WO2025175224A1

WO2025175224A1 - Orally deliverable non-naturally occurring melanocortin analogs and associated methods for modulating weight gain

Info

Publication number: WO2025175224A1
Application number: PCT/US2025/016113
Authority: WO
Inventors: Russell Potterfield; Jordan DELEV; Daniel Marks
Original assignee: Endevica Bio Inc
Current assignee: Endevica Bio Inc
Priority date: 2024-02-16
Filing date: 2025-02-14
Publication date: 2025-08-21
Anticipated expiration: 2026-08-16
Also published as: WO2025175226A1; WO2025175250A1; WO2025175235A1

Abstract

The present technology comprises methods of treating, preventing, reducing, or otherwise ameliorating one or more symptoms or conditions that may benefit from weight gain or a reduction in weight loss. The methods comprise administering a non-naturally occurring melanocortin analog of the present technology to a subject in need thereof. The methods may promote fat gain (e.g., epididymal fat or perirenal fat), increase muscle mass, increase body weight, accelerate weight gain, increase fat mass to lean mass ratio, improve body composition and/or BMI (e.g., for underweight conditions), increase waist circumference, increase cardiac mass, increase brain mass, or any combination thereof, relative to a control.

Description

ORALLY DELIVERABLE NON-NATURALLY OCCURRING MELANOCORTIN ANALOGS AND ASSOCIATED METHODS FOR MODULATING WEIGHT GAIN

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/554,944, filed February 16, 2024; U.S. Provisional Patent Application No. 63/557,409, filed February 23, 2024; U.S. Provisional Patent Application No. 63/572,896, filed April 1 , 2024; U.S. Provisional Patent Application No. 63/573,433, filed April 2, 2024; U.S. Provisional Patent Application No. 63/632,496, filed April 10, 2024; U.S. Provisional Patent Application No. 63/637,285, filed April 22, 2024; U.S. Provisional Patent Application No. 63/640,864, filed April 30, 2024; U.S. Provisional Patent Application No. 63/647,545, filed May 14, 2024; U.S. Provisional Patent Application No. 63/650,368, filed May 21 , 2024; U.S. Provisional Patent Application No. 63/654,876, filed May 31 , 2024; U.S. Provisional Patent Application No. 63/656,579, field June 5, 2024; U.S. Provisional Patent Application No. 63/663,689, filed June 24, 2024; U.S. Provisional Patent Application No. 63/675,219, filed July 24, 2024; U.S. Provisional Patent Application No. 63/681 ,055, filed August 8, 2024; and of U.S. Provisional Patent Application No. 63/692,605, filed September 9, 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 February 13, 2025, is titled “146316_8023_WO01_SL.xml” and is 920,536 bytes in size.

BACKGROUND

[0003] The ability to effectively increase weight and maintain healthy body mass in subjects suffering from various medical conditions and disorders is often challenging. These conditions, which can include muscle wasting, reduced appetite, and metabolic disorders such as cachexia, may significantly impact a subject's overall health, quality of life, and ability to respond to medical treatments. Treatment options are frequently limited by a subject's compromised physical state, affecting both the duration and dosing of therapeutic interventions. These limitations can reduce overall treatment efficacy and increase the risk that therapeutic interventions are not as effective as they could be.

[0004] Despite recent advances in therapeutic approaches for improving body mass and maintaining healthy weight levels, there remains a demand for novel approaches to address these challenges. Such approaches should be well-tolerated, with reduced adverse effects compared to conventional methods, while providing robust therapeutic activity for weight management and maintenance.

SUMMARY

[0005] The present technology comprises methods of increasing body weight and/or fat mass in a subject in need thereof, comprising administering to the subject a non-naturally occurring melanocortin analog.

[0006] In some embodiments, the present technology comprises a method of increasing body weight in a subject in need thereof, comprising administering to the subject a non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R¹ is selected from the group consisting of D-norleucine (dNIe), Arg, D-arginine (dArg), Nle, aspartic acid (Asp), D-leucine (dLeu), alanine (Ala), cysteine (Cys), D- phenylalanine (dPhe), D-tyrosine (dTyr), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys);

R² is selected from the group consisting of D-alanine (dAla), Asp, Cys, D- penicillamine (dPen), Glu, and proline (Pro);

R³ is selected from the group consisting of phenylalanine (Phe), dPhe, His, dHis, Pro, glutamine (Gin), D-glutamine (dGIn), tryptophan (Trp), D-tryptophan (dTrp), tyrosine (Tyr), dTyr, biphenylalanine (Bip), and D-biphenylalanine (dBip); R⁴ is selected from the group consisting of dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CP3)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁶ is selected from the group consisting of Trp, 4-amino-1 , 4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), 4-amino-1 ,2,4,5-tetrahydro-2- benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-[1 ,2, 3]triazolo-[1 , 5-a][1 ,4]diazepin- 6(5H)-one (Ata), 2’-naphthylalanine (Nal(2’)), and dNal(2’);

R⁷ is selected from the group consisting of Lys, Cys, Gly, dPen, and ornithine (Orn);

R⁸ is absent or dPen;

Y¹ is absent or is selected from the group consisting of D-valine (dVal), D-proline (dPro), D-tert-leucine (dTle), dArg, and dLys;

Y² is absent or is selected from the group consisting of dVal, dPro, D- hydroxyproline (dHyp), 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 R¹ or R² and R⁷ when each of R¹ or R² and R⁷ are Cys; a disulfide bond between R² and R⁷ or R⁸ when each of R² and R⁷ or R⁸ are dPen; and a lactam bridge between R¹ or R² and R⁷ when R¹ or R² is Asp or Glu, and R⁷ is Lys or Orn, provided that: when R⁴ is dPhe, then (i) R³ is d Bip; or (ii) R³ is Pro and either R⁵ is Lys or R⁶ is dNal(2’) or Nal(2’); when R⁴ is p(F)dPhe, then (i) R³ is selected from Tyr, Phe, Bip, and Trp; or (ii) R³ is Pro and either R⁶ is Nal(2’) or dNal(2’) or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R² and R⁷; when R⁴ is p(CI)dPhe, then (i) R³ is selected from dPhe, dTyr, Trp, Tyr, Pro, dHis, Phe, Bip, and Gin; or (ii) R³ is His, R¹ is Nle or Ala, R⁷ is Lys or Cys, Y³ is not dVal, and Y⁴ is absent, wherein when X¹ is present, then Y¹ is not dTle, and when X¹ is absent, then Y² is dPro; and when R⁴ is dNal(2’), then R³ is His or Pro, wherein when R³ is Pro, then the non- naturally occurring melanocortin analog is cyclized between a disulfide bond between dPen at R² and dPen at R⁷ or R⁸; and when R³ is His, then either (i) the non-naturally occurring melanocortin analog is cyclized between a lactam bond between Glu at R¹ or R² and Orn at R⁷ or (ii) Y¹-Y⁴ are absent.

[0007] In some embodiments, the present technology comprises a method of increasing body weight in a subject in need thereof, comprising administering to the subject a non-naturally occurring melanocortin analog comprising a sequence of Formula (IE):

R1._R2._R3._R4__R5__R6._R7.Y1.Y2 (I E), wherein:

R¹ is Nle;

R² is Asp or Glu;

R³ is Pro or His;

R⁴ is p(CI)dPhe or p(Br)dPhe;

R⁵ is Arg;

R⁶ is Trp;

R⁷ is Orn;

Y¹ is d Vai;

Y² is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Glu or Asp at R² and Orn at R⁷, provided that when R³ is His, then R⁴ is not p(CI)dPhe.

[0008] In some embodiments, the present technology comprises a method of preventing or reducing cachexia in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R³ is selected from the group consisting of phenylalanine (Phe), dPhe, His, dHis, Pro, glutamine (Gin), D-glutamine (dGIn), tryptophan (Trp), D-tryptophan (dTrp), tyrosine (Tyr), dTyr, biphenylalanine (Bip), and D-biphenylalanine (dBip);

R⁴ is selected from the group consisting of dPhe, 2’-D-naphthylalanine (dNal (2’)) , para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁶ is selected from the group consisting of Trp, 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia) , 4-amino-1 ,2,4,5-tetrahydro-2- benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-[1 ,2, 3]triazolo-[1 , 5-a][1 ,4]diazepin- 6(5H)-one (Ata), 2’-naphthylalanine (Nal(2’)), and dNal(2’);

R⁸ is absent or dPen; Y¹ is absent or is selected from the group consisting of D-valine (dVal), D-proline (dPro), D-tert-leucine (dTle), dArg, and dLys;

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 R¹ or R² and R⁷ when each of R¹ or R² and R⁷ are Cys; a disulfide bond between R² and R⁷ or R⁸ when each of R² and R⁷ or R⁸ are dPen; and a lactam bridge between R¹ or R² and R⁷ when R¹ or R² is Asp or Glu, and R⁷ is Lys or Orn, provided that: when R⁴ is dPhe, then (i) R³ is d Bip; or (ii) R³ is Pro and either R⁵ is Lys or R⁶ is dNal(2’) or Nal(2’); when R⁴ is p(F)dPhe, then (i) R³ is selected from Tyr, Phe, Bip, and Trp; or (ii) R³ is Pro and either R⁶ is Nal(2’) or dNal(2’) or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R² and R⁷; when R⁴ is p(CI)dPhe, then (i) R³ is selected from dPhe, dTyr, T rp, Tyr, Pro, d H is, Phe, Bip, and Gin; or (ii) R³ is His, R¹ is Nle or Ala, R⁷ is Lys or Cys, Y³ is not dVal, and Y⁴ is absent, wherein when X¹ is present, then Y¹ is not dTle, and when X¹ is absent, then Y² is dPro; and when R⁴ is dNal(2’), then R³ is His or Pro, wherein when R³ is Pro, then the non- naturally occurring melanocortin analog is cyclized between a disulfide bond between dPen at R² and dPen at R⁷ or R⁸; and when R³ is His, then either (i) the non-naturally occurring melanocortin analog is cyclized between a lactam bond between Glu at R¹ or R² and Orn at R⁷ or (ii) Y¹-Y⁴ are absent. [0009] In some embodiments, the present technology comprises a method of preventing or reducing anorexia in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁴ is selected from the group consisting of dPhe, 2’-D-naphthylalanine (dNal (2’)) , para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁶ is selected from the group consisting of Trp, 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia) , 4-amino-1 ,2,4,5-tetrahydro-2- benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-[1 ,2, 3]triazolo-[1 , 5-a] [1 ,4]diazepin- 6(5H)-one (Ata), 2’-naphthylalanine (Nal(2’)), and dNal(2’);

R⁸ is absent or dPen;

Y¹ is absent or is selected from the group consisting of D-valine (dVal), D-proline (dPro), D-tert-leucine (dTle), dArg, and dLys; Y² is absent or is selected from the group consisting of dVal, dPro, D- hydroxyproline (dHyp), 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 R¹ or R² and R⁷ when each of R¹ or R² and R⁷ are Cys; a disulfide bond between R² and R⁷ or R⁸ when each of R² and R⁷ or R⁸ are dPen; and a lactam bridge between R¹ or R² and R⁷ when R¹ or R² is Asp or Glu, and R⁷ is Lys or Orn, provided that: when R⁴ is dPhe, then (i) R³ is d Bip; or (ii) R³ is Pro and either R⁵ is Lys or R⁶ is dNal(2’) or Nal(2’); when R⁴ is p(F)dPhe, then (i) R³ is selected from Tyr, Phe, Bip, and Trp; or (ii) R³ is Pro and either R⁶ is Nal(2’) or dNal(2’) or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R² and R⁷; when R⁴ is p(CI)dPhe, then (i) R³ is selected from dPhe, dTyr, T rp, Tyr, Pro, d H is, Phe, Bip, and Gin; or (ii) R³ is His, R¹ is Nle or Ala, R⁷ is Lys or Cys, Y³ is not dVal, and Y⁴ is absent, wherein when X¹ is present, then Y¹ is not dTle, and when X¹ is absent, then Y² is dPro; and when R⁴ is dNal(2’), then R³ is His or Pro, wherein when R³ is Pro, then the non- naturally occurring melanocortin analog is cyclized between a disulfide bond between dPen at R² and dPen at R⁷ or R⁸; and when R³ is His, then either (i) the non-naturally occurring melanocortin analog is cyclized between a lactam bond between Glu at R¹ or R² and Orn at R⁷ or (ii) Y¹-Y⁴ are absent.

[0010] In some embodiments, the present technology comprises a method of preventing or reducing anorexia nervosa in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁴ is selected from the group consisting of dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CP3)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁶ is selected from the group consisting of Trp, 4-amino-1 , 4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), 4-amino-1 ,2,4,5-tetrahydro-2- benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-[1 ,2, 3]triazolo-[1 ,5-a][1 ,4]diazepin- 6(5H)-one (Ata), 2’-naphthylalanine (Nal(2’)), and dNal(2’);

R⁸ is absent or dPen;

Y² is absent or is selected from the group consisting of dVal, dPro, D- hydroxyproline (dHyp), and dTle; Y³ is absent, dVal, or dPro;

[0011] In some embodiments, the present technology comprises a method of increasing, maintaining, or reducing a loss in a body mass index (BMI) level in a subject in need thereof relative to a control, comprising administering to the subject: a non- naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁶ is selected from the group consisting of Trp, 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), 4-amino-1 ,2,4,5-tetrahydro-2- benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 , 5-a][1 ,4]diazepin- 6(5H)-one (Ata), 2’-naphthylalanine (Nal(2’)), and dNal(2’);

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

[0012] In some embodiments, the present technology comprises a method of increasing body weight in a subject in need thereof, comprising administering to the subject a non-naturally occurring melanocortin analog comprising a sequence of Formula (IE):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (IE), wherein:

R¹ is Nle; R² is Asp or Glu;

R³ is Pro or His;

R⁴ is p(CI)dPhe or p(Br)dPhe;

R⁵ is Arg;

R⁶ is Trp;

R⁷ is Orn;

Y¹ is d Vai;

[0013] In some embodiments, the present technology comprises a method of preventing or reducing cachexia in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

[0014] In some embodiments, the present technology comprises a method of preventing or reducing cachexia in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

[0015] In some embodiments, the present technology comprises a method of preventing or reducing anorexia in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

[0016] In some embodiments, the present technology comprises a method of preventing or reducing anorexia nervosa in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

[0017] In some embodiments, the present technology comprises a method of increasing, maintaining, or reducing a loss in a body mass index (BMI) level in a subject in need thereof relative to a control, comprising administering to the subject: a non- naturally occurring melanocortin analog comprising a sequence of Formula (IE).

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG. 1 shows TCMCB07 (SEQ ID NO: 271 ) levels in human plasma, simulated gastric fluid (SGF), and simulated intestinal fluid (SIF) over a 120-minute incubation period.

[0019] FIG. 2 shows TCMCB07 (SEQ ID NO: 271) plasma concentration after oral administration in cynomolgus monkeys at 30.0 mg/kg.

DETAILED DESCRIPTION

[0020] The present technology comprises non-naturally occurring melanocortin analogs, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, collectively referred to herein as melanocortin analogs, for modulating weight in subjects in need thereof. In some embodiments, the non-naturally occurring melanocortin analog is a non-naturally occurring melanocortin analog. The non-naturally occurring melanocortin analogs may be useful in treating, preventing, or reducing one or more symptoms or conditions associated with weight loss. For example, the non-naturally occurring melanocortin analogs may be used to treat, prevent, or otherwise ameliorate one or more of anorexia, anorexia nervosa, cachexia, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite. Cachexia may include cancer-induced cachexia or drug-induced cachexia.

[0021] In some embodiments, the present technology comprises methods of treating, preventing, reducing, or otherwise ameliorating one or more symptoms or conditions associated with metabolic dysfunction in a subject in need thereof. The methods comprise administering a non-naturally occurring melanocortin analog of the present technology to the subject. In some embodiments, the method comprises increasing a level of, reducing a loss of, or maintaining an appetite, a weight, a body mass index (BMI) measurement, a fat mass, or a cardiac mass in the subject.

[0022] 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.

[0023] Furthermore, the detailed description herein is presented for purposes of illustration only and not of limitation. For example, steps recited in any method or process may be executed in any order and are not limited to the order presented. Moreover, any of the steps thereof may be outsourced to or performed by one or more third parties.

Definitions

[0024] 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.

[0025] The articles “a” and “an” are used herein to refer to one or to more than one (i.e. , to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Likewise, any reference to singular includes plural embodiments, and any reference to more than one component may include a singular embodiment.

[0026] 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.

[0027] The terms “administering” or “administer” include delivery of therapies (e.g., non-naturally occurring melanocortin analogs (also referred to herein as peptides)) of the present technology to a subject either by local or systemic administration. Administration may be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer), intratracheal, intranasal, epidermal and transdermal, oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.

[0028] The terms “active ingredient” and “active compound” refer to a biologically active substance, whether naturally or non-naturally occurring, that is the main component of the pharmaceutical composition which elicits the intended effect of an administered therapeutic. This may be any component that drives the pharmacological activity or direct effect in the diagnosis, cure, mitigation, treatment, or prevention of the conditions associated with the present technology, such as but not limited to, reduced appetite and weight loss.

[0029] 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.

[0030] As used herein, a “pharmaceutically acceptable carrier” of the first or the second pharmaceutical composition refers to a carrier or diluent that does not cause significant irritation to an organism, does not abrogate the biological activity and properties of the administered active ingredient, and/or does not interact in a deleterious manner with the other components of the composition in which it is contained. The term “carrier” encompasses any excipient, binder, diluent, filler, salt, buffer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations. The choice of a carrier for use in a composition will depend upon the intended route of administration for the composition. The preparation of pharmaceutically acceptable carriers and formulations containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 21 st Edition, ed. University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia Pa., 2005, which is incorporated herein by reference in its entirety). Some examples of physiologically acceptable carriers include antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEN® (ICI, Inc.; Bridgewater, N.J.), polyethylene glycol (PEG), and PLURONICS™ (BASF; Florham Park, N.J.). An “excipient” of the first or the second pharmaceutical composition refers to an inert substance added to a composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0031] The terms “treat,” “treatment,” and “treating” refer to a manner of providing a pharmaceutical composition and/or melanocortin analog to alleviate disease outcomes. This includes utilizing administration techniques as described in the context of the present technology. Efficacy of treatment may be determined by various assessment methods as described in the context of the present technology (e.g., assessment of appetite, food consumption, body weight, muscle mass, fat mass, and measurement of biomarkers). The term “biomarker” refers to a biological output that is used as a measure of cellular response, whether that be to assess response to therapeutics, disease status, such as cachexia, or as a predictor of clinical outcomes. Biomarkers evaluated in the context of cells, tissue, or whole organisms. The term “disease” herein refers to any disorder adversely affecting biological status. This includes weight-related disorders, such as cachexia. Disease also may be in the context of human and animal health.

[0032] The terms “treat,” “treatment,” and “treating” may also refer to the reduction or inhibition of the progression and/or duration of a disease or disorder (e.g., metabolic disease, including, but not limited to, cachexia), the reduction or amelioration of the severity of the disease or disorder, and/or the amelioration of one or more symptoms thereof resulting from the administration of one or more therapies. Specifically, these terms may refer to: (1 ) a stabilization, reduction, or elimination of the disease or disorder, (2) inhibiting exacerbation of the disease or disorder, (3) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with a pathology related to or caused in part by unregulated or aberrant metabolism, (4) an increase in disease-free, relapse-free, progression-free, and/or overall survival, duration, or rate, (5) a decrease in hospitalization rate, and (6) a decrease in hospitalization length. The terms “treat,” “treatment,” and “treating” include prophylactic and/or therapeutic treatments. If it is administered prior to clinical manifestation of a condition, the treatment is considered prophylactic. Therapeutic treatment includes, e.g., ameliorating or reducing the severity of a disease or disorder, or shortening the length or frequency of the disease or disorder.

[0033] As used herein, the terms “effective amount” or “therapeutically effective amount,” refer to that amount of the active ingredient being administered which will relieve to some extent one or more of the symptoms of the disease or disorder being treated. The result may be a reduction and/or alleviation of the signs, symptoms, or causes of a disease or disorder, or any other desired alteration of a biological system. An appropriate “effective amount” may differ from one individual to another. An appropriate “effective amount” in any individual case may be determined using techniques, such as a dose escalation study.

[0034] The term “after administration” refers to any duration of time after the non- naturally occurring melanocortin analog or pharmaceutical composition thereof has been administered to a subject. “After administration” may also refer to the duration of time after one dose has been completed or after more than one dose has been completed, such as two doses, three doses, four doses, and the like. In some embodiments, “after administration” refers to completion of dosing regimen that includes one or more doses. Likewise, the term “prior to” refers to any duration of time before the non-naturally occurring melanocortin analog or pharmaceutical composition thereof has been administered to a subject. Unless otherwise specified, durations of time encompassed by “after administration” or “prior to administration” may include seconds, minutes, hours, days, weeks, months, and years.

[0035] "Appetite" in a subject and/or patient is typically assessed by their desire to eat and/or the amount of food they consume. As used herein, appetite may be assessed through a daily questionnaire given at specified or random times of the day. In the questionnaire, subjects or patients rate their hunger and/or desire to eat greater varieties of food using scales ranging from 0 (not at all) to 100 (extremely).

[0036] “Cachexia” refers to a state of general ill health and malnutrition characterized by loss of body mass including loss of weight, loss of muscle mass (skeletal, smooth, and/or cardiac muscle), loss of fat mass, or a combination thereof, and wasting. It is often associated with and induced by certain diseases or conditions such as, but not limited to, cancer, cystic fibrosis, or AIDS. The term “cancer cachexia” refers to cachexia induced by cancer. Diagnostic criterion for cachexia may include (i) weight loss of greater than 5% over past 6 months; (ii) weight loss of greater than 2% in patients with a body mass index (BMI) less than 20 kg/m²; or (iii) weight loss of greater than 2% in patients with sarcopenia (or appendicular skeletal muscle index consistent with sarcopenia). See Fearon K, et al., Lancet Oncol. 12(5):489-95 (2011 ). Cachexia may be used interchangeably with the term “Protein-Energy Wasting” (i.e. , PEW).

[0037] “Anorexia” refers to a general loss of appetite, whether brought on by medical, physiological, or psychological factors. Anorexia is often closely associated with, and generally contributes to, cachexia seen in patients with advanced cancers and other conditions.

[0038] “Anorexia nervosa” refers to the eating disorder associated with selfstarvation. Anorexia nervosa is often characterized by extreme efforts to lose weight, fear of gaining weight, and/or poor body image.

[0039] The term “Body Mass Index” or “BMI” refers to a value derived from an individual’s body weight and height. Specifically, BMI is determined by body weight (kilograms) divided by the square of height (m²) and is expressed in units of “kg/m².” "Normal" BMI ranges are known to a person of ordinary skill in the art and consider factors such as patient sex, age, height, race, and body type. Typically, a normal BMI range is about 18.5 kg/m² to about 25 kg/m².

[0040] The terms “subject” and “patient” refer to anyone being evaluated for disease, disorder, or condition or being administered a therapeutic or pharmaceutical composition. This includes people without diagnosed or confirmed disease or condition. This also includes people with diagnosed or confirmed disease or condition, such as cancer, loss of appetite, nausea, emesis, anorexia, anorexia nervosa, or cachexia.

[0041] 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.

[0042] “Melanocortin analogs,” “non-naturally occurring melanocortin analogs,” “melanocortin peptides,” “melanocortin receptor peptides,” or“melanocortins,” are used interchangeably and refer to melanocortin-receptor ligands, which are macromolecules containing at least one melanocortin pharmacophore. Melanocortin analogs are typically peptides that bind melanocortin receptors under physiological conditions. Melanocortin analogs include naturally occurring non-naturally occurring melanocortin analogs (i.e. , “synthetic peptides” or “synthetic analogs”) and truncated and/or modified versions of melanocortin full-length protein or peptides. For example, the full-length proopiomelanocortin protein (POMC), prior to proteolytic cleavage of “sub-peptides,” consists of 241 amino acids. Tissue-specific proteolytic cleavage of POMC yields peptides ranging in size from 13 amino acids to 76 amino acids. See Bicknell and Lawry, Encyclopedia of Stress, vol. 3, 257-265, Academic Press (2000). Synthesized, non- naturally occurring melanocortin analogs having increased melanocortin receptor activity as discussed herein are approximately 7-12 amino acids in size. Melanocortin analogs exhibit binding functionality with melanocortin receptors. The binding to the melanocortin receptor is inhibitory (antagonist). In addition to peptides, the non-naturally occurring melanocortin analogs include small molecule analogs of melanocortin or portions thereof comprised of organic compounds, inorganic compounds, or combinations of peptide and small molecule — i.e., peptide mimetics, or various combinations thereof. “Non-naturally occurring melanocortin analogs” may be structurally similar and/or functionally similar to biological melanocortin proteins in their ability to bind melanocortin receptors. Further, the melanocortin analogs generally contain the pharmacophore: His-Phe-Arg-Trp (SEQ ID NO: 1) or a modified version thereof, or a structural or functional peptide mimetic thereof.

[0043] A “pharmacophore” is the minimum set of amino acid residues necessary to achieve a physiological effect; or a small molecule that is (with respect to a receptor) a structural mimic of the amino acid residues required for binding to and activation of a receptor. His-Phe-Arg-Trp (SEQ ID NO: 1 ) and their analogs are the pharmacophore of melanocortin for the regulated physiological effect. Therefore, non-naturally occurring melanocortin pharmacophore analogs may be small peptides or organic molecules designed to mimic the appearance or function (including activation or deactivation of receptor activity) of the melanocortin pharmacophore core sequence peptide.

[0044] A melanocortin receptor “agonist” is a naturally occurring substance or manufactured drug substance or composition that may interact with a melanocortin receptor and initiate a pharmacological response characteristic of the melanocortin receptor.

[0045] A melanocortin receptor “antagonist” is a naturally occurring substance or manufactured drug substance or composition that opposes the melanocortin receptor- associated responses normally induced by a melanocortin receptor agonist agent.

[0046] “Potentiated therapeutic activity” refers to an increase in melanocortin activity in a non-naturally occurring melanocortin analog that has undergone derivatization at the N- and/or C-terminus. Such derivatizations do not necessarily involve the pharmacophore, but do imply a relative increase in in vivo biological halflife.

[0047] The terms “bind,” “binding,” “complex,” and “complexing,” refer to all types of physical and chemical binding, reactions, complexing, attraction, chelating and the like.

[0048] The “peptides” of the present technology may be (a) naturally-occurring, (b) produced by chemical synthesis, (c) produced by recombinant DNA technology, (d) produced by biochemical or enzymatic fragmentation of larger molecules, (e) produced by methods resulting from a combination of methods (a) through (d) listed above, or (f) produced by any other means for producing peptides.

[0049] 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.

[0050] 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.

[0051] “Amino acids” are molecules containing an amine group, a carboxylic acid group, and a side-chain that is specific to each amino acid. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen and have the generic formula H2N — CHR — COOH, wherein R represents a side chain group. The various a-amino acids differ in the side-chain moiety that is attached to the a-carbon. The “amino acids” of the present technology include the known naturally occurring protein amino acids, which are referred to by both their common three letter abbreviation and single letter abbreviation. See generally Synthetic Peptides: A User’s Guide, G. A. Grant, editor, W.H. Freeman & Co., New York (1992), the teachings of which are incorporated herein by reference, including the text and table set forth at pages 11 through 24. As set forth above, the term “amino acid” also includes stereoisomers and modifications of naturally occurring protein amino acids, 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 teachings of all of which are incorporated herein by reference.

[0052] The phrase “amino acid side chain moiety” used herein, including as used in the specification and claims, includes any side chain of any amino acid, as the term “amino acid” is defined herein. This thus includes the side chain moiety present in naturally occurring amino acids. It further includes side chain moieties in modified naturally occurring amino acids, such as glycosylated amino acids. It further includes side chain moieties in stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs, or structures designed to mimic amino acids, and the like. For example, the side chain moiety of any amino acid of the present technology is included within the definition. A “derivative” of an amino acid side chain moiety is included within the definition of an amino acid side chain moiety.

[0053] 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.

[0054] In the peptides of the present technology, conventional amino acid residues have their conventional meaning as given in Chapter 2400, of the Manual of Patent Examining Procedure, 8^th Ed. Thus, “Ala” is alanine; “Arg” is arginine; “Asn” is asparagine; “Asp” is aspartic acid; “Cys” is cysteine; “Gin” is glutamine; “Glu” is glutamic acid; “His” is histidine; “lie” is isoleucine; “Leu” is leucine; “Lys” is lysine; “Met” is methionine; he” is phenylalanine; “Pro” is proline; “Ser” is serine; “Thr” is threonine; “Trp” is tryptophan; “Tyr” is tryosine; and “Vai” is valine. Unless otherwise indicated, all amino acids abbreviations represent either isomer, i.e. , the L-isomer, the D-isomer, or combinations thereof may be used. Thus, for example, “L-Phe” is L-phenylalanine; “D- Phe” is D-phenylalanine; “D-/L-Phe” is D-phenylalanine, L-phenylalanine, or combinations thereof; The” is also D-phenylalanine, L-phenylalanine, or combinations thereof, and so on.

[0055] An alpha (a)-amino acid has the generic formula H2N — CaHR — COOH, where R is a side chain moiety and the amino group is attached to the carbon atom immediately adjacent to the carboxylate group (i.e., the a-carbon). Other types of amino acids exist when the amino group is attached to a different carbon atom. For example, beta (P)-amino acids, the carbon atom to which the amino group is attached is separated from the carboxylate group by one carbon atom, Cp. [0056] When p-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 p³ peptides and those with the side chain residue on the carbon next to the carbonyl group are called p² amino acids.

[0057] Gamma (y)-amino acids are amino acids with the carbon atom to which the amino group attaches is separated from the carboxylate moiety by two carbon atoms.

[0058] For additional modified and unusual amino acids, see §2422 of the MPEP, particularly Table 4 at 2400-24. Additionally, “Ac” indicates N-acetyl and “cyclo” refers to a cyclic structure, which is also shown as “c.” “NH2” indicates an amine group, typically added on the C-terminus of a polypeptide. Accordingly, as used herein, an — NH2 moiety on the C-terminus of a peptide indicates an amide, i.e. , — CO — NH2.

[0059] Additional abbreviations are used as follows: Nle is norleucine; Nal(2’) is 2 - naphthylalanine; Nal(1') is T-naphthylalanine; Tie is tert-leucine; Nva is norvaline; Orn is ornithine; Bip is biphenylalanine; Hyp is hydroxyproline; Mamb is 3-aminomethyl- benzoic acid; Pen is Penicillamine; Tic is 1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid; Aba is 4-amino-1 ,2,4,5-tetra-hydro-2-benzazepin-3-one; Oic is octohydroindole- 2-carboxylic acid; Ate is 2-aminotetraline-2-carboxylic acid; APC is 1-amino-4- phenylcyclohexane-carboxylic acid; APPC is 4-aminophenylpiperidine-4-carboxylic acid; Acpc is 1-aminocyclo-propane-1 -carboxylic acid; Aic is 2-aminoindone-2- carboxylic acid; Ata is 7-amino-7,8-dihydro-4H-[1 ,2,3]triazolo-[1 ,5-a][1 ,4]diazepin- 6(5H)-one; Aia is 4-amino-1 ,4,5,6-tetrahydroazepino[4,3-b]indol-3(2/-/)-one; Che is 1- amino-1 -cyclohexanecarboxylic acid loc is indoline-2-carboxylic acid, Aic is 2- aminoindone-2-carboxylic acid; Cpe is 1-amino-1 -cyclopentane carboxylic; and p(CI)dPhe is para-chloro-phenylalanine (I - iodo, F - fluoro, Br - bromo, CF3 - trifluoromethyl).

[0060] 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.”

[0061 ] 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.

[0062] An “amine” includes compounds that contain an amine group ( — NH2). [0063] 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.

[0064] 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.”

[0065] “Substantial degradation” refers to the degradation of the N-terminal extension, the C-terminal extension, both N- and C-terminal degradation or degradation to other regions of the non-naturally occurring melanocortin analog by physiological enzymes and other factors, in such a manner or to a degree that side effects appear. According to one aspect, a non-naturally occurring melanocortin analog having a C- terminal extension that resists substantial degradation is one where no more than 50% of the administered peptide causes side effects and/or displays a low half-life. In some aspects, no more than 25% of the administered peptide causes side effects and/or displays a low half-life. More preferably, in some aspects, less than 10% of the administered peptide causes side effects and/or displays a low half-life, as compared to a non-naturally occurring melanocortin analog that lacks a C-terminal extension.

[0066] 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 and PCT Patent Application Nos. WO/2024/177907 and WO2024/086381 .

Non-naturally Occurring Melanocortin Analogs

[0067] The non-naturally occurring melanocortin analogs of the present technology may comprise a non-naturally occurring melanocortin analog or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Non-naturally occurring melanocortin analogs of the present technology may be selective for the melanocortin 4 receptor (MC4R) and/or melanocortin 3 receptor (MC3R) over other melanocortin receptors, i.e., the melanocortin 1 receptor (MC1 R), the melanocortin 2 receptor (MC2R), and the melanocortin 5 receptor (MC5R). Some of the non-naturally occurring melanocortin analogs may bind 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.

[0068] 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%.

[0069] 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%.

[0070] 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).

[0071 ] The non-naturally occurring melanocortin analogs of the present technology may be one or more of (i) a full MC4R antagonist and a full MC3R antagonist; (ii) a full MC4R antagonist and a partial MC3R antagonist; (iii) a full MC4R antagonist and a full MC4R agonist; (iv) a full MC4R antagonist and a partial MC3R agonist; (v) a full MC4R antagonist having no MC3R activity; (vi) a partial MC4R antagonist and a full MC3R antagonist; (vii) a partial MC4R antagonist and a partial MC3R antagonist; a partial MC4R antagonist and a full MC4R agonist; (viii) a partial MC4R antagonist and a partial MC3R agonist; (ix) a partial MC4R antagonist having no MC3R activity; (x) a partial MC4R agonist and a full MC3R antagonist; (xi) a partial MC4R agonist and a partial MC3R antagonist; (xii) a partial MC4R agonist and a partial MC3R agonist; (xiii) a partial MC4R agonist and a full MC3R agonist; and (ixx) a partial MC4R agonist having no MC3R activity.

[0072] The non-naturally occurring melanocortin analogs in accordance with the present technology may have certain structural features that impart specific properties on the analogs, such as, for example, degradation resistance, enhanced epithelial, gastrointestinal, and/or blood brain barrier transport, and binding affinity for the melanocortin 4 receptor and/or melanocortin 3 receptor. Accordingly, in some embodiments, the non-naturally occurring melanocortin analogs have one or more beta hairpin (P-hairpin) and/or beta turn (P-turn) structures. The presence of amino acids that are structurally rigid, such as, for example, Aia, Aba, Ata, dHyp, Pro, and dPro, may lead to formation of p-hairpin and/or p-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 D- valine-D-proline (dVal-dPro) chain as their C-terminus, which may provide enhanced transport and resistance to degradation.

[0073] 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 large amino acids like p(Br)dPhe, p(l)dPhe, p(CF3)dPhe, and dNal(2’) at the R⁴ position may result in enhanced inhibition of the melanocortin 4 and the melanocortin 3 receptors. Accordingly, melanocortin analogs having like p(Br)dPhe, p(l)dPhe, p(CFs)dPhe, and dNal(2’) at R⁴ may be full antagonists on MC3R and MC4R. Additionally, smaller amino acids, such as p(CI)dPhe, may confer inhibitory activity on the melanocortin analogs when the Pro is included at the R³ position. Such melanocortin analogs may by full antagonists on MC3R and partial antagonists on MC4R.

[0074] Melanocortin analogs in accordance with the present technology may reduce lean mass loss, maintain lean mass, or promote lean mass gain in a subject in need thereof. Additionally, the melanocortin analogs of the present technology may not induce change in plasma insulin levels in the subject, as is seen for other melanocortin analog peptides and small molecules that exhibit antagonist activity on one or more melanocortin receptors. For example, a subject may maintain stable plasma insulin levels, while maintaining or gaining lean mass, following administration of a melanocortin antagonist of the present technology.

[0075] 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-Y¹-Y²-Y³-Y⁴ (I), wherein: X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁴ is selected from the group consisting of dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

[0076] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R¹ is selected from the group consisting of D-norleucine (dNIe), Arg, D-arginine (dArg), Nle, aspartic acid (Asp), D-leucine (dLeu), alanine (Ala), cysteine (Cys), D- phenylalanine (dPhe), D-tyrosine (dTyr), glutamic acid (Glu), histidine (His), D-histidine (dHis), lysine (Lys), and D-lysine (dLys); R² is selected from the group consisting of D-alanine (dAla), Asp, Cys, D- penicillamine (dPen), Glu, and proline (Pro);

R³ is selected from the group consisting of phenylalanine (Phe), dPhe, His, d H is, Pro, glutamine (Gin), D-glutamine (dGIn), tryptophan (Trp), D-tryptophan (dTrp), tyrosine (Tyr), dTyr, biphenylalanine (Bip), and D-biphenylalanine (dBip);

R⁴ is selected from the group consisting of dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁶ is selected from the group consisting of Trp, 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), 4-amino-1 ,2,4,5-tetrahydro-2- benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-[1 ,2, 3]triazolo-[1 , 5-a][1 ,4]diazepin- 6(5H)-one (Ata), 2’-naphthylalanine (Nal(2’)), and dNal(2’);

R⁸ is absent or dPen;

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 R¹ or R² and R⁷ when each of R¹ or R² and R⁷ are Cys; a disulfide bond between R² and R⁷ or R⁸ when each of R² and R⁷ or R⁸ are dPen; and a lactam bridge between R¹ or R² and R⁷ when R¹ or R² is Asp or Glu, and R⁷ is Lys or Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:

Ac-Nle-c[Cys-His-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 104);

Ac-Nle-c[Cys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 105);

Ac-Nle-c[dPen-Pro-dPhe-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 106);

Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-NH₂ (SEQ ID NO: 107);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Aba-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 108);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Aia-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 109);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Ata-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 110);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH₂ (SEQ ID NO: 111 );

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-NH₂ (SEQ ID NO: 112);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dPro-NH₂ (SEQ ID NO: 113);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH₂ (SEQ ID NO: 114);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-l_ys]-dArg-dVal-dPro-NH₂ (SEQ ID NO: 115);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH₂ (SEQ ID NO: 116);

Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH₂ (SEQ ID NO: 117);

Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH₂ (SEQ ID NO: 118);

Ac-Nle-c[Asp-dGln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 119);

Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH₂ (SEQ ID NO: 120);

Ac-dl_eu-c[Asp-Pro-dPhe-Arg-Trp-l_ys]-dVal-dPro-NH₂ (SEQ ID NO: 121 );

Ac-dl_ys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH₂ (SEQ ID NO: 122);

Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dPro-NH₂ (SEQ ID NO: 123);

Ac-dPhe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 124); dPhe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 125);

Ac-Nle-c[Asp-dTrp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 126); Ac-dTyr-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 127);

Ac-Nle-c[Asp-dTyr-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 128);

Ac-Nle-c[Asp-dTyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 129);

Ac-Nle-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 130);

Ac-Nle-c[Asp-Trp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 131 );

Ac-Nle-c[Asp-Tyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 132);

Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 133);

Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 134);

Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 135);

Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 136);

Ac-Nle-c[Asp-Bip-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 137);

Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 138);

Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 139);

Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 140);

Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH₂ (SEQ ID NO: 141 );

Ac-Arg-c(Asp-dAla-His-dPhe-Arg-Trp-Lys)-NH₂ (SEQ ID NO: 142);

Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 143);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 144);

Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 145);

Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 146);

His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 147); dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 148);

Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 149);

Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 150);

Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 151 );

Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-d al-dPro-NH₂ (SEQ ID NO: 152); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 153);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 154);

Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 155);

Ac-Nle-c[Asp-His-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 156);

Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 157);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 158);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH₂ (SEQ ID NO: 159);

Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 160);

Ac-Nle-c[Asp-Pro-dPhe-Arg-dTrp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 161);

Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 162);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 163);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH₂ (SEQ ID NO: 164);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-l_ys]-dVal-dPro-OH (SEQ ID NO: 165);

Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 166);

Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 167);

Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 168);

Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 169);

Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 170);

Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 171 );

Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 172);

Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 173);

Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 174);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH₂ (SEQ ID NO: 175);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH₂ (SEQ ID NO: 176);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH₂ (SEQ ID NO: 177);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 178); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH₂ (SEQ ID NO: 179);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH₂ (SEQ ID NO: 180);

Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 181 );

Ac-dNle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 182);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dHyp-NH₂ (SEQ ID NO: 183);

Ac-Nle-c[Asp-dBip-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 184);

Ac-Nle-c[Asp-dGln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 185);

Ac-Nle-c[Asp-dTrp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 186);

Ac-Nle-c[Asp-dTyr-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 187);

Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 188);

Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 189);

Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 190);

Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 191 );

Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 192);

Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 193);

Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 194);

Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 195);

Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 196);

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 197);

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 198);

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH₂ (SEQ ID NO: 199);

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH₂ (SEQ ID NO: 200);

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 201 );

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 202);

Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 203);

Ac-Nle-Nle-o[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 204); Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 205);

Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 206);

Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 207);

Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 208);

Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 209);

Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 210);

Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 21 1 );

Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 212);

Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 213);

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 214);

Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 215);

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 216);

Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 217);

Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 218);

Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 219);

Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 220);

Ac-dl_ys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 221 );

Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 222);

Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 223);

Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 224);

Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 225);

Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH₂ (SEQ ID NO: 226);

Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH₂ (SEQ ID NO: 227);

Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 228);

Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 229);

Ac-Nle-Nle-o[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 230); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 231 );

Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 232);

Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 233);

Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 234);

Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 235);

Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 236);

Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 237);

Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 238);

Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 239);

Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 240);

Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 241 );

Ac-Nle-c[Asp-dPhe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 242);

Ac-Nle-c[Asp-dBip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 243);

Ac-Nle-c[Asp-dGln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 244);

Ac-Nle-c[Asp-dTrp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 245);

Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 246);

Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 247);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 248);

Ac-Nle-c[Glu-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 249);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH₂ (SEQ ID NO: 250);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH₂ (SEQ ID NO: 251 );

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 252);

Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 253);

Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 254);

Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 255); Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 256);

Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 257);

Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 258);

Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 259);

Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 260);

Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 261 );

Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 262);

Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 263);

Ac-Nle-c[Asp-dTrp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 264);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 271 );

Ac-Nle-c[Asp-Trp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 272);

Ac-Nle-c[Asp-Pro-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 273);

Ac-Nle-c[Asp-Pro-His-dNal(2')-Arg-Trp-Lys]-dPro-dVal-NH₂ (SEQ ID NO: 274);

Ac-dArg-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 275);

Ac-dLeu-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 276);

Ac-Ala-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 277);

Ac-dNle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 278);

Ac-dPhe-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 279);

Ac-dTyr-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 280); dTyr-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 281 );

Tyr-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 282);

Ac-Nle-c[Cys-Pro-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 283);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 284);

Ac-Nle-c[Glu-Pro-dNal(2')-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 285);

Ac-Nle-c[Asp-Pro-dNal(2')-Lys-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 286);

Ac-Nle-c[Asp-Pro-dNal(2')-His-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 287); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 288);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 289);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 290);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 291 );

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-d\/al-NH2 (SEQ ID NO: 292);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dPro-NH2 (SEQ ID NO: 293);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-NH2 (SEQ ID NO: 294);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-NH2 (SEQ ID NO: 295);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dHyp-NH2 (SEQ ID NO: 296);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 297);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-NH2 (SEQ ID NO: 298);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dl_ys-dPro-d\/al-NH2 (SEQ ID NO: 299);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dl_ys-dPro-NH2 (SEQ ID NO: 300);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dl_ys-dVal-dPro-NH2 (SEQ ID NO: 301 );

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-dPro-dVal-NH2 (SEQ ID NO: 302);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 303);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dVal-dPro-NH2 (SEQ ID NO: 304);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 305);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dVal-NH2 (SEQ ID NO: 306);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dTle-NH2 (SEQ ID NO: 307);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 308);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 309);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dTle-NH2 (SEQ ID NO: 310);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 311 );

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 312);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 313); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH₂ (SEQ ID NO: 314);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH₂ (SEQ ID NO: 315);

Ac-Nle-c[Asp-Pro-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 316);

Ac-Nle-c[Asp-Glu-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 317);

Ac-Nle-c[Asp-dAla-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 318);

Ac-Arg-c[Asp-dAla-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 319); and

Ac-Arg-c[Cys-dAla-His-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 320).

[0077] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein R⁴ is not dPhe or p(F)dPhe. Accordingly, in some embodiments, the sequence of Formula (I) comprises a sequence of Formula (IA):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (IA), wherein:

X¹ is absent, Nle, or Arg;

R¹ is selected from the group consisting of dNIe, Arg, dArg, Nle, Asp, dLeu, Ala, Cys, dPhe, dTyr, Glu, His, dHis, Lys, and dLys;

R² is selected from the group consisting of dAla, Asp, Cys, dPen, Glu, and Pro;

R³ is selected from the group consisting of Phe, dPhe, His, dHis, Pro, Gin, dGIn, Trp, dTrp, Tyr, dTyr, Bip, and dBip;

R⁴ is selected from the group consisting of dNal(2’), p(CI)dPhe, p(l)dPhe, p(Br)dPhe, and p(CF3)dPhe;

R⁵ is Arg or His;

R⁶ is selected from the group consisting of Trp, Aia, Aba, Ata, Nal(2’), and dNal(2’);

R⁷ is selected from the group consisting of Lys, Cys, Gly, dPen, and Orn;

R⁸ is absent or dPen;

Y¹ is absent or is selected from the group consisting of dVal, dPro, dTle, dArg, and dLys; Y² is absent or is selected from the group consisting of dVal, dPro, dHyp, 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 R¹ or R² and R⁷ when each of R¹ or R² and R⁷ are Cys; a disulfide bond between R² and R⁷ or R⁸ when each of R² and R⁷ or R⁸ are dPen; and a lactam bridge between R¹ or R² and R⁷ when R¹ or R² is Asp or Glu, and R⁷ is Lys or Orn.

[0078] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (IA), wherein:

X¹ is absent, Nle, or Arg;

R⁴ is selected from the group consisting of dNal(2’), p(CI)dPhe, p(l)dPhe, p(Br)dPhe, and p(CP3)dPhe;

R⁵ is Arg or His;

R⁷ is selected from the group consisting of Lys, Cys, Gly, dPen, and Orn; R⁸ is absent or dPen;

Y¹ is absent or is selected from the group consisting of dVal, dPro, dTle, dArg, and dLys;

Y² is absent or is selected from the group consisting of dVal, dPro, dHyp, 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 R¹ or R² and R⁷ when each of R¹ or R² and R⁷ are Cys; a disulfide bond between R² and R⁷ or R⁸ when each of R² and R⁷ or R⁸ are dPen; and a lactam bridge between R¹ or R² and R⁷ when R¹ or R² is Asp or Glu, and R⁷ is Lys or Orn, provided that: when R⁴ is p(CI)dPhe, then (i) R³ is selected from dPhe, dTyr, Trp, Tyr, Pro, dHis, Phe, Bip, and Gin; or (ii) R³ is His, R¹ is Nle or Ala, R⁷ is Lys or Cys, Y³ is not dVal, and Y⁴ is absent, wherein when X¹ is present, then Y¹ is not dTle, and when X¹ is absent, then Y² is dPro; and when R⁴ is dNal(2’), then R³ is His or Pro, wherein when R³ is Pro, then the non- naturally occurring melanocortin analog is cyclized between a disulfide bond between dPen at R² and dPen at R⁷ or R⁸; and when R³ is His, then either (i) the non-naturally occurring melanocortin analog is cyclized between a lactam bond between Glu at R¹ or R² and Orn at R⁷ or (ii) Y¹-Y⁴ are absent.

[0079] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA), wherein:

X¹ is absent, Nle, or Arg; R¹ is selected from the group consisting of dNIe, Arg, dArg, Nle, Asp, dLeu, Ala, Cys, dPhe, dTyr, Glu, His, dHis, Lys, and dLys;

R⁴ is selected from the group consisting of dNal(2’), p(CI)dPhe, p(l)dPhe, p(Br)dPhe, and p(CFs)dPhe;

R⁵ is Arg or His;

R⁷ is selected from the group consisting of Lys, Cys, Gly, dPen, and Orn;

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

Ac-Nle-c[Asp-dBip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 243); Ac-Nle-c[Asp-dGln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 244);

Ac-Nle-c[Asp-dTrp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 245);

Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 246);

Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 247);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 248);

Ac-Nle-c[Glu-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 249);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH₂ (SEQ ID NO: 250);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 252);

Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 253);

Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 254);

Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 255);

Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 256);

Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 257);

Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 258);

Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 259);

Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 260);

Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 261);

Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 262);

Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 263);

Ac-Nle-c[Asp-dTrp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 264);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 271 );

Ac-Nle-c[Asp-Trp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 272);

Ac-Nle-c[Asp-Pro-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 273);

Ac-Nle-c[Asp-Pro-His-dNal(2')-Arg-Trp-Lys]-dPro-dVal-NH₂ (SEQ ID NO: 274); Ac-dArg-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 275);

Ac-dLeu-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 276);

Ac-Ala-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 277);

Ac-dNle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 278);

Ac-dPhe-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 279);

Tyr-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 282);

Ac-Nle-c[Cys-Pro-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 283);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 284);

Ac-Nle-c[Glu-Pro-dNal(2')-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 285);

Ac-Nle-c[Asp-Pro-dNal(2')-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 286);

Ac-Nle-c[Asp-Pro-dNal(2')-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 287);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 288);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 289);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 290);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 291 );

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dVal-NH2 (SEQ ID NO: 292);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dPro-NH2 (SEQ ID NO: 293);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-NH2 (SEQ ID NO: 294);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-NH2 (SEQ ID NO: 295);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dHyp-NH2 (SEQ ID NO: 296);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 297);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-NH2 (SEQ ID NO: 298);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dl_ys-dPro-dVal-NH2 (SEQ ID NO: 299);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dl_ys-dPro-NH2 (SEQ ID NO: 300); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dl_ys-dVal-dPro-NH₂ (SEQ ID NO: 301);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-dPro-dVal-NH₂ (SEQ ID NO: 302);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-dVal-dPro-NH₂ (SEQ ID NO: 303);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dVal-dPro-NH₂ (SEQ ID NO: 304);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 305);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dVal-NH₂ (SEQ ID NO: 306);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dTle-NH₂ (SEQ ID NO: 307);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dTle-dPro-NH₂ (SEQ ID NO: 308);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dTle-dVal-NH₂ (SEQ ID NO: 309);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dTle-NH₂ (SEQ ID NO: 310);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dTle-NH₂ (SEQ ID NO: 311 );

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dVal-dPro-NH₂ (SEQ ID NO: 312);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 313);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH₂ (SEQ ID NO: 314);

Ac-Nle-c[Asp-Pro-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 316);

Ac-Nle-c[Asp-Glu-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 317);

Ac-Nle-c[Asp-dAla-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 318);

Ac-Arg-c[Cys-dAla-His-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 320).

[0080] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) or (IA), wherein R⁴ is dNal(2’). When R4 is dNal(2’), then Y⁴ is absent. Accordingly, in some embodiments, the sequence of Formula (I) or (IA) is a sequence of Formula (IB):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³ (IB), wherein:

X¹ is absent or Arg; R¹ is selected from the group consisting of dNIe, Arg, dArg, Nle, Asp, dLeu, Ala, Cys, dPhe, dTyr, Glu, His, dHis, Lys, and dLys;

R² is selected from the group consisting of dAla, dPen, Glu, and Pro;

R³ is His or Pro;

R⁴ is dNal(2’);

R⁵ is Arg or His;

R⁶ is Trp;

R⁷ is selected from the group consisting of Cys, Gly, dPen, and Orn;

R⁸ is absent or dPen;

Y¹ is absent or is selected from the group consisting of dVal, dTle, dArg, and dLys;

Y² is absent or is selected from the group consisting of dVal, dPro, and dHyp;

Y³ 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 R¹ and R⁷ when each of R¹ and R⁷ are Cys; a disulfide bond between R² and R⁷ or R⁸ when each of R² and R⁷ or R⁸ are dPen; and a lactam bridge between R¹ or R² and R⁷ when R¹ or R² is Asp or Glu, and R⁷ is Lys or Orn.

[0081] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³ (IB), wherein:

X¹ is absent or Arg;

R² is selected from the group consisting of dAla, dPen, Glu, and Pro; R³ is His or Pro;

R⁴ is dNal(2’);

R⁵ is Arg or His;

R⁶ is Trp;

R⁷ is selected from the group consisting of Cys, Gly, dPen, and Orn;

R⁸ is absent or dPen;

Y² is absent or is selected from the group consisting of dVal, dPro, and dHyp;

Y³ 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 R¹ and R⁷ when each of R¹ and R⁷ are Cys; a disulfide bond between R² and R⁷ or R⁸ when each of R² and R⁷ or R⁸ are dPen; and a lactam bridge between R¹ or R² and R⁷ when R¹ or R² is Asp or Glu, and R⁷ is Lys or Orn, provided that: when R³ is Pro, then the non-naturally occurring melanocortin analog is cyclized between a disulfide bond between dPen at R² and dPen at R⁷ or R⁸, when R³ is His, then either (i) the non-naturally occurring melanocortin analog is cyclized between a lactam bond between Glu at R¹ or R² and Orn at R⁷ or (ii) Y¹-Y⁴ are absent.

[0082] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³ (IB), wherein:

R² is selected from the group consisting of dAla, dPen, Glu, and Pro;

R³ is His or Pro;

R⁴ is dNal(2’);

R⁵ is Arg or His;

R⁶ is Trp;

R⁷ is selected from the group consisting of Cys, Gly, dPen, and Orn;

R⁸ is absent or dPen;

Y² is absent or is selected from the group consisting of dVal, dPro, and dHyp;

Y³ 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 R¹ and R⁷ when each of R¹ and R⁷ are Cys; a disulfide bond between R² and R⁷ or R⁸ when each of R² and R⁷ or R⁸ are dPen; and a lactam bridge between R¹ or R² and R⁷ when R¹ or R² is Asp or Glu, and R⁷ is Lys or 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-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 271 );

Ac-Nle-c[Asp-Pro-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 273);

Ac-Nle-c[Asp-Pro-His-dNal(2')-Arg-Trp-Lys]-dPro-dVal-NH₂ (SEQ ID NO: 274);

Ac-dArg-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 275);

Ac-dLeu-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 276); Ac-Ala-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 277);

Ac-dNle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 278);

Ac-dPhe-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 279);

Ac-dTyr-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 280); dTyr-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 281);

Tyr-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 282);

Ac-Nle-c[Cys-Pro-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 283);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 284);

Ac-Nle-c[Glu-Pro-dNal(2')-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 285);

Ac-Nle-c[Asp-Pro-dNal(2')-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 286);

Ac-Nle-c[Asp-Pro-dNal(2')-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 287);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 289);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 290);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 291 );

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-d\/al-NH2 (SEQ ID NO: 292);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dPro-NH2 (SEQ ID NO: 293);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-NH₂ (SEQ ID NO: 294);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-NH2 (SEQ ID NO: 295);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dHyp-NH2 (SEQ ID NO: 296);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 297);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-NH2 (SEQ ID NO: 298);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dl_ys-dPro-dVal-NH2 (SEQ ID NO: 299);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dl_ys-dPro-NH2 (SEQ ID NO: 300);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dl_ys-dVal-dPro-NH2 (SEQ ID NO: 301);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-dPro-dVal-NH2 (SEQ ID NO: 302);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 303); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dVal-dPro-NH₂ (SEQ ID NO: 304);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 305);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dVal-NH₂ (SEQ ID NO: 306);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dTle-NH₂ (SEQ ID NO: 307);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dTle-dPro-NH₂ (SEQ ID NO: 308);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dTle-dVal-NH₂ (SEQ ID NO: 309);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dTle-NH₂ (SEQ ID NO: 310);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dTle-NH₂ (SEQ ID NO: 311 );

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dVal-dPro-NH₂ (SEQ ID NO: 312);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 313);

Ac-Nle-c[Asp-Pro-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 316);

Ac-Nle-c[Asp-Glu-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 317);

Ac-Nle-c[Asp-dAla-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 318);

Ac-Arg-c[Cys-dAla-His-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 320).

[0083] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of any one of Formulae (l)-(IB), wherein R⁴ is dNal(2’) and the sequence is cyclized through R² and R⁷ via a disulfide bond. Further, in such embodiments, R³ is Pro. Accordingly, in some embodiments, the sequence of any one of Formulae (l)-(l B) is a sequence of Formula (I B(i)):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³ (IB(i)), wherein:

R¹ is selected from the group consisting of dNIe, Arg, dArg, Nle, dLeu, Ala, dPhe, dTyr, His, dHis, Lys, and dLys;

R² is dPen;

R³ is Pro;

R⁴ is dNal(2’); R⁵ is Arg;

R⁶ is Trp;

R⁷ is Gly or dPen;

R⁸ is absent or dPen;

Y¹ is selected from the group consisting of dVal, dTle, dArg, and dLys;

Y² is selected from the group consisting of dVal, dPro, and dHyp;

Y³ is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between dPen at R² and dPen at R⁷ or R⁸.

[0084] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB(i)):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³ (IB(i)), wherein:

R² is dPen;

R³ is Pro;

R⁴ is dNal(2’);

R⁵ is Arg;

R⁶ is Trp;

R⁷ is Gly or dPen;

R⁸ is absent or dPen;

Y¹ is selected from the group consisting of dVal, dTle, dArg, and dLys;

Y² is selected from the group consisting of dVal, dPro, and dHyp;

Y³ is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between dPen at R² and dPen at R⁷ or R⁸. [0085] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of any one of Formulae (l)-(IB), wherein R⁴ is dNal(2’) and the sequence is cyclized through R¹ or R² and R⁷ via a lactam bond. Further, in such embodiments, R³ is His. Accordingly, in some embodiments, the sequence of any one of Formulae (l)-(l B) is a sequence of Formula (IB(ii)):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (IB(ii)), wherein:

X¹ is absent or Arg;

R¹ is selected from the group consisting of Nle, Cys, Asp, and Glu;

R² is selected from the group consisting of dAla, Glu, and Pro;

R³ is His;

R⁴ is dNal(2’);

R⁵ is Arg or His;

R⁶ is Trp;

R⁷ is Cys or 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 disulfide bond between R¹ and R⁷ when each of R¹ and R⁷ are Cys; and a lactam bridge between R¹ or R² and R⁷ when R¹ or R² is Asp or Glu, and R⁷ is Lys or Orn.

[0086] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB(ii)):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (IB(ii)), wherein:

X¹ is absent or Arg;

R¹ is selected from the group consisting of Nle, Cys, Asp, and Glu; R² is selected from the group consisting of dAla, Glu, and Pro;

R³ is His;

R⁴ is dNal(2’);

R⁵ is Arg or His;

R⁶ is Trp;

R⁷ is Cys or 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 disulfide bond between R¹ and R⁷ when each of R¹ and R⁷ are Cys; and a lactam bridge between R¹ or R² and R⁷ when R¹ or R² is Asp or Glu, and R⁷ is Lys or Orn, provided that either (i) the non-naturally occurring melanocortin analog is cyclized between a lactam bond between Glu at R¹ or R² and Orn at R⁷ or (ii) Y¹-Y⁴ are absent.

[0087] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB(ii)):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (IB(ii)), wherein:

X¹ is absent or Arg;

R¹ is selected from the group consisting of Nle, Cys, Asp, and Glu;

R² is selected from the group consisting of dAla, Glu, and Pro;

R³ is His;

R⁴ is dNal(2’);

R⁵ is Arg or His;

R⁶ is Trp; R⁷ is Cys or 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 disulfide bond between R¹ and R⁷ when each of R¹ and R⁷ are Cys; and a lactam bridge between R¹ or R² and R⁷ when R¹ or R² is Asp or Glu, and R⁷ is Lys or 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-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 273);

Ac-Nle-c[Asp-Pro-His-dNal(2')-Arg-Trp-Lys]-dPro-dVal-NH₂ (SEQ ID NO: 274);

Ac-Nle-c[Asp-dAla-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 318);

Ac-Arg-c[Cys-dAla-His-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 320).

[0088] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein R⁴ is not dNal(2’). For example, when R⁴ is not dNal(2’), R⁴ may be selected from p(CF3)dPhe, p(CI)dPhe, p(Br)dPhe, and p(l)dPhe. Accordingly, in some embodiments, the sequence of Formula (I) is a sequence of Formula (IC):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y²-Y³-Y⁴ (IO), wherein:

X¹ is absent or Nle;

R¹ is selected from the group consisting of Nle, Arg, dArg, Ala, His, dHis, Lys, and dLys;

R² is selected from the group consisting of Asp, Glu, and Cys;

R³ is selected from the group consisting of Phe, dPhe, His, dHis, Pro, Gin, dGIn, Trp, dTrp, Tyr, dTyr, Bip, and dBip; R⁴ is selected from the group consisting of p(CI)dPhe, p(l)dPhe, p(Br)dPhe, and p(CF₃)dPhe;

R⁵ is Arg or His;

R⁶ is selected from the group consisting of Trp, Aia, Aba, Ata, Nal(2’), and dNal(2 );

R⁷ is selected from the group consisting of Lys, Cys, and Orn;

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 moiety selected from the group consisting of: a disulfide bond between R² and R⁷ when R² and R⁷ are each Cys; and a lactam bridge between R² and R⁷ when R² is Asp or Glu, and R⁷ is Lys or Orn.

[0089] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y²-Y³-Y⁴ (IC), wherein:

X¹ is absent or Nle;

R² is selected from the group consisting of Asp, Glu, and Cys;

R⁴ is selected from the group consisting of p(CI)dPhe, p(l)dPhe, p(Br)dPhe, and p(CF₃)dPhe;

R⁵ is Arg or His; R⁶ is selected from the group consisting of Trp, Aia, Aba, Ata, Nal(2’), and dNal(2’);

R⁷ is selected from the group consisting of Lys, Cys, and Orn;

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 moiety selected from the group consisting of: a disulfide bond between R² and R⁷ when R² and R⁷ are each Cys; and a lactam bridge between R² and R⁷ when R² is Asp or Glu, and R⁷ is Lys or Orn, provided that when R⁴ is p(CI)dPhe, then (i) R³ is selected from dPhe, dTyr, Trp, Tyr, Pro, dHis, Phe, Bip, and Gin; or (ii) R³ is His, R¹ is Nle or Ala, R⁷ is Lys or Cys, Y³ is not dVal, and Y⁴ is absent, wherein when X¹ is present, then Y¹ is not dTle, and when X¹ is absent, then Y² is dPro.

[0090] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC), wherein:

X¹ is absent or Nle;

R² is selected from the group consisting of Asp, Glu, and Cys;

R⁴ is selected from the group consisting of p(CI)dPhe, p(l)dPhe, p(Br)dPhe, and p(CP₃)dPhe;

R⁵ is Arg or His;

R⁶ is selected from the group consisting of Trp, Aia, Aba, Ata, Nal(2’), and dNal(2’); R⁷ is selected from the group consisting of Lys, Cys, and Orn;

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 moiety selected from the group consisting of: a disulfide bond between R² and R⁷ when R² and R⁷ are each Cys; and a lactam bridge between R² and R⁷ when R² is Asp or Glu, and R⁷ is Lys or Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:

Ac-Nle-c[Asp-dBip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 243);

Ac-Nle-c[Asp-dGln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 244);

Ac-Nle-c[Asp-dTrp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 245);

Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 246);

Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 247);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 248);

Ac-Nle-c[Glu-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 249);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH₂ (SEQ ID NO: 250);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 252);

Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 253);

Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 254);

Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 255);

Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 256); Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 257);

Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 258);

Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 259);

Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 260);

Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 261 );

Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 262); and

Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 263).

[0091] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) or (IC), wherein R⁴ is p(Br)dPhe. Accordingly, in some embodiments, the sequence of Formula (I) or (IC) is a sequence of Formula (IC(i)):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y²-Y³-Y⁴ (IC(i)), wherein:

X¹ is absent or Nle;

R² is selected from the group consisting of Asp, Glu, and Cys;

R⁴ is p(Br)dPhe;

R⁵ is Arg or His;

R⁶ is selected from the group consisting of Trp, Nal(2’), and dNal(2’);

R⁷ is selected from the group consisting of Lys, Cys, and Orn;

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;

[0092] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC(i)):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y²-Y³-Y⁴ (IC(i)), wherein:

X¹ is absent or Nle;

R² is selected from the group consisting of Asp, Glu, and Cys;

R⁴ is p(Br)dPhe;

R⁵ is Arg or His;

R⁶ is selected from the group consisting of Trp, Nal(2’), and dNal(2’);

R⁷ is selected from the group consisting of Lys, Cys, and Orn;

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 moiety selected from the group consisting of: a disulfide bond between R² and R⁷ when R² and R⁷ are each Cys; and a lactam bridge between R² and R⁷ when R² is Asp or Glu, and R⁷ is Lys or Orn. [0093] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) or (IC), wherein R⁴ is p(CI)dPhe. Accordingly, in some embodiments, the sequence of Formula (I) or (IC) is a sequence of Formula (IC(ii)):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y²-Y³ (IC(ii)), wherein:

X¹ is absent or Nle;

R¹ is Nle or Ala;

R² is selected from the group consisting of Asp, Glu, and Cys;

R³ is selected from the group consisting of Phe, dPhe, His, dHis, Pro, Gin, Trp, Tyr, dTyr, and Bip;

R⁴ is p(CI)dPhe;

R⁵ is Arg or His;

R⁶ is selected from the group consisting of Trp, Nal(2’), and dNal(2’);

R⁷ is selected from the group consisting of Lys, Cys, and Orn;

Y¹ is selected from the group consisting of dVal, dPro, and dTle;

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 disulfide bond between R² and R⁷ when R² and R⁷ are each Cys; and a lactam bridge between R² and R⁷ when R² is Asp or Glu, and R⁷ is Lys or Orn.

[0094] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC(ii)):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y²-Y³ (IC(ii)), wherein:

X¹ is absent or Nle; R¹ is Nle or Ala;

R² is selected from the group consisting of Asp, Glu, and Cys;

R⁴ is p(CI)dPhe;

R⁵ is Arg or His;

R⁶ is selected from the group consisting of Trp, Nal(2’), and dNal(2’);

R⁷ is selected from the group consisting of Lys, Cys, and Orn;

Y¹ is selected from the group consisting of dVal, dPro, and dTle;

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 disulfide bond between R² and R⁷ when R² and R⁷ are each Cys; and a lactam bridge between R² and R⁷ when R² is Asp or Glu, and R⁷ is Lys or Orn, provided that: when R³ is His then R⁷ is Lys or Cys, Y³ is not dVal, Y⁴ is absent, and either (i) X¹ is present and Y¹ is not dTle, or (ii) X¹ is absent, and Y² is dPro.

[0095] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC(ii)):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y²-Y³ (IC(ii)), wherein:

X¹ is absent or Nle;

R¹ is Nle or Ala;

R² is selected from the group consisting of Asp, Glu, and Cys; R³ is selected from the group consisting of Phe, dPhe, His, dHis, Pro, Gin, Trp, Tyr, dTyr, and Bip;

R⁴ is p(CI)dPhe;

R⁵ is Arg or His;

R⁶ is selected from the group consisting of Trp, Nal(2’), and dNal(2’);

R⁷ is selected from the group consisting of Lys, Cys, and Orn;

Y¹ is selected from the group consisting of dVal, dPro, and dTle;

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 disulfide bond between R² and R⁷ when R² and R⁷ are each Cys; and a lactam bridge between R² and R⁷ when R² is Asp or Glu, and R⁷ is Lys or Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 248);

Ac-Nle-c[Glu-His-p(CI)dPhe-Arg-Trp-Om]-dVal-dPro-NH₂ (SEQ ID NO: 249);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH₂ (SEQ ID NO: 250);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 252); and

Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 259).

[0096] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) or (IO), wherein R⁴ is p(l)dPhe or p(CF3)dPhe. Accordingly, in some embodiments, the sequence of Formula (I) or (IC) is a sequence of Formula (IC(iii)):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (IC(iii)), wherein:

R¹ is Nle;

R² is Asp;

R³ is His or Pro;

R⁴ is p(CF₃)dPhe or p(l)dPhe;

R⁵ is Arg;

R⁶ is selected from the group consisting of Trp, Aia, Aba, and Ata;

R⁷ is Lys;

Y¹ is d Vai;

Y² is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp at R² and Lys at R⁷.

[0097] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC(iii)):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (IC(iii)), wherein:

R¹ is Nle;

R² is Asp;

R³ is His or Pro;

R⁴ is p(CF₃)dPhe or p(l)dPhe;

R⁵ is Arg;

R⁶ is selected from the group consisting of Trp, Aia, Aba, and Ata;

R⁷ is Lys;

Y¹ is d Vai;

Y² is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp at R² and Lys at R⁷. [0098] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein R⁴ is dPhe or p(F)dPhe. Further, in such embodiments, X¹ , Y³, and Y⁴ are absent. Accordingly, 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 Nle;

R² is Asp or Cys;

R³ is Pro, Phe, Trp, Tyr, Bip, and dBip;

R⁴ is p(F)dPhe or dPhe;

R⁵ is Arg or Lys;

R⁶ is selected from the group consisting of Trp, Nal(2’), and dNal(2’);

R⁷ is Lys or Cys;

Y¹ is d Vai;

Y² is 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 and R⁷ are each Cys; and a lactam bridge between R² and at R⁷, when R² is Asp and R⁷ is Lys.

[0099] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (ID):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (ID), wherein:

R¹ is Nle;

R² is Asp or Cys;

R³ is Pro, Phe, Trp, Tyr, Bip, and dBip;

R⁴ is p(F)dPhe or dPhe; R⁵ is Arg or Lys;

R⁶ is selected from the group consisting of Trp, Nal(2’), and dNal(2’);

R⁷ is Lys or Cys;

Y¹ is d Vai;

Y² is 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 and R⁷ are each Cys; and a lactam bridge between R² and at R⁷, when R² is Asp and R⁷ is Lys, provided that: when R⁴ is dPhe, then (i) R³ is d Bip; or (ii) R³ is Pro and either R⁵ is Lys or R⁶ is dNal(2’) or Nal(2’); and when R⁴ is p(F)dPhe, then (i) R³ is selected from Tyr, Phe, Bip, and Trp; or (ii) R³ is Pro and either R⁶ is Nal(2’) or dNal(2’) or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R² and R⁷.

[0100] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (ID):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (ID), wherein:

R¹ is Nle;

R² is Asp or Cys;

R³ is Pro, Phe, Trp, Tyr, Bip, and dBip;

R⁴ is p(F)dPhe or dPhe;

R⁵ is Arg or Lys;

R⁶ is selected from the group consisting of Trp, Nal(2’), and dNal(2’);

R⁷ is Lys or Cys;

Y¹ is d Vai; Y² is 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 and R⁷ are each Cys; and a lactam bridge between R² and at R⁷, when R² is Asp and R⁷ is Lys, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of:

Ac-Nle-c[Cys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 105);

Ac-Nle-c[Asp-Trp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 131 );

Ac-Nle-c[Asp-Tyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 132);

Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 136);

Ac-Nle-c[Asp-Bip-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 137);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 144);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 165);

Ac-Nle-c[Asp-dBip-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 184); and

Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 239).

[0101] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) cyclized through a lactam bond between Asp or Glu at R² and Orn at R⁷. Further, in such embodiments, R⁴ is p(CI)dPhe or p(Br)dPhe. Accordingly, in some 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;

R² is Asp or Glu;

R³ is Pro or His;

R⁴ is p(CI)dPhe or p(Br)dPhe;

R⁵ is Arg; R⁶ is Trp;

R⁷ is Orn;

Y¹ is d Vai;

Y² is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Glu or Asp at R² and Orn at R⁷.

[0102] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IE):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (IE), wherein:

R¹ is Nle;

R² is Asp or Glu;

R³ is Pro or His;

R⁴ is p(CI)dPhe or p(Br)dPhe;

R⁵ is Arg;

R⁶ is Trp;

R⁷ is Orn;

Y¹ is d Vai;

[0103] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IE), wherein:

R¹ is Nle;

R² is Asp or Glu;

R³ is Pro or His; R⁴ is p(CI)dPhe or p(Br)dPhe;

R⁵ is Arg;

R⁶ is Trp;

R⁷ is Orn;

Y¹ is d Vai;

Y² is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Glu or Asp at R² and Orn at R⁷, provided that the non-naturally occurring melanocortin analog does not comprise a sequence of:

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 248); or

Ac-Nle-c[Glu-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 249).

[0104] In some embodiments, the non-naturally occurring melanocortin analog of any one of Formulae (l)-(IE) has one or more beta hairpin (P-hairpin) and/or beta turn (P-turn) structures. In some embodiments, the presence of Aia, Aba, Ata, Pro, dPro dHyp, and dAla, provides the P-hairpin and/or p-turn structures of the non-naturally occurring melanocortin analog. In some embodiments, the disulfide bond of the sequence according to any one of Formulae (l)-(IE), if present, provides the P-hairpin and/or p-turn structures of the non-naturally occurring melanocortin analog.

[0105] As will be appreciated by the skilled artisan, non-naturally occurring melanocortin analogs comprising a sequence of any one of Formulae (l)-(IE), have an N-terminus and a C-terminus. The melanocortin analogs of the present technology are written beginning with the N-terminus at the left-most amino acid residue and ending with the C-terminus at the right most residue. Accordingly, the N-terminus of a non- naturally melanocortin analog comprising a sequence of any one of Formulae (l)-(IE) may be at X¹ or R². Analogously, the C-terminus of a non-naturally occurring melanocortin analog comprising a sequence of any one of Formulae (l)-(IE) may be at any of R⁷, R⁸, Y¹ , Y², Y³, and Y⁴. [0106] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog is modified by an acyl group. In some embodiments, the acyl group is acetyl group (

[0107] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog is not modified.

[0108] In the sequence of any one of Formulae (l)-(IE), Y¹Y²Y³Y⁴ or a fragment thereof may represent a C-terminus of the non-naturally occurring melanocortin analog. In some embodiments, Y¹-Y⁴ are absent.

[0109] In some embodiments, Y¹ and Y² are present and Y³ and Y⁴ are absent. In some embodiments, Y³ and Y⁴ are absent and Y¹ is D-valine and Y² is D-proline. In some embodiments, Y³ and Y⁴ are absent and Y¹ is D-tert-leucine and Y² is D-proline. In some embodiments, Y³ and Y⁴ are absent and Y¹ is D-arginine and Y² is D-proline. In some embodiments, Y³ and Y⁴ are absent and Y¹ is D-lysine and Y² is D-proline. In some embodiments, Y³ and Y⁴ are absent and Y¹ is D-valine and Y² is D-hydroxyproline. In some embodiments, Y³ and Y⁴ are absent and Y¹ is D-tert-leucine and Y² is D-proline.

[0110] In some embodiments, Y¹-Y³ is 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-lysine, Y² is D-valine, and Y³ is D-proline. In some embodiments, Y⁴ is absent and Y¹ is D-arginine, 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.

[0111] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified by an amide group the sequence of any one of Formulae (l)-(IE), a non-naturally occurring melanocortin analog with a C-terminus modified by an amide may be represented by a terminal -NH2.

[0112] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is not modified. In the sequence of any one of Formulae (l)-(IE), a non-naturally occurring melanocortin analog with an unmodified C-terminus may be represented by -OH or by the absence of a C-terminal group.

[0113] Non-naturally occurring melanocortin analogs of any one of Formulae (I)- (IE) 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 R¹ or R² and R⁷ when each of R¹ or R² and R⁷ are Cys; a disulfide bond between R² and R⁷ or R⁸ when each of R² and R⁷ or R⁸ are dPen; and a lactam bridge between R¹ or R² and R⁷ when R¹ or R² is Asp or Glu, and R⁷ is Lys or Orn.

[0114] In some embodiments of the sequence of any one of Formulae (l)-(IE), R⁴ is dNal(2’). In some embodiments, R⁴ is dNal(2’) and the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between dPen at R² and dPen at R⁷ or R⁸. In further embodiments, X¹ is absent, R³ is Pro, R⁵ is Arg, and R⁶ is Trp. In still further embodiments, R¹ is selected from dArg, Arg, dPhe, dTyr, dLeu, Ala, His, dHis, Lys, dLys, and dNIe, Y¹ is dVal, Y² is dPro, and Y³-Y⁴ are absent. In some embodiments, the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-dArg-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 8);

Ac-Arg-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 9);

Ac-dTyr-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 10);

Ac-Ala-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 11 );

Ac-dHis-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 12);

Ac-His-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 13);

Ac-dLys-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 14);

Ac-Lys-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 15);

Ac-dLeu-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 49);

Ac-dNle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 51 ); and

Ac-dPhe-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 61), wherein c represents cyclization through R² and R⁷ via a disulfide bond. [0115] In other further embodiments, R¹ is Nle, Y¹ is selected from dVal, dArg, dLys, and dTle, Y² is selected from dVal, dPro, and dHyp, Y³ is absent or dPro and Y⁴ is absent. In some embodiments, the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dArg-dVal-dPro-NH₂ (SEQ ID NO: 53);

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dArg-dPro-NH₂ (SEQ ID NO: 55);

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dLys-dPro-NH₂ (SEQ ID NO: 56);

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dHyp-NH₂ (SEQ ID NO: 57);

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dTle-dPro-NH₂ (SEQ ID NO: 58);

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-Gly-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 59);

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 94); and

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dLys-dVal-dPro-NH₂ (SEQ ID NO: 95), wherein c represents cyclization through R² and R⁷ or R⁸ via a disulfide bond.

[0116] Alternatively, in some embodiments, R⁴ is dNal(2’) and the non-naturally occurring melanocortin analog is cyclized through a bond other than a disulfide bond between dPen at R² and dPen at R⁷ or R⁸. In some embodiments, the non-naturally occurring melanocortin analog is cyclized through a lactam or disulfide bond between R¹ and R⁷. In further embodiments, X¹ is Arg, R² is dAla, R³ is His, and Y¹-Y⁴ are absent. In some embodiments, the sequence of any one of Formulae (l)-(IE) is:

Ac-Arg-c(Cys-dAla-His-dNal(2’)-Arg-Trp-Cys)-NH₂ (SEQ ID NO: 7); or

Ac-Arg-c(Asp-dAla-His-dNal(2’)-Arg-Trp-Lys)-NH₂ (SEQ ID NO: 63), wherein c represents cyclization through R¹ and R⁷ via a disulfide bond or a lactam bond.

[0117] In other embodiments, the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R¹ or R² and R⁷. In further embodiments, the non-naturally melanocortin analog is cyclized through a lactam bond between Glu at R¹ or R² and Orn R⁷. In still further embodiments, R³ is His, R⁵ is His, R⁶ is T rp, Y¹ is dVal, and Y² is dPro. are absent. In some embodiments, the sequence of any one of Formulae (l)-(IE) is: Ac-Arg-c[Glu-Pro-His-dNal(2’)-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 5); or

Ac-Arg-c[Glu-His-dNal(2’)-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 6), wherein c represents cyclization through R¹ or R² and R⁷ via a lactam bond.

[0118] In some embodiments of the sequence of any one of Formulae (l)-(IE), R⁴ is an amino acid other than dNal(2’). For example, R⁴ may be selected from dPhe, p(F)dPhe, p(CFs)dPhe, p(l)dPhe, p(CI)dPhe, and p(Br)dPhe. In some embodiments, R⁴ is selected from p(CF3)dPhe, p(l)dPhe, p(CI)dPhe, and p(Br)dPhe.

[0119] In some embodiments of the sequence of any one of Formulae (l)-(IE), R⁴ is p(Br)dPhe. In some embodiments, R⁴ is p(Br)dPhe and R³ is His. In further embodiments, X¹ is absent and R¹ is selected from Ala, Arg, dArg, Lys, dLys, His, and dHis. In still further embodiments, Y¹ is dVal, Y² is dPro, and Y³-Y⁴ are absent. In some embodiments, the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 34);

Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 72);

Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 73);

Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 74);

Ac-dLys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 75);

Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 76); and

Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 77), wherein c represents cyclization through R² and R⁷ via a lactam bond.

[0120] In other further embodiments, Y¹ is dTle, Y² is dPro, and Y³-Y⁴ are absent. In some embodiments, the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 36);

Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 80);

Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 81 );

Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 82); Ac-dl_ys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 83);

Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 84); and

Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 85), wherein c represents cyclization through R² and R⁷via a lactam bond.

[0121] In some embodiments, when R⁴ is p(Br)dPhe and R³ is His, then the sequence is cyclized between Asp at R² and Lys at R⁷. In further embodiments, R¹ is Nle, R⁵ is Arg, and R⁶ is Trp. In still further embodiments, X¹ is absent or Nle, Y¹ is selected from dVal, dPro, and dTle, Y² is selected from dVal, dPro, and dTle, Y³ is absent, dVal or dPro and Y⁴ is absent or dPro. In some embodiments, the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 18);

Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 25);

Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 31);

Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH₂ (SEQ ID NO: 32);

Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 35);

Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 50);

Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH₂ (SEQ ID NO: 78); and

Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 79), wherein c represents cyclization through R² and R⁷via a lactam bond.

[0122] In some embodiments, R⁵ is an amino acid other than Arg. In further embodiments, R⁵ is His. In some embodiments, the sequence of any one of Formulae (l)-(IE) is: Ac-Nle-c[Asp-His-p(Br)dPhe-His-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 19), wherein c represents cyclization through R² and R⁷via a lactam bond.

[0123] In some embodiments, R⁶ is an amino acid other than Trp. In further embodiments, R⁶ is Nal(2’) or dNal(2’). In some embodiments, the sequence of any one of Formulae (l)-(IE) is:

Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 37); or Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 52), wherein c represents cyclization through R² and R⁷ via a lactam bond.

[0124] Alternatively, in some embodiments, when R⁴ is p(Br)dPhe and R³ is His, then the sequence is cyclized through a bond other than a lactam bond between Asp at R² and Lys at R⁷. In some embodiments, the sequence is cyclized through a lactam bond between Asp or Glu at R² and Orn at R⁷. In some embodiments, the sequence of any one of Formulae (l)-(IE) is:

Ac-Nle-c[Glu-His-p(Br)dPhe-Arg-Trp-Om]-dVal-dPro-NH₂ (SEQ ID NO: 101); or

Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 102), wherein c represents cyclization through R² and R⁷ via a lactam bond.

[0125] In other embodiments, the sequence is cyclized through a disulfide bond between Cys at R² and Cys at R⁷. In some embodiments, the sequence of any one of Formulae (l)-(IE) is: Ac-Nle-c[Cys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 28), wherein c represents cyclization through R² and R⁷ via a disulfide bond.

[0126] In some embodiments, R⁴ is p(Br)dPhe and R³ is an amino acid other than His. In further embodiments, R³ is selected from Pro, Gin, dGIn, dHis, Phe, dPhe, Bip, dBip, Tyr, dTyr, Trp, and dTrp. In some embodiments, the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[Asp-Pro-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 21 );

Ac-Nle-c[Asp-Gln-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 33);

Ac-Nle-c[Asp-dHis-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 38);

Ac-Nle-c[Asp-Phe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 39);

Ac-Nle-c[Asp-dPhe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 40);

Ac-Nle-c[Asp-Bip-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 41 );

Ac-Nle-c[Asp-dBip-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 42);

Ac-Nle-c[Asp-Trp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 44);

Ac-Nle-c[Asp-dTrp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 45);

Ac-Nle-c[Asp-Tyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 46); Ac-Nle-c[Asp-dTyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 47); and Ac-Nle-c[Asp-dGln-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 62), wherein c represents cyclization through R² and R⁷ via a lactam bond.

[0127] In some embodiments of the sequence of any one of Formulae (l)-(IE), R⁴ is p(CI)dPhe. In some embodiments, R⁴ is p(CI)dPhe and R³ is His. In further embodiments, R¹ is Nle, R⁵ is His or Arg, and R⁶ is selected from Trp, Nal(2’) and dNal(2’). In some embodiments, the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 16);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 17);

Ac-Nle-c[Cys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 65);

Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 66);

Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 67);

Ac-Nle-c[Asp-His-p(CI)dPhe-His-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 68);

Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 69);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 97);

Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 98); and

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 99), wherein c represents cyclization through R² and R⁷ via a lactam bond or a disulfide bond.

[0128] Alternatively, in some embodiments, R⁴ is p(CI)dPhe and R³ is an amino acid other than His. In further embodiments, R³ is selected from Gin, dHis, Bip, Phe, dPhe, Tyr, dTyr, and Trp. In still further embodiments, R¹ is Nle, R⁵ is His or Arg, and R⁶ is selected from Trp, Nal(2’) and dNal(2’). In some embodiments, the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[Asp-dPhe-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 26);

Ac-Nle-c[Asp-Bip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 27);

Ac-Nle-c[Asp-dTyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 29); Ac-Nle-c[Asp-Trp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 43);

Ac-Nle-c[Asp-Tyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 54);

Ac-Nle-c[Asp-Phe-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 60);

Ac-Nle-c[Asp-dHis-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 70); and

Ac-Nle-c[Asp-Gln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 71 ), wherein c represents cyclization through R² and R⁷ via a lactam bond.

[0129] In other embodiments, R³ is Pro. In further embodiments R¹ is Nle, R⁵ is Arg, R⁶ is Trp, Y¹ is dVal and Y² is dPro. In some embodiments, the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[Asp-Pro-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 30);

Ac-Nle-c[Asp-Pro-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 64); and

Ac-Nle-c[Glu-Pro-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 103), wherein c represents cyclization through R² and R⁷ via a lactam bond.

[0130] In some embodiments of the sequence of any one of Formulae (l)-(IE), R⁴ is p(l)dPhe. In further embodiments, R¹ is Nle, R³ is Pro or His, R⁵ is His or Arg, R⁶ is selected from Trp, Y¹ is dVal, and Y² is dPro. In some embodiments, the sequence of any one of Formulae (l)-(IE) is:

Ac-Nle-c[Asp-Pro-p(l)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 20); or

Ac-Nle-c[Asp-His-p(l)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 23), wherein c represents cyclization through R² and R⁷ via a lactam bond.

[0131] In some embodiments of the sequence of any one of Formulae (l)-(IE), R⁴ is p(CF3)dPhe. In further embodiments, R¹ is Nle, R³ is Pro or His, R⁵ is Arg, R⁶ is selected from Trp, Aia, Aba, and Ata, Y¹ is dVal, and Y² is dPro. In some embodiments, the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[Asp-Pro-p(CF₃)dPhe-Arg-Aia-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 2);

Ac-Nle-c[Asp-Pro-p(CF₃)dPhe -Arg-Aba-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 3);

Ac-Nle-c[Asp-Pro-p(CF₃)dPhe -Arg-Ata-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 4);

Ac-Nle-c[Asp-Pro-p(CF₃)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 22); and Ac-Nle-c[Asp-His-p(CF₃)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 24), wherein c represents cyclization through R² and R⁷ via a lactam bond.

[0132] In some embodiments, of the sequence of any one of Formulae (l)-(IE), R⁴ is dPhe or p(F)dPhe. In some embodiments, R⁴ is p(F)dPhe and R³ is Pro. In further embodiments, R¹ is Nle, R⁵ is Arg or Lys, R⁶ is selected from Trp, Nal(2’) and dNal(2’), Y¹ is dVal, and Y² is dPro. In some embodiments, the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[Asp-Pro-dPhe-Lys-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 86);

Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 89);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 92);

Ac-Nle-c[Cys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 93);

Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 96); and

Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 100), wherein c represents cyclization through R² and R⁷ via a lactam bond or a disulfide bond.

[0133] Alternatively, in some embodiments, R⁴ is dPhe or p(F)dPhe and R³ is an amino acid other than Pro. In further embodiments, R³ is selected from Phe, Tyr, Trp, Bip, and dBip. In still further embodiments, R¹ is Nle, R⁵ is Arg, and R⁶ is Trp, Y¹ is dVal, and Y² is dPro. In some embodiments, the sequence of any one of Formulae (I)- (IE) is selected from the group consisting of:

Ac-Nle-c[Asp-dBip-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 48);

Ac-Nle-c[Asp-Phe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 87);

Ac-Nle-c[Asp-Bip-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 88);

Ac-Nle-c[Asp-Trp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 90); and

Ac-Nle-c[Asp-Tyr-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 91 ), wherein c represents cyclization through R² and R⁷ via a lactam bond.

[0134] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2- 103.

[0135] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2- 47, 49-85, 94, 95, 97-99, and 101-103.

[0136] 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: 5- 15, 49, 51 , 53, 55-59, 61 , 63, 94, and 95. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB(i)). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 8-15, 49, 51 , 53, 55-59, 61 , 94, and 95. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB(ii)). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 5-7 and 63.

[0137] 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: 2- 4, 16-47, 50, 52, 54, 60, 62, 64-85, 97-99, and 101 -103. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC(i)). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 18, 19, 21 , 25, 28, 31-42, 44-47, 50, 52, 62, 72- 85, 101 , and 102. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC(ii)). In some embodiments, the non- naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 16, 17, 26, 27, 29, 30, 43, 54, 60, 64-71 , 97-99, and 103. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC(iii)). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-4, 20, and 22-24.

[0138] 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: 48, 86-93, 96, and 100.

[0139] 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: 64 and 101-103.

Non-Naturallv Occurring Melanocortin Analog Synthesis

[0140] The non-naturally occurring melanocortin analogs of the present technology may be readily synthesized by any known conventional procedure for the formation of a peptide linkage between amino acids. Such conventional procedures include, for example, any solution phase procedure permitting a condensation between the free alpha amino group of an amino acid or residue thereof having the carboxyl group or other reactive groups protected and the free primary carboxyl group of another amino acid or residue thereof having the amino group or other reactive groups protected. In an exemplary procedure, the peptides of the present technology may be synthesized by solid-phase synthesis and purified according to methods known in the art. Any of a number of well-known procedures utilizing a variety of resins and reagents may be used to prepare the peptides of the present technology.

[0141] The process for synthesizing the peptides may be carried out by a procedure whereby each amino acid in the desired sequence is added one at a time in succession to another amino acid or residue thereof or by a procedure whereby peptide fragments with the desired amino acid sequence are first synthesized conventionally and then condensed to provide the desired peptide. The resulting peptide is then cyclized to yield a cyclic peptide.

[0142] Solid phase peptide synthesis methods are well known and practiced in the art. In such methods, the synthesis of peptides may be carried out by sequentially incorporating the desired amino acid residues one at a time into the growing peptide chain according to the general principles of solid phase methods. These methods are disclosed in numerous references, including Merrifield, Angew Chem. 24:799-810 (1985) and Barany et al., The Peptides, Analysis, Synthesis and Biology, Vol. 2, Gross E. and Meienhofer J., Eds. Academic Press 1-284 (1980). [0143] 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.

[0144] 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.

[0145] 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.

[0146] Solid phase synthesis is commenced from the C-terminal end of the peptide by coupling a protected alpha amino acid to a suitable resin. Such starting material is prepared by attaching an alpha amino-protected amino acid by an ester linkage to a p- benzyloxybenzyl alcohol (Wang) resin or a 2-chlorotrityl chloride resin, by an amide bond between an Fmoc-Linker, such as p-[(R,S)-a-[1-(9H-fluor-en-9-yl)- methoxyformamido]-2,4-dimethyloxybenzyl]-phenoxyacetic acid (Rink linker) to a benzhydrylamine (BHA) resin, or by other means well known in the art. Fmoc-Linker- BHA resin supports are commercially available and generally used when feasible. The resins are carried through repetitive cycles as necessary to add amino acids sequentially. The alpha amino Fmoc protecting groups are removed under basic conditions. Piperidine, piperazine, diethylamine, or morpholine (20-40% v/v) in N,N- dimethylformamide (DMF) may be used for this purpose. [0147] Following removal of the alpha amino protecting group, the subsequent protected amino acids are coupled stepwise in the desired order to obtain an intermediate, protected peptide-resin. The activating reagents used for coupling of the amino acids in the solid phase synthesis of the peptides are well known in the art. After the peptide is synthesized, if desired, the orthogonally protected side chain protecting groups may be removed using methods well known in the art for further derivatization of the peptide.

[0148] 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.

[0149] 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-(1 H-benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1 H- benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (HBTU), benzotriazole-1-yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole-1-yl-oxy-tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP), 2- (7-aza-1 H-benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TATLI), 2- (2-oxo-1 (2H)-pyridyl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TPTLI) or N,N - dicyclohexylcarbodiimide/1 -hydroxybenzotriazole (DCCI/HOBt). Coupling is convention initiated by use of a suitable base, such as N,N-diispropylethylamine (DIPEA), sym- collidine or N-methylmorpholine (NMM).

[0150] Following cleavage of peptides from the solid phase following their synthesis, the peptide may be purified by any number of methods, such as reverse phase high performance liquid chromatography (RP-HPLC), using a suitable column, such as a C18 column. Other methods of separation or purification, such as methods based on the size or charge of the peptide, may also be employed. Once purified, the peptide may be characterized by any number of methods, such as high-performance liquid chromatograph (HPLC), amino acid analysis, mass spectrometry, and the like.

Salt Forms of Non-Naturally Occurring Melanocortin Analogs

[0151] The non-naturally occurring melanocortin analog peptides of the present technology may be in the form of any salt. The term “pharmaceutically acceptable salts” refers to salts prepared from non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Exemplary salts are the ammonium, calcium, lithium, magnesium, potassium, and sodium salts. Salts derived from organic 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.

[0152] 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 peptides of the present technology are prepared in a suitable solvent from the peptide and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, citric, tartaric, maleic, succinic or methanesulfonic acid. The acetate salt form is especially useful. Where the peptides of the present technology include an acidic moiety, suitable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts.

Conjugates

[0153] The present technology further includes conjugates comprising a non- naturally occurring melanocortin analog. In some embodiments, the non-naturally melanocortin analog is conjugated to a pharmaceutical agent. Non-limiting examples of suitable pharmaceutical agents include peptides, monoclonal antibodies, and small molecules. In yet other embodiments, the non-naturally occurring melanocortin analog is conjugated to a small molecule MCR agonist.

[0154] Conjugates of the present technology further comprise a linker connecting the non-naturally occurring melanocortin analog to the pharmaceutical agent. In some embodiments, the linker is rigid. In some embodiments, the linker is flexible. In some embodiments, the linker is a cleavable linker. In some embodiments, the linker comprises a glycine-serine (Gly/Ser) linker, a proline-threonine-glycine linker, an alanine linker, a lysine linker, a threonine linker, a valine-glycine-serine-threonine linker, an elastin-like peptide linker, a hexahistidine linker, a polyethylene glycol linker, a fatty acid linker, or a hydrocarbon linker.

[0155] In some embodiments, the linker is a peptide linker. The peptide linkers of the present technology may vary from 2 to 31 amino acids of any primary sequence in length and do not impose any constraints on the conformation or interactions of the linked partners. In some embodiments, the linkers vary from about 2-30, 2-29, 2-28, 2- 27, 2-26, 2-25, 2-24, 2-23, 2-22, 2-21 , 2-20, 2-19, 2-18, 2-17, 2-16, 2-15, 2- 14, 2-13, 2-12, 2-11 , 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-31 , 3-30, 3-29, 3-28, 3-27, 3-26, 3- 25, 3-24, 3-23, 3-22, 3-21 , 3-20, 3-19, 3-18, 3-17, 3-16, 3-15, 3-14, 3-13, 3-12, 3-11 , 3- 10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-31 , 4-30, 4-29, 4-28, 4-27, 4-26, 4-25, 4-24, 4-23, 4- 22, 4-21 , 4- 20, 4-19, 4-18, 4-17, 4-16, 4-15, 4-14, 4-13, 4-12, 4-11 , 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-31 , 5- 30, 5-29, 5-28, 5-27, 5-26, 5-25, 5-24, 5-23, 5-22, 5-21 , 5-20, 5-19, 5- 18, 5-17, 5-16, 5-15, 5- 14, 5-13, 5-12, 5-11 , 5-10, 5-9, 5-8, 5-7, 5-6, 6-31 , 6-30, 6-29, 6-28, 6-27, 6-26, 6-25, 6-24, 6-23, 6-22, 6-21 , 6-20, 6-19, 6-18, 6-17, 6-16, 6-15, 6-14, 6-13, 6-12, 6-11 , 6-10, 6-9, 6-8, 6- 7, 7-31 , 7-30, 7-29, 7-28, 7-27, 7-26, 7-25, 7-24, 7- 23, 7-22, 7-21 , 7-20, 7-19, 7-18, 7-17, 7- 16, 7-15, 7-14, 7-13, 7-12, 7-11 , 7-10, 7-9, 7- 8, 8-31 , 8-30, 8-29, 8-28, 8-27, 8-26, 8-25, 8-24, 8-23, 8-22, 8-21 , 8-20, 8-19, 8-18, 8- 17, 8-16, 8-15, 8-14, 8-13, 8-12, 8-11 , 8-10, 8-9, 9-31 , 9-30, 9-29, 9-28, 9-27, 9-26, 9- 25, 9-24, 9-23, 9-22, 9-21 , 9-20, 9-19, 9-18, 9-17, 9-16, 9-15, 9-14, 9-13, 9-12, 9-11 , 9- 10, 10-31 , 10-30, 10-29, 10-28, 10-27, 10-26, 10-25, 10-24, 10-23, 10-22, 10-21 , I Q-

20, 10-19, 10-18, 10-17, 10-16, 10-15, 10-14, 10-13, 10-12, 10-11 , 11-31 , 11-30, 11-

29, 11-28, 11-27, 11-26, 11-25, 11-24, 11 -23, 11-22, 11-21 , 11-20, 11-19, 11-18, 11-

17, 11-16, 11-15, 11-14, 11-13, 11-12, 12-31 , 12-30, 12-29, 12-28, 12-27, 12-26, 12-

25,12-24, 12-23, 12-22, 12-21 , 12-20, 12-19, 12-18, 12-17, 12-16, 12-15, 12-14, 12-13, 13-31 , 13-30, 13-29, 13-28, 13-27, 13-26, 13-25, 13-24, 13-23, 13-22, 13-21 , 13-20, 13- 19, 13-18, 13-17, 13-16, 13-15, 13-14, 14-31 , 14-30, 14-29, 14-28, 14-27, 14-26, 14-

25, 14-24, 14-23, 14-22, 14-21 , 14-20, 14-19, 14-18, 14-17, 14-16, 14-15, 15-31 , 15-

30, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21 , 15-20, 15-19, 15-

18, 15-17, 15-16, 16-31 , 16-30, 16-29, 16-28, 16-27, 16-26, 16-25, 16-24, 16-23, 16-

22, 16-21 , 16-20, 16-19, 16-18, 16-17, 17-31 , 17-30, 17-29, 17-28, 17-27, 17-26, 17-

25, 17-24, 17-23, 17-22, 17-21 , 17-20, 17-19, 17-18, 18-31 , 18-30, 18-29, 18-28, 18-

27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21 , 18-20, 18-19, 19-31 , 19-30, 19-29, 19-

28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21 , 19-20, 20-31 , 20-30, 20-29, 20-

28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21 , 21-31 , 21-30, 21-29, 21-28, 21-

27, 21-26, 21-25, 21-24, 21-23, 21-22, 22-31 , 22-30, 22-29, 22-28, 22-27, 22-26, 22-

25, 22-24, 22-23, 23-31 , 23-30, 23-29, 23-28, 23-27, 23-26, 23-25, 23-24, 24-31 , 24-

30, 24-29, 24-28, 24-27, 24-26, 24-25, 25-31 , 25-30, 25-29, 25-28, 25-27, 25-26, 26-

31 , 26-30, 26-29, 26-28, 26-27, 27-31 , 27-30, 27-29, 27-28, 28-31 , 28-30, 28-29, 29-

31 , 29-30, or 30-31 amino acids of any primary sequence in length. The peptide linkers may be designed as appropriate for an intended use.

[0156] The peptide linkers may comprise one or more of a Gly-rich linker (e.g., a flexible linker connecting various domains in a single protein without interfering with the function of each domain; a linker forming stable covalently linked dimers; a linker to connect two independent domains that create a ligand-binding site or recognition sequence), a Serine linker (e.g., a coiled structure linker); a coiled structure linker comprising a Gin, Arg, Glu, Ser, and/or Pro amino acids; a rigid space linker comprising one or more of a Pro, Arg, Phe, Thr, Glu, and/or Gin residues; a linker comprising a flexible Gly-rich regions that may may generate loops connecting domains; or a linker comprising a Thr, Ser, Gly, and/or Ala residue.

[0157] In some embodiments, the linker comprises an amino acid sequence about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 100% identical to the amino acid sequence of any one of Linker A, Linker B, Linker C, Linker D, Linker E, Linker F, Linker G, Linker H, Linker I, Linker J, Linker K, Linker L, Linker M, Linker N, Linker O, Linker P, Linker Q, Linker R, or Linker S in Table 0.

[0158] In some embodiments, the linker comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 100% identical to the amino acid sequence of any one of Linker A, Linker B, Linker C, Linker D, Linker E, Linker F, Linker G, Linker H, Linker I, Linker J, Linker K, Linker L, Linker M, Linker N, Linker O, Linker P, Linker Q, Linker R, or Linker S in Table 0.

[0159] In some embodiments, the linker comprises an amino acid sequence at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 100% identical to the amino acid sequence of any one of Linker A, Linker B, Linker C, Linker D, Linker E, Linker F, Linker G, Linker H, Linker I, Linker J, Linker K, Linker L, Linker M, Linker N, Linker O, Linker P, Linker Q, Linker R, or Linker S in Table 0.

Table 0: Peptide Linker Amino Acid Sequences

[0160] Pharmaceutical Compositions

[0161] In some embodiments, the non-naturally occurring melanocortin analogs of the present technology are present in a pharmaceutical composition.

[0162] 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 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 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.

[0163] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IE), 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 Formula (IE) 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 Formula (IE) is present in the pharmaceutical composition in a concentration of about 50 mg/mL, relative to a total volume of the pharmaceutical composition.

[0164] In some embodiments, the composition comprises the non-naturally occurring melanocortin analog of any one of Formulae (l)-(IE) 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 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 a sequence of Formula (IE).

[0165] The non-naturally occurring melanocortin analogs may be formulated with one or more pharmaceutically acceptable carriers and/or excipients. The carriers and/or excipients of the present technology facilitate delivery of the non-naturally occurring melanocortin analog to a subject. Other pharmaceutically acceptable carriers and/or excipients may be included in the pharmaceutical composition to enhance dispersion, solubility, and/or stability of the non-naturally occurring melanocortin analog, and/or to reduce adverse injection site reactions.

[0166] In some embodiments, the pharmaceutical composition comprises 0.1 to 99.9999 wt.%, 1 to 99.999 wt.%, 5 to 99.99 wt.%, 10 to 99.9 wt.%, 15 to 99 wt.%, 20 to 90 wt.%, 30 to 85 wt.%, 40 to 80 wt.%, 50 to 75 wt.%, or 60 to 70 wt.% of the pharmaceutically acceptable carrier and/or excipient relative to a total weight of the pharmaceutical composition.

[0167] In some embodiments, the pharmaceutically acceptable carrier and/or excipient of the pharmaceutical composition is selected from the group consisting of water, a buffer, an inorganic salt, a fatty acid, a vegetable oil, a synthetic fatty ester, a surfactant, and a polymer.

[0168] In some embodiments, the pharmaceutically acceptable carrier and/or excipient of the pharmaceutical composition is water. In some embodiments, the pharmaceutically acceptable carrier and/or excipient of the pharmaceutical composition is a buffer.

[0169] In some embodiments, the pharmaceutical composition contains about 0.1 to about 99.9999 wt.%, about 1 to about 99.999 wt.%, about 5 to about 99.99 wt.%, about 10 to about 99.9 wt.%, about 15 to about 99 wt.%, about 20 to about 90 wt.%, about 30 to about 85 wt.%, about 40 to about 80 wt.%, about 50 to about 75 wt.%, or about 60 to about 70 wt.% of one or more pharmaceutically acceptable carriers and/or excipients relative to a total weight of the pharmaceutical composition.

[0170] In some embodiments, the pharmaceutical composition contains at least 0.1 to at least 99.9999 wt.%, at least 1 to at least 99.999 wt.%, at least 5 to at least 99.99 wt.%, at least 10 to at least 99.9 wt.%, at least 15 to at least 99 wt.%, at least 20 to at least 90 wt.%, at least 30 to at least 85 wt.%, at least 40 to at least 80 wt.%, at least 50 to at least 75 wt.%, or at least 60 to at least 70 wt.% of one or more pharmaceutically acceptable carriers and/or excipients relative to a total weight of the pharmaceutical composition.

[0171] In some embodiments, the pharmaceutical composition contains at least about 0.1 to at least about 99.9999 wt.%, at least about 1 to at least about 99.999 wt.%, at least about 5 to at least about 99.99 wt.%, at least about 10 to at least about 99.9 wt.%, at least about 15 to at least about 99 wt.%, at least about 20 to at least about 90 wt.%, at least about 30 to at least about 85 wt.%, at least about 40 to at least about 80 wt.%, at least about 50 to at least about 75 wt.%, or at least about 60 to at least about 70 wt.% of one or more pharmaceutically acceptable carriers and/or excipients relative to a total weight of the pharmaceutical composition.

[0172] Any pharmaceutically acceptable carriers and/or excipients known in the art may be included in the pharmaceutical composition. Non-limiting examples of pharmaceutically acceptable carriers and/or excipients include buffers, binders, excipients, stabilizers, lubricants, oils, adjuvants, preservatives, lipids, and antioxidants. The pharmaceutical composition may comprise any combination of the one or more pharmaceutically acceptable carriers and/or excipients previously described in relation to the first and pharmaceutical compositions. In some embodiments, the one or more pharmaceutically acceptable carriers and/or excipients comprise water.

[0173] The carriers and/or excipients of the composition may generally include one or more of the following components: (i) one or more antioxidants, (ii) one or more preservatives, (iii) one or more buffers, (iv) one or more tonicity adjustors, (v) one or more surfactants, (vi) flavor, (vii) propellants, and/or (viii) a vehicle or solvent. In some embodiments, all components are compatible with the non-naturally occurring melanocortin analog (i.e., do not react or cause the non-naturally occurring melanocortin analog to react) and are homogeneously dispersed or dissolved uniformly in the composition.

[0174] In some embodiments, the one or more pharmaceutically acceptable carriers and/or excipients are isotonic. In some embodiments, the carrier and/or excipient is isotonic to nasal fluids.

[0175] In some embodiments, the pharmaceutical composition further comprises a pharmaceutical salt. Any pharmaceutical salt known in the art may be included in the pharmaceutical composition. For examples, to achieve a desirable tonicity, the pharmaceutical composition may include a salt selected from the group consisting of sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride.

[0176] In some embodiments, the salt is present in the pharmaceutical composition in a concentration of about 0.1 mg/mL to about 50 mg/mL, about 1 mg/mL to about 25 mg/mL, or about 5 mg/mL to about 10 mg/mL, relative to a total volume of the composition.

[0177] In some embodiments, the salt is present in the pharmaceutical composition in a concentration of at least 0.1 mg/mL to at least 50 mg/mL, at least 1 mg/mL to at least 25 mg/mL, or at least 5 mg/mL to at least 10 mg/mL, relative to a total volume of the composition.

[0178] In some embodiments, the salt is present in the pharmaceutical composition in a concentration of at least about 0.1 mg/mL to at least about 50 mg/mL, at least about 1 mg/mL to at least about 25 mg/mL, or at least about 5 mg/mL to at least about 10 mg/mL, relative to a total volume of the composition.

[0179] 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.

[0180] In the pH buffered solution of the pharmaceutical composition, the water may act as a diluent and include, without limitation, water for injection (WFI), sterile water, bacteriostatic water for injection (BWFI), distilled water, bidistilled water, deionized water, deionized distilled water, and reverse osmosis water. In some embodiments, the water present in the pH buffered aqueous solution is water for injection.

[0181] 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.

[0182] 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.

[0183] 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

-go least about 75 wt%, or at least about 25 wt% to at least about 50 wt%, relative to a total weight of the composition.

[0184] 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.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] 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.

[0193] 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.

[0194] 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. [0195] 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.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to T ris 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 .

[0200] 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 .

[0201] 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 .

[0202] In addition to sodium acetate and Tris, the pharmaceutical composition may include other buffering agents. Non-limiting examples of additional buffering agents include saline, phosphate, phosphoric acid, citrate, succinate, gluconate, histidine, acetic acid, ascorbate, tartartic acid, maleic acid, glycine, lactate, lactic acid, ascorbic acid, imidazole, bicarbonate, carbonic acid, succinic acid, sodium benzoate, benzoic acid, gluconate, edetate, malate, imidazole, and mixtures thereof. In some embodiments, the pharmaceutical composition comprises acetic acid as an additional buffering agent.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] The pharmaceutical composition may further comprise an emulsifier. Nonlimiting examples of emulsifiers that may be included in the pharmaceutical composition include sodium carboxymethylcellulose, cetyl alcohol, glycerol monostearate, methylcellulose, and stearic acid. In some embodiments, when the pharmaceutical composition comprises an emulsifier, the emulsifier is sodium carboxymethylcellulose.

[0207] The pharmaceutical composition may further comprise a lipid. Lipids may enhance solubility and/or improve permeability of the non-naturally occurring melanocortin analog. In some embodiments, the lipid is a phospholipid. Non-limiting examples of phospholipids that may be included in the pharmaceutical composition include egg phosphatidylcholine, hydrogenated soybean phoshphaditylcholine, glycerophosphocholine, lecithin, and N-(carbonyl-methoxypolyethylene glycol 2000)- 1 ,2-distearoyl-glycero-3-phosphoethanolamine sodium salt. In some embodiments, when the pharmaceutical composition comprises a lipid, the lipid is N-(carbonyl- methoxypolyethylene glycol 2000)-1 ,2-distearoyl-glycero-3-phosphoethanolamine sodium salt

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] In some embodiments, the pharmaceutical composition is basic and has a pH of about 7.1 , 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1 , 8.2, 8.3, 8.4, or 8.5. In some embodiments, the pharmaceutical composition has a pH ranging from about 7.3 to about 7.4. In some embodiments, the pharmaceutical composition has a pH of 7.3 or

7.4.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] 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 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.

[0218] 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.

[0219] 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.

[0220] 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 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.

[0221] 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. [0222] 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.

[0223] 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, com oil, cottonseed oil, peanut oil, sesame oil, and/or various buffers.

[0224] 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.

[0225] 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.

[0226] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., subcutaneous administration) and comprises Tris in a concentration of about 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 3 5mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, or 120 mM.

[0227] 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.

[0228] In some embodiments, the pharmaceutical composition comprises a surfactant, such as a sorbitan ester.

[0229] In some embodiments, the pharmaceutical composition comprises a flavoring or scent, such as an aromatic oil.

[0230] 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%.

[0231] 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%.

[0232] 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%.

[0233] 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 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.

[0234] 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.

[0235] 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.

[0236] 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.

[0237] 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 1 ug to 10Oug per spray. In some embodiments, the spray device or nasal inhaler may be configured to deliver 1 ug to 100ug, 5ug to 90ug, 10ug to 80ug, 15ug to 70ug, 20ug to 60ug, 25ug, to 50ug, or 30ug to 40ug per spray.

[0238] Dosing

[0239] 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.

[0240] In some embodiments, the non-naturally occurring melanocortin analog or pharmaceutical composition thereof may be administered as a dosing regimen comprising once, twice, or three times daily administration on a (i) weekly; (ii) every other week; (iii) one week of therapy followed by two, three or four weeks off; (iv) two weeks of therapy followed by one, two, three or four weeks off; (v) three weeks of therapy followed by one, two, three, four or five week off; (vi) four weeks of therapy followed by one, two, three, four or five week off; (vii) five weeks of therapy followed by one, two, three, four or five week off; or (viii) monthly schedule. The (i)-(viii) schedules may be repeated 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 times or more. In some embodiments, the non-naturally occurring melanocortin analog or pharmaceutical composition thereof is administered at various dosages during the dosing regimen (e.g., a first dose with an effective amount of 10 mg/kg and a second dose with an effective amount of 5 mg/kg). [0241] 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.

[0242] Administration of the non-naturally occurring melanocortin analog or pharmaceutical composition thereof at any of the dosing frequencies of the present technology may be repeated for a total of about 2 dosages, about 3 dosages, about 4 dosages, about 5 dosages, about 10 dosages, about 15 dosages, about 20 dosages, about 30 dosages, about 40 dosages, about 50 dosages or more.

[0243] Administration of the non-naturally occurring melanocortin analog or pharmaceutical composition thereof at any of the dosing frequencies of the present technology may be repeated for a total of at least 2 dosages, at least 3 dosages, at least 4 dosages, at least 5 dosages, at least 10 dosages, at least 15 dosages, at least 20 dosages, at least 30 dosages, at least 40 dosages, at least 50 dosages or more.

[0244] Administration of the non-naturally occurring melanocortin analog or pharmaceutical composition thereof at any of the dosing frequencies of the present technology may be repeated for a total of at least about 2 dosages, at least about 3 dosages, at least about 4 dosages, at least about 5 dosages, at least about 10 dosages, at least about 15 dosages, at least about 20 dosages, at least about 30 dosages, at least about 40 dosages, at least about 50 dosages or more.

[0245] 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.

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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, 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.

[0250] 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. [0251] 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.

[0252] 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.

[0253] 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.

[0254] 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 administered at a dose of about 30 mg/kg or 60 mg/kg per body weight of the subject once daily.

[0255] 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.

[0256] 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.

[0257] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 50 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200 mg/kg, about 250 mg/kg, about 300 mg/kg, about 350 mg/kg, about 400 mg/kg, about 450 mg/kg, or about 500 mg/kg, 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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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.

[0264] 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.

[0265] 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. [0266] 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.

[0267] 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.

[0268] 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.

[0269] 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.

[0270] 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.

[0271] 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] 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.

[0276] 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.

[0277] 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.

[0278] 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. [0279] 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.

[0280] 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.

[0281] 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.

[0282] 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.

[0283] 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.

[0284] 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.

[0285] 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.

[0286] 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.

[0287] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 50 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200 mg/kg, about 250 mg/kg, about 300 mg/kg, about 350 mg/kg, about 400 mg/kg, about 450 mg/kg, 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.

[0288] 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.

[0289] 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.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] 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.

[0294] 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.

[0295] 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.

[0296] 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.

[0297] 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.

[0298] 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.

[0299] 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. In some embodiments, the HED based on a 10 mg/kg nonhuman primate dose ranges from about 300 mg to about 550 mg.

[0300] 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.

[0301] 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.

[0302] 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.

[0303] 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.

[0304] 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.

[0305] 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.

[0306] 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.

[0307] 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.

[0308] 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.

[0309] 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. The first dosage amount, the second dosage amount, and the third dosage amount may each be greater than, less than, equal to, or substantially equivalent to another dosage amount. For example, the first dosage amount is less than a second dosage amount which is greater than a third dosage amount also greater than the first dosage amount. The dosage amounts refer to doses administered more than once over a period of time, such as a first dosage amount administered daily, BID, TID, orweekly, a second dosage amount administered daily, BID, TID, or weekly, and a third dosage amount administered daily, BID, TID, orweekly. In some embodiments, the first dosage amount, the second dosage amount, or the third dosage amount may be administered every other day, every second day, every third day, twice per week, or twice per month. For example, the first dosage amount of 10 mg/kg may be administered once a day for 7 days, followed by the second dosage amount of 20 mg/kg once a day for 7 days, followed by the third dosage amount of 15 mg/kg twice a day for at least about 7 days. In some embodiments, the third dosage amount is administered for at least about 7 days, at least about 14 days, or at least about 21 days.

[0310] In some embodiments, the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) may be administered using more than one route of administration. For example, the first dosage amount and the second dosage amount may be administered by two different routes of administration. In addition, the first dosage amount and the second dosage amount administered via different routes of administration may be the same or different dosage amounts. In some embodiments, the first dosage amount is administered orally and the second dosage amount is administered subcutaneously. The dosage frequency and/or duration of the dosage amounts may be the same or may be different. For example, the frequency of each dosage amount may be more than once per day, once per day, once every other day, once per week, or once every other week, or once per month. As another example, the duration of each dosage amount may be one day, two days, three days, more than three days, one week, more than one week, two weeks, more than two weeks, one month, or more than one month. For example, a dosing regimen may comprise a first dosage amount administered once a day or twice a day for about 5 weeks, and a second dosage amount administered subcutaneously once a day or twice a day for about 1 week. In some embodiments, the second dosage amount is administered the day after the duration of the first dosage amount is complete, or two days, three days, more than three days, one week, more than one week, two weeks, more than two weeks, one month, or more than one month after the first dosage amount is complete. In some embodiments, the second dosage amount is administered at least about 1 week after administration of the first dosage is complete.

[0311] In some embodiments, the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) is administered at a dose of (i) 10 mg/kg once a day for 7 days, followed by (ii) 20 mg/kg once a day for 7 days, followed by (iii) 15 mg/kg twice a day for at least about 7 days. In some embodiments, (iii) is administered for at least about 7 days, at least about 14 days, or at least about 21 days.

[0312] In some embodiments, the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) comprises a (i) first dose administered orally once a day or twice a day for about 5 weeks, and (ii) second dose administered subcutaneously once a day or twice a day for about 1 week. In some embodiments, the second dose is administered at least about 1 week after administration of the first dose is complete.

[0313] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg/kg to about 20 mg/kg administered once a day for about 5 days to about 10 days; (ii) at a second dose of about 10 mg/kg to about 40 mg/kg administered once a day after administration of the first dose for about 5 days to about 10 days; (iii) at a third dose of about 5 mg/kg to about 30 mg/kg administered twice a day after administration of the second dose for at least about 5 days to about 10 days. In some embodiments, the third dose is administered twice a day for at least about 7 days or more.

[0314] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, or about 20 mg/kg administered once a day for about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, or about 10 days; (ii) at a second dose of about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, or about 40 mg/kg administered once a day after administration of the first dose about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, or about 10 days; (iii) at a third dose of about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, or about 30 mg/kg administered twice a day after administration of the second dose for at least about 5 days, about, 6 days, about 7 days, about 8 days, about 9 days, or about 10 days. In some embodiments, the third dose is administered twice a day for at least about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days or more.

[0315] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg/kg administered once a day for about 7 days; (ii) at a second dose of about 15 mg/kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 10 mg/kg administered twice a day after administration of the second dose for at least about 7 days. In some embodiments, the third dose is administered twice a day for at least about 14 days or more. [0316] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 10 mg/kg administered once a day for about 7 days; (ii) at a second dose of about 20 mg/kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 15 mg/kg administered twice a day after administration of the second dose for at least about 7 days. In some embodiments, the third dose is administered twice a day for at least about 14 days or more.

[0317] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 15 mg/kg administered once a day for about 7 days; (ii) at a second dose of about 25 mg/kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 20 mg/kg administered twice a day after administration of the second dose for at least about 7 days. In some embodiments, the third dose is administered twice a day for at least about 14 days or more.

[0318] 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 0.5 mg to about 75 mg once daily. In some embodiments, the non- naturally occurring melanocortin analog is administered at a dose of about 5 mg to about 60 mg once daily. In some embodiments, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily.

[0319] 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 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.

[0320] In some embodiments, 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. In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 10 mg/mL, about 20 mg/mL, about 30 mg/mL, about 40 mg/mL, about 50 mg/mL, or about 60 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.

[0321] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition at a dose of about 5 mg to about 1000 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 present in the pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day. In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day. In some embodiments, the administration is performed once per day.

Methods

[0322] The present technology comprises methods of treating, preventing, reducing, or otherwise ameliorating one or more symptoms or conditions that may benefit from weight gain or a reduction in weight loss. The methods comprise administering a non-naturally occurring melanocortin analog of the present technology to a subject in need thereof. The methods may promote fat gain (e.g., epididymal fat or perirenal fat), increase muscle mass, increase body weight, accelerate weight gain, increase fat mass to lean mass ratio, improve body composition and/or BMI (e.g., for underweight conditions), increase waist circumference, increase cardiac mass, increase brain mass, or any combination thereof, relative to a control. In some embodiments, the methods of the present technology increase a fat mass or a lean mass (e.g., muscle, organ, and bone mass) in the subject, relative to a control.

[0323] In some embodiments, the methods of the present technology reduce a loss in or a rate of loss in fat (e.g., epididymal fat or perirenal fat), muscle mass, body weight, weight gain, fat mass to lean mass ratio, BMI, a BMI durability, waist circumference, cardiac mass, brain mass, or any combination thereof, relative to a control.

[0324] In some embodiments, the present technology comprises methods of treating, preventing, reducing, or otherwise ameliorating one or more symptoms or conditions associated with cachexia, anorexia, or other conditions benefiting from weight gain in a subject by administering a non-naturally occurring melanocortin analog to the subject. The methods may promote lean mass gain, increase lean mass, maintain healthy lean mass, maintain a mass, or reduce a mass loss in the subject. The methods of the present technology may increase a cardiac mass, relative to a control. In some embodiments, the method improves gastrointestinal function and nutrient absorption.

[0325] The subject of the methods of the present technology may have cachexia, anorexia, anorexia nervosa, or another condition for which a therapeutic benefit is provided by weight gain or reduced rates of weight loss. In some embodiments, the subject is underweight. In some embodiments, the subject has a metabolic dysfunction or disorder, including, but not limited to, impaired glucose metabolism. In some embodiments, the subject has muscle wasting or sarcopenia.

[0326] In some embodiments, the present technology comprises methods of increasing, maintaining, or reducing a loss (e.g., a rate of loss or an absolute loss) of muscle mass. In some embodiments, the muscle mass is cardiac muscle mass, skeletal muscle mass, or both. In some embodiments, the cardiac muscle mass is determined by measuring change in heart weight. In some embodiments, the skeletal muscle mass is determined by measuring change in gastrocnemius tissue weight. In related embodiments, the muscle mass change is cardiac muscle mass change, skeletal muscle mass change, or both. In some embodiments, cardiac muscle is determined by heart weight. In some embodiments, skeletal muscle mass is determined by gastrocnemius tissue weight. In some embodiments, the muscle mass changes may be assessed by using magnetic resonance imaging (MRI) and/or or nuclear magnetic resonance (NMR).

[0327] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence according to any one of Formulae (l)-(IE). In some embodiments, the non-naturally occurring analog comprises a sequence of any one of SEQ ID NOs 2- 103.

Anti-Cancer Agents

[0328] The present technology comprises methods of treating, preventing, reducing, or otherwise ameliorating one or more conditions and/or side effects induced by anti-cancer agents (e.g., chemotherapeutic agents) as well as symptoms or conditions associated with cancer via administration of a non-naturally occurring melanocortin analog to a subject in need thereof. The methods may promote appetite and food consumption, and increase or maintain body weight, muscle mass, and/or fat mass of the subject. The methods are also effective in treating anorexia, anorexia nervosa, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, loss of appetite, nausea, emesis, and symptoms associated with hypermetabolic immunoinflammatory syndrome. In some embodiments, the methods are effective in improving quality of life and/or increasing life expectancy. The methods of the present technology include administration of a non-naturally occurring melanocortin analog to a subject in need thereof prior to onset, during, and/or after onset of such conditions and/or side effects. These methods also include administration of a non-naturally occurring melanocortin analog to a subject in need thereof prior to, during, and/or after administration of an anti-cancer agent to the subject who may have cancer or may have another condition which is not cancer, but administration of the anti-cancer agent provides therapeutic benefit to the non-cancer condition.

Cardiac Effects

[0329] The methods of the present technology may decrease the risk and/or incidence of adverse cardiovascular events associated with the use of a conventional melanocortin analog 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.

[0330] 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.

Maintenance Doses

[0331] In some embodiments, a maintenance dose of the non-naturally occurring melanocortin analog is administered to the subject to maintain weight and/or continue weight increase.

Subjects

[0332] In some embodiments, the subject is a mammal, including but not limited to a human, a non-human primate such as a chimpanzee, a domestic livestock or a farm animal such as a cow, a bison, sheep, a pig, a goat, a horse, a chicken, and a rooster, a domestic pet animal such as a dog, a cat, a rat, a mouse, and a rabbit, and a laboratory subject such as a rodent, including a rat, a mouse, and a guinea pig. In some embodiments, the subject is a human. In some embodiments, the subject is an animal such as a rat or a dog.

[0333] In some embodiments, the subject has a body mass index (BMI) of 18.5 kg/m² to 35 kg/m². In some embodiments, the subject has a BMI of less than 35 kg/m². In some embodiments, the subject has a BMI of less than 18.5 kg/m².

[0334] In some embodiments, the subject is an underweight subject. Underweight subjects include those having a body weight about 3%, 5% or less, 10% or less, 20% or less, or 30% or less, than the lower end of “normal” BMI (e.g., 18.5 kg/m2).

[0335] In some embodiments, the subject has a metabolic dysfunction.

Controls

[0336] The controls of the present technology may comprise the subject at baseline. In some embodiments, the controls of the methods of the present technology comprise a subject that is not administered a non-naturally occurring melanocortin analog of the present technology or a subject subjected to a method lacking one or more steps of the methods of the present technology.

Pharmacokinetics and Pharmacodynamics

[0337] The non-naturally occurring melanocortin analogs of the present technology exhibit pharmacokinetic (pK) and/or pharmacodynamic (pD) parameters. Such pK and/or pD may be expressed or otherwise determined relative to a control, which, in some instances, may be a non-naturally occurring melanocortin analog lacking one or more features of the non-naturally occurring melanocortin analogs of the present technology.

[0338] In some embodiments, the pK and/or pD of the non-naturally occurring melanocortin analogs may be assessed using concentration and/or temporal measurements (e.g., Tfinai, Cmax, T ¹/2 (h)), AUC, or Tmax. In some embodiments, the non- naturally occurring melanocortin analogs have reduced clearance and/or metabolism, increased uptake, absorption, and/or stability, relative to a control.

[0339] Clearance

[0340] “Clearance” may refer to the elimination, absorption, and/or metabolism of the non-naturally occurring melanocortin analogs in the subject’s plasma. Clearance may be assessed as volume of plasma cleared of the non-naturally occurring melanocortin analogs over time (e.g., mL/min, L/hr, or L/day) and/or may be normalized to body weight of the subject (e.g., mL/min/kg). Reduced clearance may also be represented by an increase in half-life or volume of distribution (Vd). In some embodiments, measuring clearance comprises measuring a terminal elimination rate constant (Az) or an inter-compartmental clearance (Q).

[0341] In some embodiments, the reduction in clearance 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. In some embodiments, the reduced clearance comprises an intestinal fluid clearance, a gastric fluid clearance, a liver clearance, or a liver microsome clearance.

[0342] In some embodiments, the reduction in clearance comprises a measurement during administration of the non-naturally occurring melanocortin analogs. In some embodiments, the reduction in clearance comprises a measurement at the completion of administration of the non-naturally occurring melanocortin analogs.

[0343] Concentration

[0344] In some embodiments, the non-naturally occurring melanocortin analogs of the present technology comprise an increased tissue, plasma, serum, or aqueous concentration relative to a control. “Concentration” may comprise a measurement reflecting one or more of the absolute amounts of the non-naturally occurring melanocortin analogs, the absorption of the non-naturally occurring melanocortin analogs, the metabolism of non-naturally occurring melanocortin analogs, or the elimination of non-naturally occurring melanocortin analogs. The aqueous concentration may comprise an intestinal fluid concentration or a gastric fluid concentration.

[0345] The increased tissue, plasma, and/or serum concentration may be an increase in concentration 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 concentration may be measured at an intermediate time point or a final time point and may be measured as a mean residence time (MRT), an average concentration (Cavg), a trough concentration (Ctrough), or a concentration at the end of administration (e.g., infusion) time (CT).

[0346] In some embodiments, the increased concentration is reflected by an increase in peak plasma concentration (Cmax). An increase in Cmax may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control. In some embodiments, Cmax comprises a dose normalized Cmax (DNCmax).

[0347] In some embodiments, the increased concentration is reflected by an increase in minimum plasma concentration (Cmin). An increase in Cmin may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control. In some embodiments, Cmin comprises a dose normalized Cmin (DNCmin).

[0348] In some embodiments, the increased concentration is reflected by a reduction in time to reach Cmax (Tmax). A reduced T_max may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control.

[0349] In some embodiments, the increased concentration is reflected by a final measurable concentration (Tfinai). An increased Tfinai may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control.

[0350] In some embodiments, the increased concentration is reflected by an increase in area under the curve (AUC). An increase in AUC may signify increased exposure to the non-naturally occurring melanocortin analogs and/or may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control. The AUC measurement may comprise an Area Under the Curve for Concentration of Drug in Non-Compartmental Analysis (DNAUC).

[0351] In some embodiments, the increased concentration is reflected by a reduction in a partition coefficient or an increase in a partition coefficient, relative to a control. The reduced partition coefficient may reflect an increase in aqueous solubility (e.g., an intestinal fluid or a gastric fluid), relative to the control. In some embodiments, the increased partition coefficient may reflect an increase in membrane permeability, relative to the control.

[0352] In some embodiments, the increase in tissue, plasma, and/or serum concentration 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.

[0353] In some embodiments, the increase in tissue, plasma, and/or serum concentration 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.

[0354] In some embodiments, the increase in tissue, plasma, and/or serum concentration 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.

[0355] In some embodiments, the increase in tissue, plasma, and/or serum concentration comprises a measurement during administration of the non-naturally occurring melanocortin analogs.

[0356] In some embodiments, the increase in tissue, plasma, and/or serum concentration comprises a measurement at the completion of administration of the non- naturally occurring melanocortin analogs.

[0357] 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.

[0358] 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 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 Cmax.

[0359] Distribution

[0360] 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.

[0361] In some embodiments, the measurement of distribution comprises measuring a volume of distribution at the terminal phase (Vd or Vdu), a central volume of distribution (V), a peripheral volume of distribution (V2), an apparent volume of distribution (V_z), or a measurement of distribution comprises measuring a volume of distri bution at steady state (Vss). A high or increased Vd, VdB, Vz, and/or Vss may suggest large distribution beyond the tissue, plasma, and/or serum compartment, relative to the control.

[0362] 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.

[0363] 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.

[0364] 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.

[0365] In some embodiments, the increase in distribution comprises a measurement during administration of the non-naturally occurring melanocortin analogs.

[0366] In some embodiments, the increase in distribution comprises a measurement at the completion of administration of the non-naturally occurring melanocortin analogs.

[0367] Additional pD and pK Embodiments

[0368] In some embodiments, the non-naturally occurring melanocortin analog of the present technology exhibits one or more of the following:

[0369] (a) an increase in half-life relative to a control;

[0370] (b) a reduction in clearance relative to a control;

[0371] (c) an increase in tissue concentration relative to a control; [0372] (d) an increase in plasma concentration relative to a control;

[0373] (e) an increase in serum concentration relative to a control;

[0374] (f) an increase in distribution relative to a control;

[0375] (g) an increase in an AUC measurement relative to a control;

[0376] (h) an increase in a DNAUC measurement relative to a control;

[0377] (i) an increase in Tfinai relative to a control;

[0378] (j) an increase in Cmax relative to a control;

[0379] (k) an increase in Cmin relative to a control;

[0380] (I) an increase in DNCmin relative to a control;

[0381] (m) an increase in MRT relative to a control;

[0382] (n) an increase in Cavg relative to a control;

[0383] (o) an increase in Ctrough relative to a control;

[0384] (p) an increase in CT relative to a control;

[0385] (q) an increase in Vd relative to a control;

[0386] (r) a reduction in Tmax relative to a control; or

[0387] (s) a reduction in Q relative to a control.

[0388] In some embodiments, the non-naturally occurring melanocortin analog of the present technology exhibits one or more of the following, relative to a control:

[0389] (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;

[0390] (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;

[0391] (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; [0392] (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;

[0393] (e) an increase in serum concentration by at least about 5%, 10%, 20%,

[0394] (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;

[0395] (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;

[0396] (h) an increase in a DNAUC measurement by at least about 5%, 10%, 20%,

[0397] (i) an increase in Tfinai by at least about 5%, 10%, 20%, 30%, 40%, 50%,

[0398] (j) an increase in Cmax by at least about 5%, 10%, 20%, 30%, 40%, 50%,

[0399] (k) an increase in Cmin by at least about 5%, 10%, 20%, 30%, 40%, 50%,

[0400] (I) an increase in DNCmin by at least about 5%, 10%, 20%, 30%, 40%, 50%,

[0401] (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; [0402] (n) an increase in Ca_Vg by at least about 5%, 10%, 20%, 30%, 40%, 50%,

[0403] (o) an increase in Ctrough by at least about 5%, 10%, 20%, 30%, 40%, 50%,

[0404] (p) an increase in CT by at least about 5%, 10%, 20%, 30%, 40%, 50%,

[0405] (q) an increase in Vd by at least about 5%, 10%, 20%, 30%, 40%, 50%,

[0406] (r) a reduction i n T max by at least about 5%, 10%, 20%, 30%, 40%, 50%,

60%, 70%, 80%, 90%, or 100% relative to a control; or

[0407] (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.

EXAMPLES

[0408] The following examples are intended to illustrate various embodiments of the present technology. As such, the specific embodiments discussed are not to be construed as limitations on the scope of the present technology. It will be apparent to one skilled in the art that various equivalents, changes, and modifications may be made without departing from the scope of present technology, and it is understood that such equivalent embodiments, are to be included herein. Further, all references cited herein are hereby incorporated by reference in their entirety, as if fully set forth herein.

Example 1: Peptide Synthesis-Generic

[0409] 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 solidphase synthesis utilized a variety of resins and reagents and may involve additional purification steps.

[0410] 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.

[0411 ] 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.

[0412] 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-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)-a-[1-(9H-fluor-en-9-yl)- methoxyformamido]-2,4-dimethyloxybenzyl]-phenoxyacetic acid (Rink linker) via an amide linkage.

[0413] The non-naturally occurring melanocortin analog was then synthesized by sequential amino acid addition or combination of peptide fragments. Subsequently, the peptide was cleaved from the solid-phase support and purified by methods known in the art, such as, for example, reverse phase high performance liquid chromatography (RP-HPLC) using a suitable column, such as a C18 column. Additionally, or alternatively, other methods of separation or purification were employed, including, but not limited to, methods based on the size or charge of the peptide. Once purified, the peptide was characterized by methods such as high-performance liquid chromatograph (HPLC), amino acid analysis, mass spectrometry, and the like.

Example 2: Peptide Synthesis-Protecting Groups

[0414] 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.

[0415] Additionally, protection of the alpha amino group of an amino acid residue or fragment was performed while that entity reacting with the carboxyl group, followed by the selective removal of the alpha amino protecting group to allow a subsequent reaction to take place at that site. Specific protecting groups for solid phase synthesis methods and solution phase synthesis methods are known to those having ordinary skill in the art. Alpha amino groups were protected by a suitable protecting group, including a urethane-type protecting group, such as benzyloxycarbonyl (Z) and substituted benzyloxycarbonyl, such as p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, p-biphenyl-isopropoxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc) and p-methoxybenzyloxycarbonyl (Moz); aliphatic urethane-type protecting groups, such as t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropoxycarbonyl, and allyloxycarbonyl. Fmoc was also used for alpha amino protection. Guanidine 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.

[0416] Alpha aminoprotecting groups may be removed under basic conditions, such as, for example, using a solution of piperidine, piperazine, diethylamine, or morpholine (20-40% v/v) in N,N-dimethylformamide (DMF). In synthesis methods in which alpha amino protecting groups were used, protecting groups were removed after synthesis of the peptide and before or after cleavage of the solid-phase support.

Example 3: Peptide Synthesis-Additional Modifications

[0417] If necessary, the peptides were further modified to obtain N-terminus modifications, such as acetylation, while on resin, or were removed from the resin by use of a cleaving reagent and then modified. Likewise, C-terminus modification (e.g., amidation), was performed if needed.

[0418] Additionally, the cyclized peptide structures were obtained prior to cleavage from the peptide resin. For cyclization through reactive side chain moieties, the desired side chains were deprotected, and the peptide suspended in a suitable solvent and a cyclic coupling agent added. Suitable solvents, for example DMF, dichloromethane (DCM) or 1-methyl-2-pyrrolidone (NMP), were used for the cyclization. Suitable cyclic coupling reagents (e.g., 2-(1 H-benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3-tetramethyluronium hexafluorophosphate (HBTLI), benzotriazole- 1-yl-oxy- tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole- 1-yl-oxy- tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP), 2-(7-aza-1 H-benzotriazol- 1-yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TATU), 2-(2-oxo-1 (2H)-pyridyl)- 1,1 ,3,3-tetramethyluronium tetrafluoroborate (TPTU), N,N'-dicyclohexylcarbodiimide/1- hydroxybenzotriazole (DCCI/HOBt)) were also used for the cyclization. Coupling was initiated by a suitable base, such as N,N-diispropylethylamine (DIPEA), sym-collidine or N-methylmorpholine (NMM).

Example 4: Biological Data

[0419] The agonist and antagonist activity of exemplary non-naturally occurring melanocortin analogs at the melanocortin receptors (e.g., MC1 R, MC3R, MC4R, and MC5R) were measured via cAMP accumulation assay, according to the following procedure. Experimental design and execution were conducted by Epics Therapeutics S.A. EuroscreenFast (Bruxelles, Belgium).

Compound Handing

[0420] Compounds were delivered as powder (1 mg) or 10 mM solutions (100 pl) in 100% DMSO. Powders were solubilized in 100% DMSO at a concentration of 10 mM (master solution) in a solvent volume defined. Serial dilutions were performed from master solution in 100% DMSO to obtain intermediate concentrations 200-, 300- or 400- fold higher than the concentrations to be tested, depending on the assay. Each sample was diluted 100-fold in the assay buffer and dispensed in a test plate. Amounts, solvents, and dilutions were estimated based on standard small-molecule drugs. Cell lines used for functional assays are shown in Table 1 .

Table 1. Cell lines

Compound Testing

[0421] Compounds were tested for (i) agonist and/or antagonist activity at the human MC3 (FAST-0232C) and MC4 (FAST-0233C) receptors, (ii) agonist activity at the human MC1 (FAST-0232C) receptor, and/or (iii) agonist activity at the human MC5 (FAST-0233C) receptor at the following nanomolar concentrations, in duplicate: 0.0001 , 0.001 , 0.01 , 0.03, 0.1 , 0.3, 1 , 10, 100, and 1 ,000.

Testing Protocol

[0422] Cyclic AMP (cAMP) Homogenous Time-Resolved Fluorescence (HTRF) assay for Gs coupled receptor:

[0423] CHO-K1 cells expressing recombinant human receptor grown prior to the test in media without antibiotic were detached by gentle flushing with PBS-EDTA (5 mM EDTA), recovered by centrifugation and resuspended in assay buffer (KRH: 5 mM KCI, 1.25 mM MgS04, 124 mM NaCI, 25 mM HEPES, 13.3 mM Glucose, 1.25 mM KH2PO4, 1 .45 mM CaCI2, 0.5 g/l BSA, supplemented with 1 mM IBMX or 25pM Rolipram).

[0424] Dose response curves were performed in parallel with the reference compounds.

[0425] For agonist test (384well): 5 pl of cells were mixed with 5 pl of the test compound at increasing concentrations and then incubated 30 min at room temperature. After addition of the lysis buffer containing cAMP-d2 and anti-cAMP cryptate detection reagents, plates were incubated 1-hour at room temperature, and fluorescence ratios were measured according to the manufacturer specification, with the HTRF kit.

[0426] For antagonist test (384well): 5 pl of cells were mixed in the wells of an assay plate with 5 pl of a mix of test compound at increasing concentrations and reference agonist for a final concentration corresponding to the historical EC80. The plates were then incubated 30 min at room temperature. After addition of the lysis buffer containing cAMP-d2 and anti-cAMP cryptate detection reagents, plates were incubated 1-hour at room temperature, and fluorescence ratios were measured according to the manufacturer specification, with the HTRF kit.

Quality Control for Compound Testing

[0427] 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.

[0428] Reference values thus obtained for the test were compared to historical values obtained from the same receptor and used to validate the experimental session.

[0429] 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.

[0430] 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

[0431 ] Group A included non-naturally occurring melanocortin analogs A1 to A19, all of which are cyclic peptides comprising the motif Pro-dNal(2’)-Arg-Trp (SEQ ID NO: 270). Group A non-naturally occurring melanocortin analogs are provided in Table 2.

Table 2. Group A non-naturally occurring melanocortin analogs

[0432] Group B included non-naturally occurring melanocortin analogs B1 to B4, all of which are cyclic peptides comprising the motif dAla-His-dNal(2’)-Arg-Trp (SEQ ID NO: 269) or a derivative thereof. Derivatives of the motif having a sequence of SEQ ID NO: 269 may include substitution of dAla for another amino acid, for example, Pro, or deletion of dAla. Group B non-naturally occurring melanocortin analogs are provided in Table 3.

Table 3. Group B non-naturally occurring melanocortin analogs

[0433] Group C included non-naturally occurring melanocortin analogs C1 to C28, all of which are cyclic peptides comprising the motif His-p(Br)dPhe-Arg-Trp (SEQ ID NO: 266) or a derivative thereof. Group C non-naturally occurring melanocortin analogs that are derivatives of the motif having a sequence of SEQ ID NO: 266 may include substitution of Arg for another amino acid, for example, His, or substitution of Trp for another amino acid, for example, dNal(2’) or Nal(2’). Group C non-naturally occurring melanocortin analogs are provided in Table 4.

Table 4. Group C non-naturally occurring melanocortin analogs

[0434] Group D included non-naturally occurring melanocortin analogs D1 to D14, all of which are cyclic peptides comprising a derivative of the motif His-p(Br)dPhe-Arg- Trp (SEQ ID NO: 266). Derivatives of the motif having a sequence of SEQ ID NO: 266 that are included in Group D melanocortin analogs may include substitution of His for a similar amino acid, for example, Pro, dHis, Gin, dGIn, Phe, dPhe, Tye, dTyr, Trp, dTrp, Bip, or dBip or substitution of p(Br)dPhe for a similar amino acid, for example, p(l)dPhe. Group D non-naturally occurring melanocortin analogs are provided in Table 5.

Table 5. Group D non-naturally occurring melanocortin analogs

[0435] Group E included non-naturally occurring melanocortin analogs E1 to E10, all of which are cyclic peptides comprising the motif His-p(CI)dPhe-Arg-Trp (SEQ ID NO: 267). Group E non-naturally occurring melanocortin analogs are provided in Table 6.

Table 6. Group E non-naturally occurring melanocortin analogs [0436] Group F included non-naturally occurring melanocortin analogs F1 to F11 , all of which are cyclic peptides comprising a derivative of the motif His-p(CI)dPhe-Arg- Trp (SEQ ID NO: 267). Derivatives of the motif having a sequence of SEQ ID NO: 267 that are included in Group F melanocortin analogs include substitution of His for another amino acid, for example, Pro, dHis, Gin, Phe, dPhe, Tye, dTyr, Trp, or Bip. Group F non-naturally occurring melanocortin analogs are provided in Table 7.

Table 7. Group F non-naturally occurring melanocortin analogs

[0437] Group G included non-naturally occurring melanocortin analogs G1 to G5, all of which are cyclic peptides comprising the motif Pro-p(CF3)dPhe-Arg-Trp (SEQ ID NO: 265) or a derivative thereof. Derivatives of the motif having a sequence of SEQ ID NO: 265 may include substitution of Pro for another amino acid, for example, His or substitution of Trp for another amino acid, for example, Aba, Aia, or Ata. Group G non- naturally occurring melanocortin analogs are provided in Table 8.

[0438] Table 8. Group F non-naturally occurring melanocortin analogs

[0439] Group H included non-naturally occurring melanocortin analogs H1 to H4, all of which are cyclic peptides comprising a derivative of the motif Pro-p(F)dPhe-Arg- Trp (SEQ ID NO: 268). Derivatives of the motif having a sequence of SEQ ID NO: 268 may include substitution of Pro for another amino acid, for example, dBip, Bip, Phe, Trp, or Tyr, or substitution of p(F)dPhe for another amino acid, for example, dPhe. Group H non-naturally occurring melanocortin analogs are provided in Table 9.

Table 9. Group H non-naturally occurring melanocortin analogs

Agonist activity of melanocortin analogs on melanocortin 1 and 5 receptors

[0440] Administration of some non-naturally occurring melanocortin analogs activated melanocortin 1 receptor (MC1 R) and/or melanocortin 5 receptor (MC5R) activity, as measured by cAMP levels (Table 10).

Table 10. Dose-response results of melanocortin analogs and control against the melanocortin 1 receptor (MC1 R) and melanocortin 5 receptor (MC5R)

Agonist activity of melanocortin analogs on melanocortin 3 and 4 receptors

[0441] Administration of some non-naturally occurring melanocortin analogs activated melanocortin 3 receptor (MC3R) activity and/or melanocortin 4 receptor (MC4R) activity, as measured by cAMP levels (Table 11).

Table 11. Dose-response results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) nd = not determined

Antagonist activity of melanocortin analogs on melanocortin 3 or 4 receptor

[0442] Administration of some non-naturally occurring melanocortin analogs inhibited melanocortin 3 receptor (MC3R) and/or melanocortin 4 receptor (MC4R) activity, as measured by cAMP levels.

Table 12. Dose-response results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R)

nd = not determined

Residual binding of melanocortin analogs on melanocortin 1 receptor

[0443] The residual binding of some of the non-naturally occurring melanocortin analogs was measured on the melanocortin 1 receptor (MC1 R) by RLB assay. Among the non-naturally occurring melanocortin analogs, E8 had the lowest ECso value at 0.29 nM (Table 13).

Table 13. Dose-response binding results of melanocortin analogs and control against the melanocortin 1 receptor (MC1 R)

Residual binding of melanocortin analogs on melanocortin 3 receptor

[0444] The residual binding of some of the non-naturally occurring melanocortin analogs was measured on the melanocortin 3 receptor (MC3R) by RLB assay. Among the non-naturally occurring melanocortin analogs, C1 had the lowest ECso value at 0.52 nM (Table 14).

Table 14. Dose-response binding results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R)

Residual binding of melanocortin analogs on melanocortin 4 receptor

[0445] 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, E8 had the lowest ECso values at 0.22 nM (Table 15).

Table 15. Dose-response binding results of melanocortin analogs and control against the melanocortin 4 receptor (MC4R)

Residual binding of melanocortin analogs on melanocortin 5 receptor

[0446] 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, E8 had the lowest ECso value at 1 .11 nM (Table 16).

Table 16. Dose-response binding results of melanocortin analogs and control against the melanocortin 5 receptor (MC5R) Example 5: Assessing TCMCB07 Bioavailability

Oral Bioavailability

[0447] To assess the oral bioavailability of TCMCB07 (Ac-Nle-c[Asp-Pro-dNal(2’)- Arg-Trp-Lys]-dVal-dPro-NH2; SEQ ID NO: 271), TCMCB07 was subjected to in vitro assays to evaluate absorption and stability. TCMCB07 levels were first assessed for stability in human plasma, simulated gastric fluid (SGF), and simulated intestinal fluid (SIF) over a 120-minute incubation period (FIG. 1).

[0448] TCMCB07 plasma concentration was next measured following oral administration in cynomolgus monkeys at 30.0 mg/kg (FIG. 2), the results of which are shown in Table 17. TCMCB07 plasma concentration in male and female-divided cynomolgus monkeys at the same concentration or oral administration are shown in Table 18.

Table 17: Pharmacokinetics of TCMCB07 (ng/mL)

ND = Not determined

BQL = Below the lower limit of quantitation (LLOQ)

Table 18: TCMCB07 Plasma Concentration in Male and Female Monkeys

Subcutaneous Administration

[0449] TCMCB07 pharmacokinetics were next assessed following 10 mg/kg SC administration in male Sprague Dawley rats (Table 19). This showed that TCMCB07 was detectable in the plasma for at least 24 hours following SC administration.

Table 19: Plasma TCMCB07 levels in Rodents

[0450] TCMCB07 plasma concentration was further assessed in rats and Beagle dogs following IP or oral administration (Table 20). This showed that TCMCB07 was detectable in the plasma across species tested and through multiple administration routes.

Table 20: TCMCB07 Administration in Different Species - Plasma Levels

Example 6: Assessing absorption, distribution, metabolism, and excretion of non-naturally occurring melanocortin analogs of the present technology

[0451] Non-naturally occurring melanocortin analogs of the present technology, TCMCB07, C1 (SEQ ID NO: 18), and F4 (SEQ ID NO: 30), were assessed for solution properties, in vitro absorption, and in vitro metabolism for absorption, distribution, metabolism, and excretion (ADME) properties. Various ADM E outcomes are outlined in Table 21 ([Test]: Test Compound Concentration; Comp.: Compound; Rep: replicate; recov.: recovery; T1/2: half-life (minutes); Avg.: mean; Perm.: permeability).

Aqueous Solubility

[0452] Aqueous solubility (pM) was determined by comparing the peak area of the principal peak in a calibration standard (200 pM) 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 chromatogram of the calibration standard of each test compound, along with a LIV/VIS spectrum with labeled absorbance maxima, was generated.

HPLC-UV Screen

[0453] A chromatogram of the test compound (200 pM) along with a UV/VIS spectrum with labeled absorbance maxima, was generated.

Protein Binding

[0454] 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 (%)= (Area_P-AreabArea_P)*100

Recovery (%)=((Area_P+Areab)/Area_c)*100 where:

Area_P = Peak area of analyte in protein matrix

Areab = Peak area of analyte in buffer

Area_c = Peak area of analyte in control sample

Partition Coefficient

[0455] The total amount of compound was determined as the peak area of the principal peak in a calibration standard (100 pM) 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 [0456] 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.

ADME-Tox: In Vitro Absorption

Permeability

[0457] The apparent permeability coefficient (Papp) of the test compound was calculated as follows:

P app(Cm/S)⁼(VR'CR,end/At)-(1 /A*(CD,rnid^— 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.

At 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

[0458] The recovery of the test compound was calculated as follows:

Recovery (%)-((VD-CD,end+VR-CR,end)/(VD-CDo))* 100 where: VD and VR are the volumes of the donor and receiver chambers, respectively. Co.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.

CDO 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

[0459] 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)

[0460] 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 pL/min/pmol, pL/min/mg or pL/min/Mcell) was calculated according to the following formula:

CLint = 0.693/(Ti/2*(mg protein/pL or million cells/pL or pmol CYP isoyme/pL))

Table 21 : ADME Assessment of TCMCB07 and Reference Compounds

in vitro absorption: A-B permeability (Caco-2, pH 6.5/7.4)

Example 7; CYP Inhibition of Non-Naturallv Occurring Melanocortin Analogs

[0461] 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 non-naturally occurring melanocortin analog, TCMCB07 (Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]- dVal-dPro-NH2; SEQ ID NO: 271 ), was tested at concentrations ranging from 0.1 p.M to 100 p.M 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 preincubation) inhibition assays were performed. The results of the CYP inhibition assays including ICso values at each of the CYP enzymes are shown in Table 22.

Table 22. CYP Inhibition of TCMCB07 Additional Embodiments

[0462] Various embodiments of the present technology are set forth below in paragraphs [0463] to [0588]:

[0463] 1. A method of increasing body weight in a subject in need thereof, comprising administering to the subject a non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁴ is selected from the group consisting of dPhe, 2’-D-naphthylalanine (dNal (2’)) , para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CP3)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁶ is selected from the group consisting of Trp, 4-amino-1 , 4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia) , 4-amino-1 ,2,4,5-tetrahydro-2- benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-[1 ,2, 3]triazolo-[1 ,5-a][1 ,4]diazepin- 6(5H)-one (Ata), 2’-naphthylalanine (Nal(2’)), and dNal(2’);

R⁷ is selected from the group consisting of Lys, Cys, Gly, dPen, and ornithine

(Orn); R⁸ is absent or dPen;

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 R¹ or R² and R⁷ when each of R¹ or R² and R⁷ are Cys; a disulfide bond between R² and R⁷ or R⁸ when each of R² and R⁷ or R⁸ are dPen; and a lactam bridge between R¹ or R² and R⁷ when R¹ or R² is Asp or Glu, and R⁷ is Lys or Orn, provided that: when R⁴ is dPhe, then (i) R³ is d Bip; or (ii) R³ is Pro and either R⁵ is Lys or R⁶ is dNal(2’) or Nal(2’); when R⁴ is p(F)dPhe, then (i) R³ is selected from Tyr, Phe, Bip, and Trp; or (ii) R³ is Pro and either R⁶ is Nal(2’) or dNal(2’) or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R² and R⁷; when R⁴ is p(CI)dPhe, then (i) R³ is selected from dPhe, dTyr, T rp, Tyr, Pro, dHis, Phe, Bip, and Gin; or (ii) R³ is His, R¹ is Nle or Ala, R⁷ is Lys or Cys, Y³ is not dVal, and Y⁴ is absent, wherein when X¹ is present, then Y¹ is not dTle, and when X¹ is absent, then Y² is dPro; and when R⁴ is dNal(2’), then R³ is His or Pro, wherein when R³ is Pro, then the non- naturally occurring melanocortin analog is cyclized between a disulfide bond between dPen at R² and dPen at R⁷ or R⁸; and when R³ is His, then either (i) the non-naturally occurring melanocortin analog is cyclized between a lactam bond between Glu at R¹ or R² and Orn at R⁷ or (ii) Y¹-Y⁴ are absent.

[0464] 2. Use of a non-naturally occurring melanocortin analog for increasing body weight in a subject in need thereof, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁵ is selected from the group consisting of Arg, His, and Lys;

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 R¹ or R² and R⁷ when each of R¹ or R² and R⁷ are Cys; a disulfide bond between R² and R⁷ or R⁸ when each of R² and R⁷ or R⁸ are dPen; and a lactam bridge between R¹ or R² and R⁷ when R¹ or R² is Asp or Glu, and R⁷ is Lys or Orn, provided that: when R⁴ is dPhe, then (i) R³ is d Bip; or (ii) R³ is Pro and either R⁵ is Lys or R⁶ is dNal(2’) or Nal(2’); when R⁴ is p(F)dPhe, then (i) R³ is selected from Tyr, Phe, Bip, and Trp; or (ii) R³ is Pro and either R⁶ is Nal(2’) or dNal(2’) or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R² and R⁷; when R⁴ is p(CI)dPhe, then (i) R³ is selected from dPhe, dTyr, T rp, Tyr, Pro, d H is, Phe, Bip, and Gin; or (ii) R³ is His, R¹ is Nle or Ala, R⁷ is Lys or Cys, Y³ is not dVal, and Y⁴ is absent, wherein when X¹ is present, then Y¹ is not dTle, and when X¹ is absent, then Y² is dPro; and when R⁴ is dNal(2’), then R³ is His or Pro, wherein when R³ is Pro, then the non- naturally occurring melanocortin analog is cyclized between a disulfide bond between dPen at R² and dPen at R⁷ or R⁸; and when R³ is His, then either (i) the non-naturally occurring melanocortin analog is cyclized between a lactam bond between Glu at R¹ or R² and Orn at R⁷ or (ii) Y¹-Y⁴ are absent. [0465] 3. A method of increasing body weight in a subject in need thereof, comprising administering to the subject a non-naturally occurring melanocortin analog comprising a sequence of Formula (IE):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (IE), wherein:

R¹ is Nle;

R² is Asp or Glu;

R³ is Pro or His:

R⁴ is p(CI)dPhe or p(Br)dPhe;

R⁵ is Arg;

R⁶ is Trp;

R⁷ is Orn;

Y¹ is d Vai;

[0466] 4. Use of a non-naturally occurring melanocortin analog for increasing body weight in a subject in need thereof, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

[0467] 5. The method or the use of any one of embodiments 1 to 4, wherein the method further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject.

[0468] 6. The method of the use of embodiment 5, wherein the lean mass is lean muscle mass.

[0469] 7. The method or the use of any one of embodiments 1 to 6, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 1 mg/kg to about 1000 mg/kg per body weight of the subject once daily. [0470] 8. The method or the use of embodiment 7, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 1 mg/kg or 3 mg/kg per body weight of the subject once daily.

[0471 ] 9. The method or the use of embodiment 7, 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.

[0472] 10. The method or the use of any one of embodiments 1 to 6, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily.

[0473] 11 . The method or the use of any one of embodiments 1 to 6, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily.

[0474] 12. The method or the use of any one of embodiments 1 to 8, wherein the non-naturally occurring melanocortin analog is an antagonist of a melanocortin 4 receptor.

[0475] 13. The method or the use of embodiment 12, wherein the non- naturally occurring melanocortin analog is a full antagonist of the melanocortin 4 receptor.

[0476] 14. The method or the use of embodiment 12, wherein the non- naturally occurring melanocortin analog is a partial antagonist of the melanocortin 4 receptor.

[0477] 15. The method or the use of any one of embodiments 1 to 14, wherein the non-naturally occurring melanocortin analog is an antagonist of a melanocortin 3 receptor.

[0478] 16. The method or the use of embodiment 15, wherein the non- naturally occurring melanocortin analog is a full antagonist of the melanocortin 3 receptor.

[0479] 17. The method or the use of embodiment 15, wherein the non- naturally occurring melanocortin analog is a partial antagonist of the melanocortin 3 receptor. [0480] 18. The method or the use of any one of embodiments 1 to 14, wherein the non-naturally occurring melanocortin analog is an agonist of the melanocortin 3 receptor.

[0481] 19. The method or the use of embodiment 18, wherein the non- naturally occurring melanocortin analog is a full agonist of the melanocortin 3 receptor.

[0482] 20. The method or the use of embodiment 18, wherein the non- naturally occurring melanocortin analog is a partial agonist of the melanocortin 3 receptor.

[0483] 21. The method or the use of embodiment 18, wherein the non- naturally occurring melanocortin analog has no melanocortin 3 receptor activity.

[0484] 22. The method or the use of any one of embodiments 1 to 21 , wherein the method or the use further comprises preventing or reducing one or more side effects associated with a metabolic disorder, relative to a control.

[0485] 23. A method of preventing or reducing cachexia in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

[0486] 24. Use of a non-naturally occurring melanocortin analog for preventing or reducing cachexia in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁴ is selected from the group consisting of dPhe, 2’-D-naphthylalanine (dNal(2’)), para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para- bromo-D-phenylalanine (p(Br)dPhe), para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe); R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

[0487] 25. A method of preventing or reducing anorexia in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁵ is selected from the group consisting of Arg, His, and Lys; R⁶ is selected from the group consisting of Trp, 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), 4-amino-1 ,2,4,5-tetrahydro-2- benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-[1 ,2, 3]triazolo-[1 ,5-a][1 ,4]diazepin- 6(5H)-one (Ata), 2’-naphthylalanine (Nal(2’)), and dNal(2’);

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

[0488] 26. Use of a non-naturally occurring melanocortin analog for preventing or reducing anorexia in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁶ is selected from the group consisting of Trp, 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia) , 4-amino-1 ,2,4,5-tetrahydro-2- benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-[1 ,2, 3]triazolo-[1 ,5-a][1 ,4]diazepin- 6(5H)-one (Ata), 2’-naphthylalanine (Nal(2’)), and dNal(2’);

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

[0489] 27. A method of increasing, maintaining, or reducing a loss in a body mass index (BMI) level in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁶ is selected from the group consisting of Trp, 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia) , 4-amino-1 ,2,4,5-tetrahydro-2- benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-[1 ,2, 3]triazolo-[1 , 5-a] [1 ,4]diazepin- 6(5H)-one (Ata), 2’-naphthylalanine (Nal(2’)), and dNal(2’); R⁷ is selected from the group consisting of Lys, Cys, Gly, dPen, and ornithine

(Orn);

R⁸ is absent or dPen;

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 R¹ or R² and R⁷ when each of R¹ or R² and R⁷ are Cys; a disulfide bond between R² and R⁷ or R⁸ when each of R² and R⁷ or R⁸ are dPen; and a lactam bridge between R¹ or R² and R⁷ when R¹ or R² is Asp or Glu, and R⁷ is Lys or Orn, provided that: when R⁴ is dPhe, then (i) R³ is d Bip; or (ii) R³ is Pro and either R⁵ is Lys or R⁶ is dNal(2’) or Nal(2 ); when R⁴ is p(F)dPhe, then (i) R³ is selected from Tyr, Phe, Bip, and Trp; or (ii) R³ is Pro and either R⁶ is Nal(2’) or dNal(2’) or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R² and R⁷; when R⁴ is p(CI)dPhe, then (i) R³ is selected from dPhe, dTyr, T rp, Tyr, Pro, dHis, Phe, Bip, and Gin; or (ii) R³ is His, R¹ is Nle or Ala, R⁷ is Lys or Cys, Y³ is not dVal, and Y⁴ is absent, wherein when X¹ is present, then Y¹ is not dTle, and when X¹ is absent, then Y² is dPro; and when R⁴ is dNal(2’), then R³ is His or Pro, wherein when R³ is Pro, then the non- naturally occurring melanocortin analog is cyclized between a disulfide bond between dPen at R² and dPen at R⁷ or R⁸; and when R³ is His, then either (i) the non-naturally occurring melanocortin analog is cyclized between a lactam bond between Glu at R¹ or R² and Orn at R⁷ or (ii) Y¹-Y⁴ are absent.

[0490] 28. Use of a non-naturally occurring melanocortin analog for increasing, maintaining, or reducing a loss in a BMI level in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁷ is selected from the group consisting of Lys, Cys, Gly, dPen, and ornithine (Orn); R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

[0491] 29. A method of increasing body weight in a subject in need thereof, comprising administering to the subject a non-naturally occurring melanocortin analog comprising a sequence of Formula (IE):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (IE), wherein:

R¹ is Nle;

R² is Asp or Glu;

R³ is Pro or His;

R⁴ is p(CI)dPhe or p(Br)dPhe;

R⁵ is Arg;

R⁶ is Trp;

R⁷ is Orn;

Y¹ is d Vai;

[0492] 30. Use of a non-naturally occurring melanocortin analog for increasing body weight in a subject in need thereof, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

[0493] 31. A method of preventing or reducing cachexia in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

[0494] 32. Use of a non-naturally occurring melanocortin analog for preventing or reducing cachexia in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IE). [0495] 33. A method of preventing or reducing anorexia in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

[0496] 34. Use of a non-naturally occurring melanocortin analog for preventing or reducing anorexia in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

[0497] 35. A method of increasing, maintaining, or reducing a loss in a body mass index (BMI) level in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

[0498] 36. Use of a non-naturally occurring melanocortin analog for increasing, maintaining, or reducing a loss in a BMI level in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

[0499] 37. The method or the use of any one of embodiments 1-36, wherein the method or the use prevents fat mass gain after administration of the non-naturally occurring melanocortin analog, relative to a control.

[0500] 38. The method or the use of any one of embodiments 1-37, wherein the method or the use reduces increases a fat mass level after administration of the non-naturally occurring melanocortin analog, relative to a control.

[0501] 39. The method or the use of any one of embodiments 1-38, wherein the method or the use maintains or increases brain mass in the subject during or after administration of the non-naturally occurring melanocortin analog, relative to a control.

[0502] 40. The method or the use of any one of embodiments 1-38, wherein the method or the use prevents or reduces brain mass loss in the subject during or after administration of the non-naturally occurring melanocortin analog, relative to a control.

[0503] 41. The method or the use of any one of embodiments 1 , 2, 5-46, or

37-40, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I):

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

[0504] 42. The method or the use of any one of embodiments 1 , 2, 5-46, or

37-40, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁶ is selected from the group consisting of Trp, 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), 4-amino-1 ,2,4,5-tetrahydro-2- benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-[1 ,2, 3]triazolo-[1 ,5-a][1 ,4]diazepin- 6(5H)-one (Ata), 2’-naphthylalanine (Nal(2’)), and dNal(2’);

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

Ac-Nle-c[Cys-His-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 104);

Ac-Nle-c[Cys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 105);

Ac-Nle-c[dPen-Pro-dPhe-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 106);

Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-NH₂ (SEQ ID NO: 107);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Aba-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 108);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Aia-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 109);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Ata-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 110);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH₂ (SEQ ID NO: 111 );

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-NH₂ (SEQ ID NO: 112);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dPro-NH₂ (SEQ ID NO: 113);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH₂ (SEQ ID NO: 114);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH₂ (SEQ ID NO: 115);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-l_ys]-dVal-dHyp-NH₂ (SEQ ID NO: 116);

Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH₂ (SEQ ID NO: 117);

Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH₂ (SEQ ID NO: 118);

Ac-Nle-c[Asp-dGln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 119);

Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH₂ (SEQ ID NO: 120);

Ac-dLeu-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 121 );

Ac-dl_ys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH₂ (SEQ ID NO: 122);

Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dPro-NH₂ (SEQ ID NO: 123);

Ac-Nle-c[Asp-dTrp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 126);

Ac-dTyr-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 127);

Ac-Nle-c[Asp-dTyr-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 128);

Ac-Nle-c[Asp-dTyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 129);

Ac-Nle-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 130);

Ac-Nle-c[Asp-Trp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 131 );

Ac-Nle-c[Asp-Tyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 132);

Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 133);

Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 134);

Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 135);

Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 136);

Ac-Nle-c[Asp-Bip-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 137);

Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 138);

Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 139);

Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 140);

Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH₂ (SEQ ID NO: 141 );

Ac-Arg-c(Asp-dAla-His-dPhe-Arg-Trp-Lys)-NH₂ (SEQ ID NO: 142);

Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 143);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 144);

Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 145);

Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 146);

Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 149);

Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 150); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 151 );

Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 152);

Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 153);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 154);

Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 155);

Ac-Nle-c[Asp-His-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 156);

Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 157);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 158);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH₂ (SEQ ID NO: 159);

Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 160);

Ac-Nle-c[Asp-Pro-dPhe-Arg-dTrp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 161);

Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 162);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-l_ys]-dPro-dVal-OH (SEQ ID NO: 163);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH₂ (SEQ ID NO: 164);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-l_ys]-dVal-dPro-OH (SEQ ID NO: 165);

Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 166);

Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 167);

Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 168);

Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 169);

Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 170);

Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 171 );

Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 172);

Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 173);

Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 174);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH₂ (SEQ ID NO: 175);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH₂ (SEQ ID NO: 176); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH₂ (SEQ ID NO: 177);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 178);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH₂ (SEQ ID NO: 179);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH₂ (SEQ ID NO: 180);

Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 181 );

Ac-dNle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 182);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dHyp-NH₂ (SEQ ID NO: 183);

Ac-Nle-c[Asp-dBip-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 184);

Ac-Nle-c[Asp-dGln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 185);

Ac-Nle-c[Asp-dTrp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 186);

Ac-Nle-c[Asp-dTyr-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 187);

Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 188);

Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 189);

Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 190);

Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 191 );

Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 192);

Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 193);

Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 194);

Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 195);

Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 196);

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 197);

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 198);

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH₂ (SEQ ID NO: 199);

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 201 );

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 202); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 203);

Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 204);

Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 205);

Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 206);

Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 207);

Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 208);

Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 209);

Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 210);

Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 21 1 );

Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 212);

Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 213);

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 214);

Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 215);

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 216);

Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 217);

Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 218);

Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 219);

Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 220);

Ac-dl_ys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 221 );

Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 222);

Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 223);

Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 224);

Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 225);

Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH₂ (SEQ ID NO: 226);

Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 228); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 229);

Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 230);

Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 231 );

Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 232);

Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 233);

Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 234);

Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 235);

Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 236);

Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 237);

Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 238);

Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 239);

Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 240);

Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 241 );

Ac-Nle-c[Asp-dPhe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 242);

Ac-Nle-c[Asp-dBip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 243);

Ac-Nle-c[Asp-dGln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 244);

Ac-Nle-c[Asp-dTrp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 245);

Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 246);

Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 247);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 248);

Ac-Nle-c[Glu-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 249);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH₂ (SEQ ID NO: 250);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 252);

Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 253); Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 254);

Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 255);

Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 256);

Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 257);

Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 258);

Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 259);

Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 260);

Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 261);

Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 262);

Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 263);

Ac-Nle-c[Asp-dTrp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 264);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 271 );

Ac-Nle-c[Asp-Trp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 272);

Ac-Nle-c[Asp-Pro-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 273);

Ac-Nle-c[Asp-Pro-His-dNal(2')-Arg-Trp-Lys]-dPro-dVal-NH₂ (SEQ ID NO: 274);

Ac-dArg-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 275);

Ac-dLeu-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 276);

Ac-Ala-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 277);

Ac-dNle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 278);

Ac-dPhe-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 279);

Tyr-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 282);

Ac-Nle-c[Cys-Pro-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 283);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 284);

Ac-Nle-c[Glu-Pro-dNal(2')-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 285); Ac-Nle-c[Asp-Pro-dNal(2')-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 286);

Ac-Nle-c[Asp-Pro-dNal(2')-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 287);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 288);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 289);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 290);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 291 );

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dVal-NH2 (SEQ ID NO: 292);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dPro-NH2 (SEQ ID NO: 293);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-NH₂ (SEQ ID NO: 294);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-NH2 (SEQ ID NO: 295);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dHyp-NH2 (SEQ ID NO: 296);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 297);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-NH2 (SEQ ID NO: 298);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dl_ys-dPro-dVal-NH2 (SEQ ID NO: 299);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dl_ys-dPro-NH2 (SEQ ID NO: 300);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dl_ys-dVal-dPro-NH2 (SEQ ID NO: 301);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-dPro-dVal-NH2 (SEQ ID NO: 302);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 303);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dVal-dPro-NH2 (SEQ ID NO: 304);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 305);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dVal-NH2 (SEQ ID NO: 306);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dTle-NH2 (SEQ ID NO: 307);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 308);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 309);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dTle-NH2 (SEQ ID NO: 310);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 311 ); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dVal-dPro-NH₂ (SEQ ID NO: 312);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 313);

Ac-Nle-c[Asp-Pro-Pro-dNal(2')-Arg-Trp-Lys]-d al-dPro-NH₂ (SEQ ID NO: 316);

Ac-Nle-c[Asp-Glu-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 317);

Ac-Nle-c[Asp-dAla-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 318);

Ac-Arg-c[Cys-dAla-His-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 320).

[0505] 43. The method or the use of any one of embodiments 1 , 2, 5-46, or

37-42, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IA):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (IA), wherein:

X¹ is absent, Nle, or Arg;

R⁵ is Arg or His;

R⁷ is selected from the group consisting of Lys, Cys, Gly, dPen, and Orn;

R⁸ is absent or dPen; Y¹ is absent or is selected from the group consisting of dVal, dPro, dTle, dArg, and dLys;

Y³ is absent, dVal, or dPro;

[0506] 44. The method or the use of any one of embodiments 1 , 2, 5-46, or

37-42, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IB):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³ (IB), wherein:

X¹ is absent or Arg;

R² is selected from the group consisting of dAla, dPen, Glu, and Pro;

R³ is His or Pro;

R⁴ is dNal(2’);

R⁵ is Arg or His;

R⁶ is Trp;

R⁷ is selected from the group consisting of Cys, Gly, dPen, and Orn; R⁸ is absent or dPen;

Y² is absent or is selected from the group consisting of dVal, dPro, and dHyp;

[0507] 45. The method or the use of embodiment 44, wherein the non- naturally occurring melanocortin analog comprises a sequence according to Formula (IB(I)):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³ (IB(i)), wherein:

R² is dPen;

R³ is Pro;

R⁴ is dNal(2’);

R⁵ is Arg;

R⁶ is Trp;

R⁷ is Gly or dPen;

R⁸ is absent or dPen;

Y¹ is selected from the group consisting of dVal, dTle, dArg, and dLys; Y² is selected from the group consisting of dVal, dPro, and dHyp;

[0508] 46. The method or the use of embodiment 44 or 45, wherein the non- naturally occurring melanocortin analog comprises a sequence according to Formula (IB(ii)):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (IB(ii)), wherein:

X¹ is absent or Arg;

R¹ is selected from the group consisting of Nle, Cys, Asp, and Glu;

R² is selected from the group consisting of dAla, Glu, and Pro;

R³ is His;

R⁴ is dNal(2’);

R⁵ is Arg or His;

R⁶ is Trp;

R⁷ is Cys or 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 disulfide bond between R¹ and R⁷ when each of R¹ and R⁷ are Cys; and a lactam bridge between R¹ or R² and R⁷ when R¹ or R² is Asp or Glu, and R⁷ is Lys or Orn. [0509] 47. The method or the use of any one of embodiments 1 , 2, 5-46, or

37-42, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IC):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y²-Y³-Y⁴ (IC), wherein:

X¹ is absent or Nle;

R² is selected from the group consisting of Asp, Glu, and Cys;

R⁵ is Arg or His;

R⁷ is selected from the group consisting of Lys, Cys, and Orn;

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 moiety selected from the group consisting of: a disulfide bond between R² and R⁷ when R² and R⁷ are each Cys; and a lactam bridge between R² and R⁷ when R² is Asp or Glu, and R⁷ is Lys or Orn. [0510] 48. The method or the use of embodiment 47, wherein the non- naturally occurring melanocortin analog comprises a sequence according to Formula (IC(i)):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y²-Y³-Y⁴ (IC(i)), wherein:

X¹ is absent or Nle;

R² is selected from the group consisting of Asp, Glu, and Cys;

R⁴ is p(Br)dPhe;

R⁵ is Arg or His;

R⁶ is selected from the group consisting of Trp, Nal(2’), and dNal(2’);

R⁷ is selected from the group consisting of Lys, Cys, and Orn;

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;

[0511] 49. The method or the use of embodiment 47 or 48, wherein the non- naturally occurring melanocortin analog comprises a sequence according to Formula (IC(ii)):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y²-Y³ (IC(ii)), wherein: X¹ is absent or Nle;

R¹ is Nle or Ala;

R² is selected from the group consisting of Asp, Glu, and Cys;

R⁴ is p(CI)dPhe;

R⁵ is Arg or His;

R⁶ is selected from the group consisting of Trp, Nal(2’), and dNal(2’);

R⁷ is selected from the group consisting of Lys, Cys, and Orn;

Y¹ is selected from the group consisting of dVal, dPro, and dTle;

Y² is dVal, or dPro;

[0512] 50. The method or the use of any one of embodiments 1 , 2, 5-46, or

37-41 , wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IC(iii)):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (IC(iii)), wherein:

R¹ is Nle;

R² is Asp;

R³ is His or Pro;

R⁴ is p(CF₃)dPhe or p(l)dPhe;

R⁵ is Arg;

R⁶ is selected from the group consisting of Trp, Aia, Aba, and Ata; R⁷ is Lys;

Y¹ is dVal;

[0513] 51. The method or the use of any one of embodiments 1 , 2, 5-46, or

37-42, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (ID):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (ID), wherein:

R¹ is Nle;

R² is Asp or Cys;

R³ is Pro, Phe, Trp, Tyr, Bip, and dBip;

R⁴ is p(F)dPhe or dPhe;

R⁵ is Arg or Lys;

R⁶ is selected from the group consisting of Trp, Nal(2’), and dNal(2’);

R⁷ is Lys or Cys;

Y¹ is dVal;

[0514] 52. The method or the use of any one of embodiments 1 , 2, 5-46, or

37-42, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IE):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (IE), wherein:

R¹ is Nle;

R² is Asp or Glu;

R³ is Pro or His;

R⁴ is p(CI)dPhe or p(Br)dPhe;

R⁵ is Arg;

R⁶ is Trp;

R⁷ is Orn;

Y¹ is dVal;

[0515] 53. The method or the use of embodiment 52, wherein the non- naturally occurring melanocortin analog comprises a sequence according to Formula (IE), wherein:

R¹ is Nle;

R² is Asp or Glu;

R³ is Pro or His;

R⁴ is p(CI)dPhe or p(Br)dPhe;

R⁵ is Arg;

R⁶ is Trp;

R⁷ is Orn;

Y¹ is dVal;

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 248); or

Ac-Nle-c[Glu-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 249).

[0516] 54. The method or the use of any one of embodiments 1-53, wherein an N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an acyl group.

[0517] 55. The method or the use of embodiment 54, wherein the acyl group is an acetyl group.

[0518] 56. The method or the use of any one of embodiments 1-53, wherein an N-terminus of the non-naturally occurring melanocortin analog, if present, is not modified.

[0519] 57. The method or the use of any one of embodiments 1-56, wherein a C-terminus of the non-naturally occurring melanocortin analog is modified by an amide group.

[0520] 58. The method or the use of any one of embodiments 1-56, wherein a C-terminus of the non-naturally occurring melanocortin analog is not modified.

[0521] 59. The method or the use of any one of embodiments 1-58, wherein

R⁴ is dNal(2’).

[0522] 60. The method or the use of any one of embodiments 1-59, wherein

R¹ is selected from dArg, Arg, dPhe, dTyr, dLeu, Ala, His, dHis, Lys, dLys, and dNIe.

[0523] 61. The method or use of embodiment 60, wherein Y¹ is dVal, Y² is dPro, and Y³-Y⁴ are absent.

[0524] 62. The method or the use of any one of embodiments 1-61 , wherein the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-dArg-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 8);

Ac-Arg-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 9);

Ac-dTyr-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 10);

Ac-Ala-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 11 ); Ac-dHis-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 12);

Ac-His-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 13);

Ac-dLys-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 14);

Ac-Lys-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 15);

Ac-dLeu-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 49);

Ac-dNle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 51 ); and

Ac-dPhe-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 61), wherein c represents cyclization through R² and R⁷via a disulfide bond.

[0525] 63. The method or the use of any one of embodiments 1-60, wherein

Y¹ is dTle, Y² is dPro, and Y³-Y⁴ are absent.

[0526] 64. The method or the use of any one of embodiments 1-60 and 52, wherein the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dArg-dVal-dPro-NH₂ (SEQ ID NO: 53);

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dArg-dPro-NH₂ (SEQ ID NO: 55);

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dLys-dPro-NH₂ (SEQ ID NO: 56);

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dHyp-NH₂ (SEQ ID NO: 57);

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dTle-dPro-NH₂ (SEQ ID NO: 58);

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-Gly-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 59);

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 94); and

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dLys-dVal-dPro-NH₂ (SEQ ID NO: 95), wherein c represents cyclization through R¹ and R⁹via a lactam bond.

[0527] 65. The method or the use of any one of embodiments 1-55, wherein

X¹ is Arg, R² is dAla, R³ is His and Y¹-Y⁴ are absent.

[0528] 66. The method or the use of any one of embodiments 1-55 and 54, wherein the sequence of any one of Formulae (l)-(IE) is:

Ac-Arg-c(Cys-dAla-His-dNal(2’)-Arg-Trp-Cys)-NH₂ (SEQ ID NO: 7); or Ac-Arg-c(Asp-dAla-His-dNal(2’)-Arg-Trp-Lys)-NH₂ (SEQ ID NO: 63), wherein c represents cyclization through R¹ and R⁸ via a lactam bond.

[0529] 67. The method or the use of any one of embodiments 1-59, wherein

R³ is His, R⁵ is His Y¹ is dVal, Y² is dPro, and Y³-Y⁴ are absent.

[0530] 68. The method or the use of any one of embodiments 1-59 and 56, wherein the sequence of any one of Formulae (l)-(l E) is:

Ac-Arg-c[Glu-Pro-His-dNal(2’)-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 5); or

[0531] 69. The method or the use of any one of embodiments 1-58, wherein

R⁴ is p(Br)dPhe and R³ is His.

[0532] 70. The method or the use of any one of embodiments 1-58 and 58, wherein X¹ is absent and R¹ is selected from Ala, Arg, dArg, Lys, dLys, His, and dHis.

[0533] 71. The method or the use of any one of embodiments 1-58, 58, and

59, wherein the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 34);

Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 72);

Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 73);

Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 74);

Ac-dLys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 75);

Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 76); and

[0534] 72. The method or the use of any one of embodiments 1-59, 58, and

59, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of:

Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 36); Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 80);

Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 81 );

Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 82);

Ac-dl_ys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 83);

Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 84); and

Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 85), wherein c represents cyclization through R² and R⁷ via a lactam bond.

[0535] 73. The method or the use of any one of embodiments 1-58 and 58, wherein X¹ is absent or Nle, Y¹ is selected from dVal, dPro, and dTle, Y² is selected from dVal, dPro, and dTle, Y³ is absent, dVal or dPro and Y⁴ is absent or dPro.

[0536] 74. The method or the use of any one of embodiments 1-58, 58, and

62, wherein the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 18);

Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 25);

Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 31 );

Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH₂ (SEQ ID NO: 32);

Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 35);

Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 50);

Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 79), wherein c represents cyclization through R² and R⁷ via a lactam bond.

[0537] 75. The method or the use of any one of embodiments 1-58 and 58, wherein R⁵ is His.

[0538] 76. The method or the use of any one of embodiments 1-58, 58, and

64, wherein the sequence of any one of Formulae (l)-(IE) is: Ac-Nle-c[Asp-His- p(Br)dPhe-His-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 19), wherein c represents cyclization through R² and R⁷ via a lactam bond.

[0539] 77. The method or the use of any one of embodiments 1-58 and 58, wherein R⁶ is Nal(2’) or dNal(2’).

[0540] 78. The method or the use of any one of embodiments 1-58, 58, and

66, wherein the sequence of any one of Formulae (l)-(IE) is:

Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 37); or

Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 52), wherein c represents cyclization through R² and R⁷ via a lactam bond.

[0541] 79. The method or the use of any one of embodiments 1-58 and 58, wherein the sequence of any one of Formulae (l)-(IE) is cyclized through a lactam bond between Asp or Glu at R² and Orn at R⁷.

[0542] 80. The method or the use of any one of embodiments 1-58, 58, and

68, wherein the sequence of any one of Formulae (l)-(IE) is:

Ac-Nle-c[Glu-His-p(Br)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 101 ); or

[0543] 81. The method or the use of any one of embodiments 1-58 and 58, wherein the sequence of any one of Formulae (l)-(IE) is cyclized through a lactam bond between Cys at R² and Cys at R⁷.

[0544] 82. The method or the use of any one of embodiments 1-58, 58, and

70, wherein the sequence of any one of Formulae (l)-(IE) is: Ac-Nle-c[Cys-His- p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 28), wherein c represents cyclization through R² and R⁷via a disulfide bond.

[0545] 83. The method or the use of any one of embodiments 1-58, wherein

R⁴ is p(Br)dPhe and R³ is selected from Pro, Gin, dGIn, dHis, Phe, dPhe, Bip, d Bip, Tyr, dTyr, Trp, and dTrp. [0546] 84. The method or the use of any one of embodiments 1-58 and 72, wherein the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[Asp-Pro-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 21 );

Ac-Nle-c[Asp-Gln-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 33);

Ac-Nle-c[Asp-dHis-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 38);

Ac-Nle-c[Asp-Phe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 39);

Ac-Nle-c[Asp-dPhe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 40);

Ac-Nle-c[Asp-Bip-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 41 );

Ac-Nle-c[Asp-dBip-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 42);

Ac-Nle-c[Asp-Trp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 44);

Ac-Nle-c[Asp-dTrp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 45);

Ac-Nle-c[Asp-Tyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 46);

Ac-Nle-c[Asp-dTyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 47); and

Ac-Nle-c[Asp-dGln-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 62), wherein c represents cyclization through R² and R⁷ via a lactam bond.

[0547] 85. The method or the use of any one of embodiments 1-58, R⁴ is p(CI)dPhe and R³ is His.

[0548] 86. The method or the use of any one of embodiments 1-58 and 74, wherein the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 16);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 17);

Ac-Nle-c[Cys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 65);

Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 66);

Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 67);

Ac-Nle-c[Asp-His-p(CI)dPhe-His-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 68); Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 69);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 97);

Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 98); and

[0549] 87. The method or the use of any one of embodiments 1-58, wherein

R⁴ is p(CI)dPhe and R³ is selected from Gin, dHis, Bip, Phe, dPhe, Tyr, dTyr, and Trp.

[0550] 88. The method or the use of any one of embodiments 1-58 and 76, wherein the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[Asp-dPhe-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 26);

Ac-Nle-c[Asp-Bip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 27);

Ac-Nle-c[Asp-dTyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 29);

Ac-Nle-c[Asp-Trp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 43);

Ac-Nle-c[Asp-Tyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 54);

Ac-Nle-c[Asp-Phe-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 60);

Ac-Nle-c[Asp-dHis-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 70); and

[0551] 89. The method or the use of any one of embodiments 1-58, wherein

R⁴ is p(CI)dPhe and R³ is Pro.

[0552] 90. The method or the use of any one of embodiments 1-58 and 78, wherein the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[Asp-Pro-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 30);

Ac-Nle-c[Asp-Pro-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 64); and Ac-Nle-c[Glu-Pro-p(CI)dPhe-Arg-Trp-Om]-dVal-dPro-NH₂ (SEQ ID NO: 103), wherein c represents cyclization through R² and R⁷ via a lactam bond.

[0553] 91 . The method or the use of any one of embodiments 1-58, wherein

R⁴ is p(l)dPhe.

[0554] 92. The method or the use of any one of embodiments 1-58 and 80, wherein the sequence of any one of Formulae (l)-(l E) is:

Ac-Nle-c[Asp-Pro-p(l)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 20); or

[0555] 93. The method or the use of any one of embodiments 1-58, wherein

R⁴ is p(CP₃)dPhe.

[0556] 94. The method or the use of any one of embodiments 1-58 and 82, wherein the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[Asp-Pro-p(CF₃)dPhe-Arg-Aia-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 2);

Ac-Nle-c[Asp-Pro-p(CF₃)dPhe -Arg-Aba-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 3);

Ac-Nle-c[Asp-Pro-p(CF₃)dPhe -Arg-Ata-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 4);

Ac-Nle-c[Asp-Pro-p(CF₃)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 22); and

Ac-Nle-c[Asp-His-p(CF₃)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 24), wherein c represents cyclization through R² and R⁷ via a lactam bond.

[0557] 95. The method or the use of any one of embodiments 1-58, wherein

R⁴ is dPhe or p(F)dPhe and R³ is Pro.

[0558] 96. The method or the use of any one of embodiments 1-58 and 84, wherein the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[Asp-Pro-dPhe-Lys-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 86);

Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 89);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 92); Ac-Nle-c[Cys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 93);

Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 96); and

[0559] 97. The method or the use of any one of embodiments 1-58, wherein

R⁴ is dPhe or p(F)dPhe and R³ selected from Phe, Tyr, Trp, Bip, and dBip.

[0560] 98. The method or the use of any one of embodiments 1 , 2, 5-28, or

37-97, wherein the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[Asp-dBip-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 48);

Ac-Nle-c[Asp-Phe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 87);

Ac-Nle-c[Asp-Bip-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 88);

Ac-Nle-c[Asp-Trp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 90); and

Ac-Nle-c[Asp-Tyr-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 91), wherein c represents cyclization through R² and R⁷via a lactam bond.

[0561] 99. The method or the use of any one of embodiments 1-98, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-103.

[0562] 100. The method or the use of embodiment 99, wherein the non- naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-47, 49-85, 94, 95, 97-99, and 101-103.

[0563] 101. The method or the use of embodiment 99, wherein the non- naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 5-15, 49, 51 , 53, 55-59, 61 , 63, 94, and 95

[0564] 102. The method or the use of embodiment 101 , wherein the non- naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 8-15, 49, 51 , 53, 55-59, 61 , 94, and 95. [0565] 103. The method or the use of embodiment 101 , wherein the non- naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 5-7 and 63.

[0566] 104. The method or the use of embodiment 99, wherein the non- naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-4, 16-47, 50, 52, 54, 60, 62, 64-85, 97-99, and 101-103.

[0567] 105. The method or the use of embodiment 104, wherein the non- naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 18, 19, 21 , 25, 28, 31-42, 44-47, 50, 52, 62, 72-85, 101 , and 102.

[0568] 106. The method or the use of embodiment 104, wherein the non- naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 16, 17, 26, 27, 29, 30, 43, 54, 60, 64-71 , 97-99, and 103.

[0569] 107. The method or the use of embodiment 104, wherein the non- naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-4, 20, and 22-24.

[0570] 108. The method or the use of embodiment 100, wherein the non- naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 48, 86-93, 96, and 100.

[0571] 109. The method or the use of embodiment 100, wherein the non- naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 64 and 101-103.

[0572] 110. The method or the use of any one of embodiments 1-109, wherein the non-naturally occurring melanocortin analog is present in a pharmaceutical composition.

[0573] 111. The method or the use of embodiment 110, wherein the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients and/or carriers.

[0574] 112. The method or the use of embodiment 111 , wherein the one or more pharmaceutically acceptable excipients and/or carriers of the pharmaceutical composition comprise water. [0575] 113. The method or the use of any one of embodiments 1 -112, wherein the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.

[0576] 114. The method or the use of any one of embodiments 1-113, wherein the non-naturally occurring melanocortin analog crosses a blood-brain-barrier of a subject.

[0577] 115. The method or the use embodiment 113, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (IE) and is administered at least once daily in an amount ranging from 0.001 mg/kg to 25 mg/kg per body weight of the subject.

[0578] 116. The method or the use of embodiment 115, wherein the non- naturally occurring melanocortin analog comprises a sequence of Formula (IE)and is administered at least once daily in an amount ranging from 0.5 mg/kg to 10 mg/kg per body weight of the subject.

[0579] 117. The method or the use of any one of embodiments 1-116, wherein the non-naturally occurring melanocortin analog is administered to a subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

[0580] 118. The method or the use of any one of embodiments 1-116, wherein the non-naturally occurring melanocortin analog is administered to a subject for 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

[0581] 119. The method or the use of any one of embodiments 1-118, wherein the method or the use further comprises maintaining muscle mass or promoting muscle mass gain in the subject.

[0582] 120. A non-naturally occurring melanocortin analog comprising a sequence according to Formula (IE):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (IE), wherein:

R¹ is Nle; R² is Asp or Glu;

R³ is Pro or His;

R⁴ is p(CI)dPhe or p(Br)dPhe;

R⁵ is Arg;

R⁶ is Trp;

R⁷ is Orn;

Y¹ is dVal;

[0583] 121. The non-naturally occurring melanocortin analog of embodiment

120, wherein:

R¹ is Nle;

R² is Asp or Glu;

R³ is Pro or His;

R⁴ is p(CI)dPhe or p(Br)dPhe;

R⁵ is Arg;

R⁶ is Trp;

R⁷ is Orn;

Y¹ is dVal;

Y² is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Glu or Asp at R² and Orn at R⁷, provided that the non-naturally occurring melanocortin analog does not comprise a sequence of: Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 248); or

Ac-Nle-c[Glu-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 249).

[0584] 122. The non-naturally occurring melanocortin analog of embodiment

120 or 121 , wherein the sequence of Formula (IE) is selected from the group consisting of SEQ ID NOs: 64 and 101-103.

[0585] 123. A method of preventing or reducing anorexia nervosa in a subject in need thereof relative to a control, comprising administering to the subject: a non- naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁶ is selected from the group consisting of Trp, 4-amino-1 , 4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia) , 4-amino-1 ,2,4,5-tetrahydro-2- benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-[1 ,2, 3]triazolo-[1 , 5-a][1 ,4]diazepin- 6(5H)-one (Ata), 2’-naphthylalanine (Nal(2’)), and dNal(2’); R⁷ is selected from the group consisting of Lys, Cys, Gly, dPen, and ornithine

(Orn);

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

[0586] 124. Use of a non-naturally occurring melanocortin analog for preventing or reducing anorexia nervosa in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁶ is selected from the group consisting of Trp, 4-amino-1 ,4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), 4-amino-1 ,2,4,5-tetrahydro-2- benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-[1 ,2, 3]triazolo-[1 , 5-a] [1 ,4]diazepin- 6(5H)-one (Ata), 2’-naphthylalanine (Nal(2’)), and dNal(2’);

Y³ is absent, dVal, or dPro;

[0587] 125. A method of preventing or reducing anorexia nervosa in a subject in need thereof relative to a control, comprising administering to the subject: a non- naturally occurring melanocortin analog comprising a sequence of Formula (IE).

[0588] 126. Use of a non-naturally occurring melanocortin analog for preventing or reducing anorexia nervosa in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

[0589] 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.

Claims

CLAIMS I/We claim:

1. A method of increasing body weight in a subject in need thereof, comprising administering to the subject a non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁵ is selected from the group consisting of Arg, His, and Lys;

Y³ is absent, dVal, or dPro;

2. Use of a non-naturally occurring melanocortin analog for increasing body weight in a subject in need thereof, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁶ is selected from the group consisting of Trp, 4-amino-1 , 4,5,6- tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia) , 4-amino-1 ,2,4,5-tetrahydro-2- benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-[1 ,2, 3]triazolo-[1 , 5-a] [1 ,4]diazepin- 6(5H)-one (Ata), 2’-naphthylalanine (Nal(2’)), and dNal(2’);

Y³ is absent, dVal, or dPro;

3. A method of increasing body weight in a subject in need thereof, comprising administering to the subject a non-naturally occurring melanocortin analog comprising a sequence of Formula (IE):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (IE), wherein:

R¹ is Nle;

R² is Asp or Glu;

R³ is Pro or His:

R⁴ is p(CI)dPhe or p(Br)dPhe;

R⁵ is Arg;

R⁶ is Trp;

R⁷ is Orn;

Y¹ is d Vai;

4. Use of a non-naturally occurring melanocortin analog for increasing body weight in a subject in need thereof, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

5. The method or the use of any one of claims 1 to 4, wherein the method further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject.

6. The method of the use of claim 5, wherein the lean mass is lean muscle mass.

7. The method or the use of any one of claims 1 to 6, wherein the non- naturally occurring melanocortin analog is administered at a dose of about 1 mg/kg to about 1000 mg/kg per body weight of the subject once daily.

8. The method or the use of claim 7, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 1 mg/kg or 3 mg/kg per body weight of the subject once daily.

9. The method or the use of claim 7, 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.

10. The method or the use of any one of claims 1 to 6, wherein the non- naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily.

11. The method or the use of any one of claims 1 to 6, wherein the non- naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily.

12. The method or the use of any one of claims 1 to 8, wherein the non- naturally occurring melanocortin analog is an antagonist of a melanocortin 4 receptor.

13. The method or the use of claim 12, wherein the non-naturally occurring melanocortin analog is a full antagonist of the melanocortin 4 receptor.

14. The method or the use of claim 12, wherein the non-naturally occurring melanocortin analog is a partial antagonist of the melanocortin 4 receptor.

15. The method or the use of any one of claims 1 to 14, wherein the non- naturally occurring melanocortin analog is an antagonist of a melanocortin 3 receptor.

16. The method or the use of claim 15, wherein the non-naturally occurring melanocortin analog is a full antagonist of the melanocortin 3 receptor.

17. The method or the use of claim 15, wherein the non-naturally occurring melanocortin analog is a partial antagonist of the melanocortin 3 receptor.

18. The method or the use of any one of claims 1 to 14, wherein the non- naturally occurring melanocortin analog is an agonist of the melanocortin 3 receptor.

19. The method or the use of claim 18, wherein the non-naturally occurring melanocortin analog is a full agonist of the melanocortin 3 receptor.

20. The method or the use of claim 18, wherein the non-naturally occurring melanocortin analog is a partial agonist of the melanocortin 3 receptor.

21. The method or the use of claim 18, wherein the non-naturally occurring melanocortin analog has no melanocortin 3 receptor activity.

22. The method or the use of any one of claims 1 to 21 , wherein the method or the use further comprises preventing or reducing one or more side effects associated with a metabolic disorder, relative to a control.

23. A method of preventing or reducing cachexia in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R² is selected from the group consisting of D-alanine (dAla), Asp, Cys, D- penicillamine (dPen), Glu, and proline (Pro); R³ is selected from the group consisting of phenylalanine (Phe), dPhe, His, d H is, Pro, glutamine (Gin), D-glutamine (dGIn), tryptophan (Trp), D-tryptophan (dTrp), tyrosine (Tyr), dTyr, biphenylalanine (Bip), and D-biphenylalanine (dBip);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

24. Use of a non-naturally occurring melanocortin analog for preventing or reducing cachexia in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

25. A method of preventing or reducing anorexia in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

26. Use of a non-naturally occurring melanocortin analog for preventing or reducing anorexia in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

27. A method of increasing, maintaining, or reducing a loss in a body mass index (BMI) level in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

28. Use of a non-naturally occurring melanocortin analog for increasing, maintaining, or reducing a loss in a BMI level in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

29. A method of increasing body weight in a subject in need thereof, comprising administering to the subject a non-naturally occurring melanocortin analog comprising a sequence of Formula (IE):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (IE), wherein:

R¹ is Nle;

R² is Asp or Glu;

R³ is Pro or His;

R⁴ is p(CI)dPhe or p(Br)dPhe;

R⁵ is Arg;

R⁶ is Trp;

R⁷ is Orn;

Y¹ is d Vai;

30. Use of a non-naturally occurring melanocortin analog for increasing body weight in a subject in need thereof, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

31 . A method of preventing or reducing cachexia in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

32. Use of a non-naturally occurring melanocortin analog for preventing or reducing cachexia in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

33. A method of preventing or reducing anorexia in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

34. Use of a non-naturally occurring melanocortin analog for preventing or reducing anorexia in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

35. A method of increasing, maintaining, or reducing a loss in a body mass index (BMI) level in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

36. Use of a non-naturally occurring melanocortin analog for increasing, maintaining, or reducing a loss in a BMI level in a subject in need thereof relative to a control, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

37. The method or the use of any one of claims 1-36, wherein the method or the use prevents fat mass gain after administration of the non-naturally occurring melanocortin analog, relative to a control.

38. The method or the use of any one of claims 1-37, wherein the method or the use reduces increases a fat mass level after administration of the non-naturally occurring melanocortin analog, relative to a control.

39. The method or the use of any one of claims 1-38, wherein the method or the use maintains or increases brain mass in the subject during or after administration of the non-naturally occurring melanocortin analog, relative to a control.

40. The method or the use of any one of claims 1-38, wherein the method or the use prevents or reduces brain mass loss in the subject during or after administration of the non-naturally occurring melanocortin analog, relative to a control.

41 . The method or the use of any one of claims 1 , 2, 5-46, or 37-40, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

42. The method or the use of any one of claims 1 , 2, 5-46, or 37-40, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

Ac-Nle-c[Cys-His-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 104);

Ac-Nle-c[Cys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 105);

Ac-Nle-c[dPen-Pro-dPhe-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 106);

Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-NH₂ (SEQ ID NO: 107);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Aba-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 108);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Aia-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 109); Ac-Nle-c[Asp-Pro-dPhe-Arg-Ata-Lys]-dVal-dPro-NH2 (SEQ ID NO: 110);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 111 );

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-NH2 (SEQ ID NO: 112);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dl_ys-dPro-NH2 (SEQ ID NO: 113);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH2 (SEQ ID NO: 114);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 115);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 116);

Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 117);

Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 118);

Ac-Nle-c[Asp-dGln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 119);

Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 120);

Ac-dLeu-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 121 );

Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH2 (SEQ ID NO: 122);

Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dPro-NH2 (SEQ ID NO: 123);

Ac-dPhe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 124); dPhe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 125);

Ac-Nle-c[Asp-dTrp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 126);

Ac-dTyr-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 127);

Ac-Nle-c[Asp-dTyr-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 128);

Ac-Nle-c[Asp-dTyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 129);

Ac-Nle-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 130);

Ac-Nle-c[Asp-Trp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 131 );

Ac-Nle-c[Asp-Tyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 132);

Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 133);

Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 134);

Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 135); Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 136);

Ac-Nle-c[Asp-Bip-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 137);

Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 138);

Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 139);

Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 140);

Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH₂ (SEQ ID NO: 141 );

Ac-Arg-c(Asp-dAla-His-dPhe-Arg-Trp-Lys)-NH₂ (SEQ ID NO: 142);

Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 143);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 144);

Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 145);

Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 146);

Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 149);

Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 150);

Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 151 );

Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 152);

Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 153);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 154);

Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 155);

Ac-Nle-c[Asp-His-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 156);

Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 157);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 158);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH₂ (SEQ ID NO: 159);

Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 160);

Ac-Nle-c[Asp-Pro-dPhe-Arg-dTrp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 161); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 162);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 163);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH₂ (SEQ ID NO: 164);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 165);

Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 166);

Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 167);

Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 168);

Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 169);

Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 170);

Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 171 );

Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 172);

Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 173);

Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 174);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH₂ (SEQ ID NO: 175);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-l_ys]-dTle-dTle-dVal-NH₂ (SEQ ID NO: 176);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH₂ (SEQ ID NO: 177);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 178);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH₂ (SEQ ID NO: 179);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-l_ys]-dVal-dPro-dVal-dPro-NH₂ (SEQ ID NO: 180);

Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 181 );

Ac-dNle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 182);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dHyp-NH₂ (SEQ ID NO: 183);

Ac-Nle-c[Asp-dBip-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 184);

Ac-Nle-c[Asp-dGln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 185);

Ac-Nle-c[Asp-dTrp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 186);

Ac-Nle-c[Asp-dTyr-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 187); Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 188);

Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 189);

Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 190);

Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 191 );

Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 192);

Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 193);

Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 194);

Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 195);

Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 196);

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 197);

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 198);

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH₂ (SEQ ID NO: 199);

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 201 );

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 202);

Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 203);

Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 205);

Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 206);

Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 207);

Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 208);

Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 209);

Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 210);

Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 21 1 );

Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-l_ys]-dVal-dPro-NH₂ (SEQ ID NO: 212);

Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 213); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 214);

Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 215);

Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 216);

Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 217);

Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 218);

Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 219);

Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 220);

Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 221 );

Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 222);

Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 223);

Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 224);

Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 225);

Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH₂ (SEQ ID NO: 226);

Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 228);

Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 229);

Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 230);

Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 232);

Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 233);

Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 234);

Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 235);

Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 236);

Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 237);

Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 238);

Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 239); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 240);

Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 241 );

Ac-Nle-c[Asp-dPhe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 242);

Ac-Nle-c[Asp-dBip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 243);

Ac-Nle-c[Asp-dGln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 244);

Ac-Nle-c[Asp-dTrp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 245);

Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 246);

Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 247);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Orn]-d al-dPro-NH₂ (SEQ ID NO: 248);

Ac-Nle-c[Glu-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 249);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH₂ (SEQ ID NO: 250);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 252);

Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 253);

Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 254);

Ac-Lys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 255);

Ac-dl_ys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 256);

Ac-His-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 257);

Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 258);

Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 259);

Ac-dArg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 260);

Ac-Arg-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 261);

Ac-dLys-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 262);

Ac-dHis-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 263);

Ac-Nle-c[Asp-dTrp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 264); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 271 );

Ac-Nle-c[Asp-Trp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 272);

Ac-Nle-c[Asp-Pro-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 273);

Ac-Nle-c[Asp-Pro-His-dNal(2')-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 274);

Ac-dArg-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 275);

Ac-dLeu-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 276);

Ac-Ala-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 277);

Ac-dNle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 278);

Ac-dPhe-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 279);

Tyr-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 282);

Ac-Nle-c[Cys-Pro-dNal(2')-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 283);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 284);

Ac-Nle-c[Glu-Pro-dNal(2')-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 285);

Ac-Nle-c[Asp-Pro-dNal(2')-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 286);

Ac-Nle-c[Asp-Pro-dNal(2')-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 287);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 288);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 289);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 290);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 291 );

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dVal-NH2 (SEQ ID NO: 292);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dPro-NH2 (SEQ ID NO: 293);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-NH₂ (SEQ ID NO: 294);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-NH2 (SEQ ID NO: 295);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dHyp-NH2 (SEQ ID NO: 296); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 297);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-NH2 (SEQ ID NO: 298);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dLys-dPro-dVal-NH2 (SEQ ID NO: 299);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dl_ys-dPro-NH2 (SEQ ID NO: 300);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dLys-dVal-dPro-NH2 (SEQ ID NO: 301);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-dPro-dVal-NH2 (SEQ ID NO: 302);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 303);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dVal-dPro-NH2 (SEQ ID NO: 304);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 305);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dVal-NH2 (SEQ ID NO: 306);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dTle-NH2 (SEQ ID NO: 307);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 308);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 309);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dTle-NH2 (SEQ ID NO: 310);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 311 );

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 312);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 313);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dVal-d\/al-dPro-NH2 (SEQ ID NO: 314);

Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 315);

Ac-Nle-c[Asp-Pro-Pro-dNal(2')-Arg-Trp-Lys]-d\/al-dPro-NH2 (SEQ ID NO: 316);

Ac-Nle-c[Asp-Glu-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 317);

Ac-Nle-c[Asp-dAla-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 318);

Ac-Arg-c[Asp-dAla-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 319); and Ac-Arg-c[Cys-dAla-His-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 320).

43. The method or the use of any one of claims 1 , 2, 5-46, or 37-42, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IA):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (IA), wherein:

X¹ is absent, Nle, or Arg;

R⁵ is Arg or His;

R⁷ is selected from the group consisting of Lys, Cys, Gly, dPen, and Orn;

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

44. The method or the use of any one of claims 1 , 2, 5-46, or 37-42, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IB):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³ (IB), wherein:

X¹ is absent or Arg;

R² is selected from the group consisting of dAla, dPen, Glu, and Pro;

R³ is His or Pro;

R⁴ is dNal(2’);

R⁵ is Arg or His;

R⁶ is Trp;

R⁷ is selected from the group consisting of Cys, Gly, dPen, and Orn;

R⁸ is absent or dPen;

Y² is absent or is selected from the group consisting of dVal, dPro, and dHyp;

45. The method or the use of claim 44, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I B(l)):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³ (IB(i)), wherein:

R² is dPen;

R³ is Pro;

R⁴ is dNal(2’);

R⁵ is Arg;

R⁶ is Trp;

R⁷ is Gly or dPen;

R⁸ is absent or dPen;

Y¹ is selected from the group consisting of dVal, dTle, dArg, and dLys;

Y² is selected from the group consisting of dVal, dPro, and dHyp;

46. The method or the use of claim 44 or 45, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IB(ii)):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (IB(ii)), wherein:

X¹ is absent or Arg;

R³ is His;

R⁴ is dNal(2’);

R⁵ is Arg or His;

R⁶ is Trp;

R⁷ is Cys or Orn;

Y¹ is absent or dVal;

47. The method or the use of any one of claims 1 , 2, 5-46, or 37-42, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IC):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y²-Y³-Y⁴ (IC), wherein:

X¹ is absent or Nle;

R² is selected from the group consisting of Asp, Glu, and Cys;

R⁷ is selected from the group consisting of Lys, Cys, and Orn;

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;

48. The method or the use of claim 47, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IC(i)):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y²-Y³-Y⁴ (IC(i)), wherein:

X¹ is absent or Nle;

R² is selected from the group consisting of Asp, Glu, and Cys;

R⁴ is p(Br)dPhe;

R⁵ is Arg or His;

R⁶ is selected from the group consisting of Trp, Nal(2’), and dNal(2’);

R⁷ is selected from the group consisting of Lys, Cys, and Orn;

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;

49. The method or the use of claim 47 or 48, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IC(ii)):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y²-Y³ (IC(ii)), wherein:

X¹ is absent or Nle;

R¹ is Nle or Ala;

R² is selected from the group consisting of Asp, Glu, and Cys;

R⁴ is p(CI)dPhe;

R⁵ is Arg or His;

R⁶ is selected from the group consisting of Trp, Nal(2’), and dNal(2’);

R⁷ is selected from the group consisting of Lys, Cys, and Orn;

Y¹ is selected from the group consisting of dVal, dPro, and dTle;

Y² is dVal, or dPro;

50. The method or the use of any one of claims 1 , 2, 5-46, or 37-41 , wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IC(iii)):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (IC(iii)), wherein:

R¹ is Nle;

R² is Asp;

R³ is His or Pro;

R⁴ is p(CFs)dPhe or p(l)dPhe;

R⁵ is Arg;

R⁶ is selected from the group consisting of Trp, Aia, Aba, and Ata;

R⁷ is Lys;

Y¹ is d Vai;

51 . The method or the use of any one of claims 1 , 2, 5-46, or 37-42, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (ID):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (ID), wherein:

R¹ is Nle;

R² is Asp or Cys;

R³ is Pro, Phe, Trp, Tyr, Bip, and dBip;

R⁴ is p(F)dPhe or dPhe; R⁵ is Arg or Lys;

R⁶ is selected from the group consisting of Trp, Nal(2’), and dNal(2’);

R⁷ is Lys or Cys;

Y¹ is d Vai;

52. The method or the use of any one of claims 1 , 2, 5-46, or 37-42, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IE):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (IE), wherein:

R¹ is Nle;

R² is Asp or Glu;

R³ is Pro or His;

R⁴ is p(CI)dPhe or p(Br)dPhe;

R⁵ is Arg;

R⁶ is Trp;

R⁷ is Orn;

Y¹ is d Vai;

-2Q7-

53. The method or the use of claim 52, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IE), wherein:

R¹ is Nle;

R² is Asp or Glu;

R³ is Pro or His:

R⁴ is p(CI)dPhe or p(Br)dPhe;

R⁵ is Arg;

R⁶ is Trp;

R⁷ is Orn;

Y¹ is d Vai;

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Om]-dVal-dPro-NH₂ (SEQ ID NO: 248); or

Ac-Nle-c[Glu-His-p(CI)dPhe-Arg-Trp-Om]-dVal-dPro-NH₂ (SEQ ID NO: 249).

54. The method or the use of any one of claims 1-53, wherein an N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an acyl group.

55. The method or the use of claim 54, wherein the acyl group is an acetyl group.

56. The method or the use of any one of claims 1-53, wherein an N-terminus of the non-naturally occurring melanocortin analog, if present, is not modified.

57. The method or the use of any one of claims 1 -56, wherein a C-terminus of the non-naturally occurring melanocortin analog is modified by an amide group.

58. The method or the use of any one of claims 1-56, wherein a C-terminus of the non-naturally occurring melanocortin analog is not modified.

59. The method or the use of any one of claims 1-58, wherein R⁴ is dNal(2’).

60. The method or the use of any one of claims 1-59, wherein R¹ is selected from dArg, Arg, dPhe, dTyr, dLeu, Ala, His, dHis, Lys, dLys, and dNIe.

61 . The method or use of claim 60, wherein Y¹ is dVal, Y² is dPro, and Y³-Y⁴ are absent.

62. The method or the use of any one of claims 1-61 , wherein the sequence of any one of Formulae (l)-(l E) is selected from the group consisting of: Ac-dArg-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 8);

Ac-Arg-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 9);

Ac-dTyr-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 10);

Ac-Ala-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 11);

Ac-dHis-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 12);

Ac-His-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 13);

Ac-dl_ys-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 14);

Ac-Lys-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 15);

Ac-dLeu-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 49);

Ac-dNle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 51 ); and

63. The method or the use of any one of claims 1-60, wherein Y¹ is dTle, Y² is dPro, and Y³-Y⁴ are absent.

64. The method or the use of any one of claims 1-60 and 52, wherein the sequence of any one of Formulae (l)-(l E) is selected from the group consisting of: Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dArg-dVal-dPro-NH₂ (SEQ ID NO: 53);

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dArg-dPro-NH₂ (SEQ ID NO: 55);

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dLys-dPro-NH₂ (SEQ ID NO: 56);

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dHyp-NH₂ (SEQ ID NO: 57);

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dTle-dPro-NH₂ (SEQ ID NO: 58);

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-Gly-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 59);

Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dVal-dPro-NH₂ (SEQ ID NO: 94); and Ac-Nle-c[dPen-Pro-dNal(2')-Arg-Trp-dPen]-dLys-dVal-dPro-NH₂ (SEQ ID NO: 95), wherein c represents cyclization through R¹ and R⁹via a lactam bond.

65. The method or the use of any one of claims 1 -55, wherein X¹ is Arg, R² is dAla, R³ is His and Y¹-Y⁴ are absent.

66. The method or the use of any one of claims 1-55 and 54, wherein the sequence of any one of Formulae (l)-(IE) is:

Ac-Arg-c(Cys-dAla-His-dNal(2’)-Arg-Trp-Cys)-NH₂ (SEQ ID NO: 7); or

Ac-Arg-c(Asp-dAla-His-dNal(2’)-Arg-Trp-Lys)-NH₂ (SEQ ID NO: 63), wherein c represents cyclization through R¹ and R⁸via a lactam bond.

67. The method or the use of any one of claims 1-59, wherein R³ is His, R⁵ is His Y¹ is dVal, Y² is dPro, and Y³-Y⁴ are absent.

68. The method or the use of any one of claims 1-59 and 56, wherein the sequence of any one of Formulae (l)-(IE) is:

Ac-Arg-c[Glu-Pro-His-dNal(2’)-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 5); or

69. The method or the use of any one of claims 1 -58, wherein R⁴ is p(Br)dPhe and R³ is His.

70. The method or the use of any one of claims 1-58 and 58, wherein X¹ is absent and R¹ is selected from Ala, Arg, dArg, Lys, dLys, His, and dHis.

71. The method or the use of any one of claims 1 -58, 58, and 59, wherein the sequence of any one of Formulae (l)-(l E) is selected from the group consisting of:

Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 34);

Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 72);

Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 73);

Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 74);

Ac-dLys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 75);

Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 76); and Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 77), 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, 58, and 59, wherein the sequence of any one of Formulae (l)-(ID) is selected from the group consisting of: Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 36);

Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 80);

Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 81 );

Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 82);

Ac-dLys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 83);

Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 84); and Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 85), wherein c represents cyclization through R² and R⁷ via a lactam bond.

73. The method or the use of any one of claims 1-58 and 58, wherein X¹ is absent or Nle, Y¹ is selected from dVal, dPro, and dTle, Y² is selected from dVal, dPro, and dTle, Y³ is absent, dVal or dPro and Y⁴ is absent or dPro.

74. The method or the use of any one of claims 1 -58, 58, and 62, wherein the sequence of any one of Formulae (l)-(l E) is selected from the group consisting of:

Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 18);

Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH₂ (SEQ ID NO: 25);

Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 31 );

Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH₂ (SEQ ID NO: 32);

Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 35);

Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 50);

75. The method or the use of any one of claims 1-58 and 58, wherein R⁵ is His.

76. The method or the use of any one of claims 1 -58, 58, and 64, wherein the sequence of any one of Formulae (l)-(IE) is: Ac-Nle-c[Asp-His-p(Br)dPhe-His-Trp-Lys]- dVal-dPro-NH₂ (SEQ ID NO: 19), wherein c represents cyclization through R² and R⁷ via a lactam bond.

77. The method or the use of any one of claims 1-58 and 58, wherein R⁶ is Nal(2’) or dNal(2’).

78. The method or the use of any one of claims 1 -58, 58, and 66, wherein the sequence of any one of Formulae (l)-(IE) is: Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 37); or Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 52), wherein c represents cyclization through R² and R⁷ via a lactam bond.

79. The method or the use of any one of claims 1-58 and 58, wherein the sequence of any one of Formulae (l)-(IE) is cyclized through a lactam bond between Asp or Glu at R² and Orn at R⁷.

80. The method or the use of any one of claims 1 -58, 58, and 68, wherein the sequence of any one of Formulae (l)-(IE) is:

Ac-Nle-c[Glu-His-p(Br)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 101 ); or

81. The method or the use of any one of claims 1-58 and 58, wherein the sequence of any one of Formulae (l)-(IE) is cyclized through a lactam bond between Cys at R² and Cys at R⁷.

82. The method or the use of any one of claims 1 -58, 58, and 70, wherein the sequence of any one of Formulae (l)-(IE) is: Ac-Nle-c[Cys-His-p(Br)dPhe-Arg-Trp-Cys]- dVal-dPro-NH₂ (SEQ ID NO: 28), wherein c represents cyclization through R² and R⁷ via a disulfide bond.

83. The method or the use of any one of claims 1 -58, wherein R⁴ is p(Br)dPhe and R³ is selected from Pro, Gin, dGIn, dHis, Phe, dPhe, Bip, dBip, Tyr, dTyr, Trp, and dTrp.

84. The method or the use of any one of claims 1-58 and 72, wherein the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[Asp-Pro-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 21 );

Ac-Nle-c[Asp-Gln-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 33); Ac-Nle-c[Asp-dHis-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 38);

Ac-Nle-c[Asp-Phe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 39);

Ac-Nle-c[Asp-dPhe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 40);

Ac-Nle-c[Asp-Bip-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 41 );

Ac-Nle-c[Asp-dBip-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 42);

Ac-Nle-c[Asp-Trp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 44);

Ac-Nle-c[Asp-dTrp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 45);

Ac-Nle-c[Asp-Tyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 46);

Ac-Nle-c[Asp-dTyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 47); and Ac-Nle-c[Asp-dGln-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 62), wherein c represents cyclization through R² and R⁷ via a lactam bond.

85. The method or the use of any one of claims 1-58, R⁴ is p(CI)dPhe and R³ is His.

86. The method or the use of any one of claims 1-58 and 74, wherein the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 16);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 17);

Ac-Nle-c[Cys-His-p(CI)dPhe-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 65);

Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 66);

Ac-Nle-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 67);

Ac-Nle-c[Asp-His-p(CI)dPhe-His-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 68);

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 97);

Ac-Ala-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 98); and Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dTle-dPro-NH₂ (SEQ ID NO: 99), wherein c represents cyclization through R² and R⁷ via a lactam bond or a disulfide bond.

87. The method or the use of any one of claims 1 -58, wherein R⁴ is p(CI)dPhe and R³ is selected from Gin, dHis, Bip, Phe, dPhe, Tyr, dTyr, and Trp.

88. The method or the use of any one of claims 1-58 and 76, wherein the sequence of any one of Formulae (l)-(l E) is selected from the group consisting of:

Ac-Nle-c[Asp-dPhe-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 26);

Ac-Nle-c[Asp-Bip-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 27);

Ac-Nle-c[Asp-dTyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 29);

Ac-Nle-c[Asp-Trp-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 43);

Ac-Nle-c[Asp-Tyr-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 54);

Ac-Nle-c[Asp-Phe-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 60);

Ac-Nle-c[Asp-dHis-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 70); and

Ac-Nle-c[Asp-Gln-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 71), wherein c represents cyclization through R² and R⁷via a lactam bond.

89. The method or the use of any one of claims 1 -58, wherein R⁴ is p(CI)dPhe and R³ is Pro.

90. The method or the use of any one of claims 1-58 and 78, wherein the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[Asp-Pro-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 30);

Ac-Nle-c[Asp-Pro-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 64); and

Ac-Nle-c[Glu-Pro-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 103), wherein c represents cyclization through R² and R⁷via a lactam bond.

91 . The method or the use of any one of claims 1 -58, wherein R⁴ is p(l)dPhe.

92. The method or the use of any one of claims 1-58 and 80, wherein the sequence of any one of Formulae (l)-(IE) is:

Ac-Nle-c[Asp-Pro-p(l)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 20); or Ac-Nle-c[Asp-His-p(l)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 23), wherein c represents cyclization through R² and R⁷ via a lactam bond.

93. The method or the use of any one of claims 1-58, wherein R⁴ is p(CP₃)dPhe.

94. The method or the use of any one of claims 1-58 and 82, wherein the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[Asp-Pro-p(CF₃)dPhe-Arg-Aia-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 2);

Ac-Nle-c[Asp-Pro-p(CF₃)dPhe -Arg-Aba-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 3);

Ac-Nle-c[Asp-Pro-p(CF₃)dPhe -Arg-Ata-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 4);

Ac-Nle-c[Asp-Pro-p(CF₃)dPhe-Arg-Trp-Lys]-d al-dPro-NH₂ (SEQ ID NO: 22); and Ac-Nle-c[Asp-His-p(CF₃)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 24), wherein c represents cyclization through R² and R⁷ via a lactam bond.

95. The method or the use of any one of claims 1 -58, wherein R⁴ is dPhe or p(F)dPhe and R³ is Pro.

96. The method or the use of any one of claims 1-58 and 84, wherein the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-dPhe-Lys-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 86);

Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 89);

Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 92);

Ac-Nle-c[Cys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH₂ (SEQ ID NO: 93);

Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 96); and Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 100), wherein c represents cyclization through R² and R⁷ via a lactam bond or a disulfide bond.

97. The method or the use of any one of claims 1 -58, wherein R⁴ is dPhe or p(F)dPhe and R³ selected from Phe, Tyr, Trp, Bip, and dBip.

98. The method or the use of any one of claims 1 , 2, 5-28, or 37-97, wherein the sequence of any one of Formulae (l)-(IE) is selected from the group consisting of:

Ac-Nle-c[Asp-dBip-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 48);

Ac-Nle-c[Asp-Phe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 87);

Ac-Nle-c[Asp-Bip-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 88);

Ac-Nle-c[Asp-Trp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 90); and

Ac-Nle-c[Asp-Tyr-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 91), wherein c represents cyclization through R² and R⁷ via a lactam bond.

99. The method or the use of any one of claims 1-98, wherein the non- naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-103.

100. The method or the use of claim 99, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-47, 49-85, 94, 95, 97-99, and 101-103.

101. The method or the use of claim 99, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 5-15, 49, 51 , 53, 55-59, 61 , 63, 94, and 95.

102. The method or the use of claim 101 , wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 8-15, 49, 51 , 53, 55-59, 61 , 94, and 95.

103. The method or the use of claim 101 , wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 5-7 and 63.

104. The method or the use of claim 99, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-4, 16-47, 50, 52, 54, 60, 62, 64-85, 97-99, and 101-103.

105. The method or the use of claim 104, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 18, 19, 21 , 25, 28, 31-42, 44-47, 50, 52, 62, 72-85, 101 , and 102.

106. The method or the use of claim 104, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 16, 17, 26, 27, 29, 30, 43, 54, 60, 64-71 , 97-99, and 103.

107. The method or the use of claim 104, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-4, 20, and 22-24.

108. The method or the use of claim 100, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 48, 86-93, 96, and 100.

109. The method or the use of claim 100, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 64 and 101- 103.

110. The method or the use of any one of claims 1-109, wherein the non- naturally occurring melanocortin analog is present in a pharmaceutical composition.

111. The method or the use of claim 110, wherein the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients and/or carriers.

112. The method or the use of claim 1 11 , wherein the one or more pharmaceutically acceptable excipients and/or carriers of the pharmaceutical composition comprise water.

113. The method or the use of any one of claims 1-112, wherein the non- naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.

114. The method or the use of any one of claims 1-113, wherein the non- naturally occurring melanocortin analog crosses a blood-brain-barrier of a subject.

115. The method or the use claim 113, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (IE) and is administered at least once daily in an amount ranging from 0.001 mg/kg to 25 mg/kg per body weight of the subject.

116. The method or the use of claim 115, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (IE)and is administered at least once daily in an amount ranging from 0.5 mg/kg to 10 mg/kg per body weight of the subject.

117. The method or the use of any one of claims 1-116, wherein the non- naturally occurring melanocortin analog is administered to a subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

118. The method or the use of any one of claims 1-116, wherein the non- naturally occurring melanocortin analog is administered to a subject for 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

119. The method or the use of any one of claims 1-118, wherein the method or the use further comprises maintaining muscle mass or promoting muscle mass gain in the subject.

120. A non-naturally occurring melanocortin analog comprising a sequence according to Formula (IE):

R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-Y¹-Y² (IE), wherein:

R¹ is Nle;

R² is Asp or Glu;

R³ is Pro or His;

R⁴ is p(CI)dPhe or p(Br)dPhe;

R⁵ is Arg;

R⁶ is Trp;

R⁷ is Orn;

Y¹ is d Vai;

121. The non-naturally occurring melanocortin analog of claim 120, wherein: R¹ is Nle;

R² is Asp or Glu;

R³ is Pro or His;

R⁴ is p(CI)dPhe or p(Br)dPhe; R⁵ is Arg;

R⁶ is Trp;

R⁷ is Orn;

Y¹ is d Vai;

Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 248); or

Ac-Nle-c[Glu-His-p(CI)dPhe-Arg-Trp-Orn]-dVal-dPro-NH₂ (SEQ ID NO: 249).

122. The non-naturally occurring melanocortin analog of claim 120 or 121 , wherein the sequence of Formula (IE) is selected from the group consisting of SEQ ID NOs: 64 and 101-103.

123. A method of preventing or reducing anorexia nervosa in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

124. Use of a non-naturally occurring melanocortin analog for preventing or reducing anorexia nervosa in a subject in need thereof relative to a control, the non- naturally occurring melanocortin analog comprising a sequence of Formula (I):

X¹-R¹-R²-R³-R⁴-R⁵-R⁶-R⁷-R⁸-Y¹-Y²-Y³-Y⁴ (I), wherein:

X¹ is absent, norleucine (Nle), or arginine (Arg);

R⁵ is selected from the group consisting of Arg, His, and Lys;

R⁸ is absent or dPen;

Y³ is absent, dVal, or dPro;

125. A method of preventing or reducing anorexia nervosa in a subject in need thereof relative to a control, comprising administering to the subject: a non-naturally occurring melanocortin analog comprising a sequence of Formula (IE).

126. Use of a non-naturally occurring melanocortin analog for preventing or reducing anorexia nervosa in a subject in need thereof relative to a control, the non- naturally occurring melanocortin analog comprising a sequence of Formula (IE).