiclone. 183. The method or the use of claim 178, wherein the inhalant is selected from the group consisting of an aerosol, a butane, freon, helium, nitrous oxide, propane, and a nitrite. 184. The method or the use of claim 180, wherein the nicotine comprises nicotine in a tobacco chew, a nicotine pouch, or a smoking device. 185. The method or the use of claim 184, wherein the smoking device is selected from the group consisting of cigarettes, electronic cigarettes, cigars, and vape products. 186. The method or the use of any one of claims 1-185, wherein the subject has or had an opioid use disorder or an alcohol use disorder. -377- 146316.8034.WO00\181226204.17
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US20170081383A1 (en) * 2012-03-13 2017-03-23 Tensive Controls Inc. Melanocortin analogs having enhanced activity and transport

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