Orally deliverable non-naturally occurring melanocortin analogs and uses thereof for treating substance use disorders

Abstract

Provided herein are non-naturally occurring melanocortin analogs that selectively bind at least a portion of a melanocortin receptor The melanocortin receptor may be a melanocortin 3 receptor (MC3R) or a melanocortin 4 receptor (MC4R). The non-naturally occurring melanocortin analogs may have a dissociation constant (Kd) value for a melanocortin receptor or one or more amino acids thereof that is less than that of a conventional melanocortin analog.

Description

Docket No.: 146316.8032.WO02 ORALLY DELIVERABLE NON-NATURALLY OCCURRING MELANOCORTIN ANALOGS AND USES THEREOF FOR TREATING SUBSTANCE USE DISORDERS CROSS-REFERENCE TO RELATED APPLICATION(S)

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 656,574, filed June 5, 2024; U.S. Provisional Patent Application No. 63 / 663,663, filed June 24, 2024; U.S. Provisional Patent Application No.63 / 675,181, filed July 24, 2024; U.S. Provisional Patent Application No. 63 / 681,082, filed August 8, 2024; and U.S. Provisional Patent Application No. 63 / 692,552, 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 14, 2024, is titled “1463168032WO02.xml” and is 187,842 bytes in size. BACKGROUND

[0003] Melanocortin receptors (e.g., melanocortin 3 receptor, melanocortin 4 receptor) are major molecular targets for pain management. The vast majority of clinically prescribed pain medications are melanocortin receptor ligands (i.e., opioid drugs) that are structurally similar to or derived from morphine or other opiates. While these medications serve as effective painkillers, usage can result in several unwanted adverse side effects, including increased tolerance, addiction, overdose, respiratory distress, and constipation.

[0004] Opioid and other substance addictions, for example, alcohol and nicotine addictions, contribute to millions of premature deaths each year. Although current therapies aimed at treating addiction can be effective, many substance users are unable to overcome their addiction, despite having a desire to quit.

[0005] Even after recent advances in pain medication development, there remains considerable need for new medications to manage pain with improved therapeutic profiles -1- 180092653.1Docket No.: 146316.8032.WO02 (e.g., robust therapeutic activity and reduced unwanted adverse side effects) compared to conventional opioid drugs. There is also a growing demand for new therapies to treat opioid use disorders (i.e., opioid addictions) and other addictions (e.g., alcohol use disorder, and nicotine addiction). SUMMARY

[0006] The present technology comprises non-naturally occurring melanocortin analogs and associated uses. In some embodiments, the present technology comprises a non-naturally occurring melanocortin analog comprising a sequence according to Formula (IC): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IC), wherein: R1is Nle; R2is Asp or Glu; R3is Pro; R4is p(F)dPhe or dPhe; R5is Arg; R6is Trp; R7is Orn; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7, provided that: when R4is dPhe, then R2is Glu. -2- 180092653.1Docket No.: 146316.8032.WO02 BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIG 1. illustrates 24-hour plasma concentrations of non-naturally occurring melanocortin analogs of the present technology following oral administration of Compound Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 19; M1) to Cynomolgus Monkeys at 30.0 mg / kg.

[0008] FIGS.2A-2C illustrate 24-hour plasma concentrations of non-naturally occurring melanocortin analogs of the present technology following oral (PO) administration of Compound D (Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 218; O7) to Cynomolgus Monkeys at 3 mg / kg, 10.0 mg / kg, 30.0 mg / kg, or 60 mg / kg.

[0009] FIGS. 3A-3D illustrate 24-hour plasma and cerebrospinal fluid (CSF) concentrations of non-naturally occurring melanocortin analogs of the present technology following subcutaneous (SC) administration of Compound D (FIGS. 3A-3D) to Rats at 1.0 mg / kg, 3.0 mg / kg, and 10.0 mg / kg.

[0010] FIGS. 4A-4D illustrate plasma and CSF concentrations of non-naturally occurring melanocortin analogs following IP administration of Compound D to Rats at 1.0 mg / kg, 3.0 mg / kg, and 10.0 mg / kg.

[0011] FIGS.5A-5C illustrate 24-hour plasma and CSF concentrations of non-naturally occurring melanocortin analogs of the present technology following PO administration of Compound D to Rats at 10.0 mg / kg and 30.0 mg / kg.

[0012] FIGS.6A-6D show the plasma and CSF concentration of Compound F (Ac-Nle- c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2; SEQ ID NO: 31; A3) following SC administration to Rats at 1.0 mg / kg, 3.0 mg / kg, and 10.0 mg / kg.

[0013] FIGS.7A-7C show the plasma and CSF concentration of Compound F of FIGS. 6A-6D following IP administration to Rats at 1.0 mg / kg, 3.0 mg / kg, and 10.0 mg / kg.

[0014] FIGS.8 shows the plasma and CSF concentration of Compound F of FIGS.6A- 6D following IV bolus administration to Rats at 1.0 mg / kg.

[0015] FIG.9 shows the mean plasma concentration of Compound F of FIGS.6A-6D over time following SC, IP, or IV bolus administration in rats at different dosages. -3- 180092653.1Docket No.: 146316.8032.WO02

[0016] FIGS.10A and 10B show preliminary weight loss and daily food intake results in rats administered 3 mg / kg of A3 (Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2; SEQ ID NO: 31), O7 (Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 218) and O11 (Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 216).

[0017] FIGS.11A-11D show food intake (g) at baseline in monkeys having diet-induced obesity (n=6) from 0.5 to 72 hours after saline administration at day 1 (D1). FIG.11A shows net weight of food intake among individual monkeys. FIG. 11B shows net weight of food intake for each group average. FIG. 11C shows cumulative food intake among individual monkeys. FIG.11D shows cumulative food intake for each group average.

[0018] FIGS.12A-12H show food intake (g) in the same monkeys as FIGS.11A-11D administered 1 mg / kg or 3 mg / kg of O7 (Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2; SEQ ID NO: 218) or O11 (Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 216) on day 8 (D8). FIG.12A shows net weight of food intake among individual monkeys at day 8 (D8). FIG.12B shows net weight of food intake for each group average of monkeys administered the same compound at D8. FIG.12C shows cumulative food intake among individual monkeys of FIG. 12A at D8. FIG. 12D shows cumulative food intake for each group average of monkeys of FIG.12C administered the same compound at D8. FIG. 12E shows net weight of food intake among individual monkeys at day 12 (D12). FIG.12F shows net weight of food intake for each group average of monkeys administered the same compound at D12. FIG. 12G shows cumulative food intake among individual monkeys at D12. FIG. 12H shows cumulative food intake for each group average of monkeys administered the same compound at D12.

[0019] FIGS.13A-13D show food intake patterns in the monkeys administered saline of FIGS.11A-11D, relative compared to the same monkeys administered 1mg / kg or 3 mg / kg of O7 (Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 218) or O11 (Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 216) (FIGS. 13C and 13D) in FIGS.12A-12H.

[0020] FIGS. 14A-14C show changes in daily caloric intake (FIG. 14A), cumulative caloric intake (FIG.14B), percent change in caloric consumption from baseline through day 6 (FIG.14C) for diet-induced obese monkeys orally administered 10 mg / kg of O7 (Ac-Nle- -4- 180092653.1Docket No.: 146316.8032.WO02 c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 218). (PO: oral administration; QD: once daily).

[0021] FIGS. 15A-15J show changes in cumulative caloric intake, percent change in caloric consumption from baseline, food intake of a normal diet, food intake of a high fat diet, food intake in calories, and food preference for diet-induced obese monkeys orally administered O7 (Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 218) or O11 (Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 216). (PO: oral administration; QD: once daily; BID: twice daily).

[0022] FIG. 15K shows normalized cumulative food consumption in rats subcutaneously administered MC4R selective agonists (A07D (Ac-Nle-c[Asp-Pro-dPhe-Arg- Trp-Lys]-dVal-dPro-NH2; SEQ ID NO: 31), O7 (Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]- dVal-dPro-NH2; SEQ ID NO: 218) and O11 (Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal- dPro-NH2; SEQ ID NO: 216)) (n=5 per group) or a same dose of MC3R / MC4R co-agonists (O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 326)) (n=5) compared to saline controls (n=4). Rats were administered 0.5 mg / kg A07D, O7, O10, or O11 for days 1-7 and 1 mg / kg for days 8-17.

[0023] FIGS.16A-16G show changes in body weight for diet included obese monkeys orally administered O7 (Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 218). FIGS. 16A and 16B show daily body weight (FIG. 16A) and percent change in body weight from baseline (FIGS.16B) for the diet-induced obese monkeys of FIGS.14A- 14C through day 8. FIGS. 16C shows percent change in body weight as a percentage of initial weight for the monkeys of FIGS.16A and 16B through day 15. FIG.16D shows body weight change as a percentage of initial weight in diet induced obese monkeys orally administered O7 or O10 at increasing dosages. FIG.16E shows body weight change in the monkeys of FIG. 16D. FIG. 16F shows body weight changes as a percentage of initial in monkeys orally administered a non-naturally occurring melanocortin analog of the present technology (PO) under different dosing regimens. FIG. 16G shows body weight percent change from initial weight in monkeys orally administered O7 at different doses (PO: oral administration; SC: subcutaneous administration; QD: once daily; BID: twice daily; BIW: twice weekly). -5- 180092653.1Docket No.: 146316.8032.WO02

[0024] FIG. 16K shows changes in body weight as a percentage of day 1 in rats administered saline, a melanocortin 4 receptor (MC4R) selective agonist (A07D (Ac-Nle- c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2; SEQ ID NO: 31), O7 (Ac-Nle-c[Glu-Pro- p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 218) and O11 (Ac-Nle-c[Glu-Pro-dPhe- Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 216)), or a same dose of melanocortin 3 receptor (MC3R) / MC4R coagonist ((O10)(Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 326)).

[0025] FIG. 17 shows plasma concentration of O7 after oral (PO) administration to cynomolgus monkeys at 10 mg / kg or 30 mg / kg.

[0026] FIG.18 shows plasma concentration of C29 (Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp- Lys]-dLys-dVal-dPro-NH2; SEQ ID NO: 160) after oral administration to cynomolgus monkeys at 10 mg / kg or 30 mg / kg.

[0027] FIGS.19A-19D show blood glucose levels following administration of A07D to Sprague-Dawley rats at 1 mg / kg or 3 mg / kg. OGTT: Oral Glucose Tolerance Test.

[0028] FIGS.20A-20G show measurements of diastolic blood pressure (DBP), systolic blood pressure (SBP), heart rate, and heart rate corrected QT interval (QTc) in rats administered setmelanotide at 0.5 mg / kg, 1.0 mg / kg, 3.0 mg / kg, or 6.0 mg / kg, relative to control rats administered saline (FIGS.20A-20D) and cardiac data for A07D (“A3”; Ac-Nle- c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2; SEQ ID NO: 31) up to 180 minutes after subcutaneous injection (FIGS.20E-20G).

[0029] FIGS. 21A-21D show the plasma and cerebrospinal fluid (CSF) concentration of A07D (“A3”; Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2; SEQ ID NO: 31) in rats over time following subcutaneous administration.

[0030] FIG.22 shows plasma concentration of A07D (Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp- Lys]-dVal-dPro-NH2; SEQ ID NO: 31) administered at 1mg / kg intravenously, 10 mg / kg orally, or 30 mg / kg orally to fasted male cynomolgus monkeys.

[0031] FIGS.23A and 23B show results of a morphine conditioned placed preference (CPP) study in rats administered vehicle and saline, vehicle and morphine, or A07D (Ac- Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2; SEQ ID NO: 31) and morphine. FIG 23A -6- 180092653.1Docket No.: 146316.8032.WO02 illustrates the experimental timeline. FIG 23B illustrates CPP scores in each group before and after each test. DETAILED DESCRIPTION

[0032] The present technology comprises methods of treating, preventing, reducing, or otherwise ameliorating one or more symptoms or conditions associated with pain, addiction, addictive agent use, or withdrawal from an addictive substance using a non-naturally occurring melanocortin analog. In some embodiments, the non-naturally occurring melanocortin analog is administered orally. In some embodiments, the non-naturally occurring melanocortin analog is a melanocortin receptor agonist and / or an melanocortin receptor agonist. In some embodiments, the method comprises preventing, stabilizing, or reducing one or more of a dose used or consumed of an addictive substance, a dependency on an addictive substance, an amount / frequency of an addictive substance, use (e.g., dose or dosage) of an opioid reversal agent, relapse associated with use of an addictive substance, use (e.g., frequency / amount) of a conventional medication used to treat an addiction, an incidence of or need for hospitalization associated with use of an addictive substance, or an incidence in or a need for rehabilitation from an addiction. In some embodiments, the methods promote or increase cessation of an addictive substance.

[0033] 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.

[0034] 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 -7- 180092653.1Docket No.: 146316.8032.WO02 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.

[0035] While the embodiments are described in sufficient detail to enable those skilled in the art to practice the present technology, it should be understood that other embodiments may be realized, and that logical changes may be made without departing from the spirit and scope of the present technology. Thus, the detailed description herein is presented for purposes of illustration only and not of limitation. For example, steps 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

[0036] 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.

[0037] 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.

[0038] 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 -8- 180092653.1Docket No.: 146316.8032.WO02 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.

[0039] 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.

[0040] 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, substance use disorders.

[0041] 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.

[0042] As used herein, a “pharmaceutically acceptable carrier” of the pharmaceutical composition refers to a carrier or diluent that does not cause significant irritation to an organism, does not abrogate the biological activity and properties of the administered active ingredient, and / or does not interact in a deleterious manner with the other components of the 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, 21st Edition, ed. University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia Pa., 2005, which is incorporated herein by reference in its entirety). Some examples of physiologically acceptable carriers include antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, -9- 180092653.1Docket No.: 146316.8032.WO02 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 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.

[0043] The term “weight loss agent” refers to a therapeutic agent useful for the treatment or prevention of metabolic dysfunction or one or more symptoms associated with metabolic dysfunction in a subject. In some embodiments, such weight loss agents may be effective to treat, reduce, prevent, or otherwise be useful for a subject having a disease or condition that is not metabolic dysfunction, or besides metabolic dysfunction. The present technology is expected to be useful for subjects that may receive, have received, or are receiving one or more doses of a weight loss agent regardless of the underlying disease or condition that the subject has or develops.

[0044] The terms “treat”, “treatment”, and “treating” may also refer to the reduction or inhibition of the progression and / or duration of a disease, the reduction or amelioration of the severity of the disease, and / or the amelioration of one or more symptoms thereof resulting from the administration of one or more therapies.

[0045] 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.

[0046] 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. 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. -10- 180092653.1Docket No.: 146316.8032.WO02

[0047] 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 an alcohol use disorder or an opioid use disorder.

[0048] 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.

[0049] “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 pro- opiomelanocortin protein (POMC), prior to proteolytic cleavage of “sub-peptides,” consists of 241 amino acids. Tissue-specific proteolytic cleavage of POMC yields peptides ranging in size from 13 amino acids to 76 amino acids. See Bicknell and Lawry, Encyclopedia of Stress, vol. 3, 257-265, Academic Press (2000). Synthesized, non-naturally occurring melanocortin analogs having increased melanocortin receptor activity as discussed herein are approximately 7-12 amino acids in size. Melanocortin analogs exhibit binding functionality with melanocortin receptors. 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 -11- 180092653.1Docket No.: 146316.8032.WO02 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] “Potentiated therapeutic activity” refers to an increase in melanocortin activity in a non-naturally occurring melanocortin analog that has undergone derivatization at the N- and / or C-terminus. Such derivatizations do not necessarily involve the pharmacophore, but do imply a relative increase in in vivo biological half-life.

[0054] The terms “bind,” “binding,” “complex,” and “complexing,” refer to all types of physical and chemical binding, reactions, complexing, attraction, chelating and the like.

[0055] 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. -12- 180092653.1Docket No.: 146316.8032.WO02

[0056] 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.

[0057] 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.

[0058] “Amino acids” are molecules containing an amine group, a carboxylic acid group, and a side-chain that is specific to each amino acid. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen and have the generic formula H2N—CHR— COOH, wherein R represents a side chain group. The various α-amino acids differ in the side-chain moiety that is attached to the α-carbon. The “amino acids” of the present technology include the known naturally occurring protein amino acids, which are referred to by both their common three letter abbreviation and single letter abbreviation. See generally Synthetic Peptides: A User’s Guide, G. A. Grant, editor, W.H. Freeman & Co., New York (1992), the teachings of which are incorporated herein by reference, including the text and table set forth at pages 11 through 24. As set forth above, the term “amino acid” also includes stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino -13- 180092653.1Docket No.: 146316.8032.WO02 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.

[0059] 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.

[0060] 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.

[0061] 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, 8thEd. Thus, “Ala” is alanine; “Arg” is arginine; “Asn” is asparagine; “Asp” is aspartic acid; “Cys” is cysteine; “Gln” is glutamine; “Glu” is glutamic acid; “His” is histidine; “Ile” is isoleucine; “Leu” is leucine; “Lys” is lysine; “Met” is methionine; “Phe” is phenylalanine; “Pro” is proline; “Ser” is serine; “Thr” is threonine; “Trp” is tryptophan; “Tyr” is tryosine; and “Val” is valine. Unless otherwise indicated, all amino 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” -14- 180092653.1Docket No.: 146316.8032.WO02 is D-phenylalanine, L-phenylalanine, or combinations thereof; “Phe” is also D-phenylalanine, L-phenylalanine, or combinations thereof, and so on.

[0062] An alpha (α)-amino acid has the generic formula H2N—CαHR—COOH, where R is a side chain moiety and the amino group is attached to the carbon atom immediately adjacent to the carboxylate group (i.e., the α-carbon). Other types of amino acids exist when the amino group is attached to a different carbon atom. For example, beta (β)-amino acids, the carbon atom to which the amino group is attached is separated from the carboxylate group by one carbon atom, Cβ.

[0063] When β-amino acids are incorporated into peptides, two main types of β- peptides exist: those with the side chain residue, R, on the carbon next to the amine are called β3peptides and those with the side chain residue on the carbon next to the carbonyl group are called β2amino acids.

[0064] Gamma (γ)-amino acids are amino acids where the carbon atom to which the amino group attaches is separated from the carboxylate moiety by two carbon atoms.

[0065] 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.

[0066] Additional abbreviations are used as herein follows: Nle is norleucine, Nal(2’) is 2′-naphthylalanine, Nal(1') is 1′-naphthylalanine, Tle is tert-leucine, Orn is ornithine, Bip is biphenylalanine; cisPro(guan) is cis-4-guanidyl-proline, transPro(guan) is trans-4-guanidyl- proline, Hyp is hydroxyproline; 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; Atc is 2-aminotetraline-2-carboxylic acid, APC is 1- amino-4-phenylcyclohexane-carboxylic acid, APPC is 4-aminophenylpiperidine-4-carboxylic acid, Ata is 7-amino-7,8-dihydro-4H-[1,2,3]triazolo-[1,5-a][1,4]diazepin-6(5H)-one, Aia is 4- amino-1,4,5,6-tetrahydroazepino[4,3-b]indol-3(2H)-one, Che is 1-amino-1- cyclohexanecarboxylic acid, Ioc is indoline-2-carboxylic acid, Cpe is 1-amino-1- -15- 180092653.1Docket No.: 146316.8032.WO02 cyclopentane carboxylic, and p(Cl)dPhe is para-chloro-phenylalanine (F – fluoro, Br – bromo).

[0067] 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.”

[0068] 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.

[0069] An “amine” includes compounds that contain an amine group (—NH2).

[0070] 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.

[0071] 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.”

[0072] “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 embodiment, 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 embodiments, no more than 25% of the administered peptide causes side effects and / or displays a low half-life. More preferably, in some embodiments, 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. -16- 180092653.1Docket No.: 146316.8032.WO02

[0073] The disclosure of all publications, patents, and published patent applications listed herein are hereby incorporated by reference in their entireties, including but not limited to U.S. Patent Nos.8,541,545 and 9,534,018. Non-naturally Occurring Melanocortin Analogs

[0074] The non-naturally occurring melanocortin analogs of the present technology may comprise a non-naturally occurring melanocortin analog or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Non-naturally occurring melanocortin analogs of the present technology may be selective for the melanocortin 4 receptor (MC4R) and / or melanocortin 3 receptor (MC3R) over other melanocortin receptors, i.e., the melanocortin 1 receptor (MC1R), the melanocortin 2 receptor (MC2R), and the melanocortin 5 receptor (MC5R). Some of the non-naturally occurring melanocortin analogs may bind only the MC3R or the MC4R. Alternatively, some of the non-naturally occurring melanocortin analogs may bind the MC3R with greater affinity than the MC4R, whereas other melanocortin analogs may bind the MC4R with greater affinity than the MC3R. Certain melanocortin analogs may bind the MC3R with the same or generally similar affinity as the MC4R.

[0075] The non-naturally occurring melanocortin analogs of the present technology may be full agonists or full antagonists for one or more melanocortin receptors. A full agonist may comprise a non-naturally occurring melanocortin analog having a maximum effect (Emax) agonist value of greater than or equal to 85%. Similarly, a full antagonist may comprise a non-naturally occurring melanocortin analog having an Emax antagonist value of greater than or equal to 85%.

[0076] The non-naturally occurring melanocortin analogs of the present technology may be partial agonists or partial antagonists. A partial agonist may comprise a non-naturally occurring melanocortin analog having a maximum effect Emax agonist value of less than 85%. Similarly, a partial antagonist may comprise a non-naturally occurring melanocortin analog having an Emax antagonist value of less than 85%. -17- 180092653.1Docket No.: 146316.8032.WO02

[0077] 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).

[0078] If a non-naturally occurring melanocortin analog’s Emax antagonist value is greater than it’s Emax agonist value, then the non-naturally occurring melanocortin analog may be classified as an antagonist (e.g., a full antagonist or a partial antagonist).

[0079] The non-naturally occurring melanocortin analogs of the present technology may be one or more of (i) a full MC4R agonist and a full MC3R antagonist; (ii) a full MC4R agonist and a partial MC3R antagonist; and (iii) a full MC4R agonist having no MC3R activity.

[0080] The non-naturally occurring melanocortin analogs of the present technology may avoid cardiac activation typically seen in conventional melanocortin peptide and small molecule agonists. For example, a subject may maintain a stable heart rate, systolic blood pressure, and / or diastolic blood pressure following administration of a melanocortin analog of the present technology.

[0081] 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 (β-hairpin) and / or beta turn (β-turn) structures. The presence of amino acids that are structurally rigid, such as, for example, Aia, Aba, Ata, Hyp, dHyp, Pro, dPro, transPro(guan), and cisPro(guan), may lead to formation of β-hairpin and / or β-turn structures in the non-naturally occurring melanocortin analog. Additionally, disulfide bridges (e.g., cyclization via disulfide bond) may induce and / or stabilize beta-turn structures of the non-naturally occurring melanocortin analogs. In general, cyclization may stabilize beta-turns, and D-amino acids may induce and / or stabilize beta-turns. Further, in some embodiments, melanocortin analogs include D- valine-D-proline (dVal-dPro) chain as their C-terminus, which may provide enhanced transport and resistance to degradation. -18- 180092653.1Docket No.: 146316.8032.WO02

[0082] The presence of certain structural features may impart the non-naturally occurring melanocortin analogs of the present technology with specific binding properties. For example, inclusion of p(F)dPhe or dPhe at the R4position may result in enhanced binding and activation of the melanocortin 4 receptor. Accordingly, melanocortin analogs having p(F)dPhe or dPhe at R4may be full agonists on MC4R. Further, inclusion of Pro at the R3position may result in partial agonism of the melanocortin 3 receptor, whereas inclusion of His at the R3position may result in full agonism of the melanocortin 3 receptor.

[0083] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I): X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4-Y5-Y6-Y7(I), wherein: X1is absent or selected from the group consisting of norleucine (Nle), arginine (Arg), D-arginine (dArg), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); X2is absent, phenylalanine (Phe), or Nle; X3is absent, Phe, or Nle; R1is selected from the group consisting of Nle, D-norleucine (dNle), Ala, D-alanine (dAla), Arg, dArg, Lys, dLys, His, dHis, ornithine (Orn), D-ornithine (dOrn), D-leucine (dLeu), D-tyrosine (dTyr), Phe, D-phenylalanine (dPhe), tryptophan (Trp), D-tryptophan (dTrp), aspartic acid (Asp), cysteine (Cys), and D-cysteine (dCys); R2is selected from the group consisting of Asp, proline (Pro), D-aspartic acid (dAsp), Cys, dCys, D-penicillamine (dPen), Ala, dAla, Trp, Phe, dPhe, His, dHis, Tyr, glutamic acid (Glu), and dTyr; R3is absent or selected from the group consisting of His, Ala, Pro, hydroxyproline (Hyp), leucine (Leu), D-glutamine (dGln), Phe, dPhe, Trp, dTrp, Tyr, dTyr, 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), 4-amino-1,4,5,6-tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), 2-aminotetraline-2-carboxylic acid (Atc), 1-amino-4-phenylcyclohexane-carboxylic -19- 180092653.1Docket No.: 146316.8032.WO02 acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), tetrahydro-isoquinoline-3- carboxylic acid (Tic), biphenylalanine (Bip), octohydroindole-2-carboxylic acid (Oic), 1- amino-1-cyclohexanecarboxylic acid (Che), indoline-2-carboxylic acid (Ioc), and 1-amino-1- cyclopentane carboxylic (Cpe); R4is selected from the group consisting of Phe, dPhe, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe); R5is selected from the group consisting of Arg, His, cis-4-guanidyl-proline (cisPro(guan)), and trans-4-guanidyl-proline (transPro(guan)); R6is selected from the group consisting of Trp, dTrp, Phe, Aia, Aba, Ata, 2’-D- naphthylalanine (dNal(2’)), 2’-naphthylalanine (Nal(2’)), and 1’-naphthylalanine (Nal(1’)); R7is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, penicillamine (Pen), dPen, and Orn; R8is absent or Lys; Y1is absent or selected from the group consisting of valine (Val), D-valine (dVal), β2- valine (β2-Val), β3-valine (β3-Val), Pro, D-proline (dPro), β-proline (β-Pro), Hyp, D- hydroxyproline (dHyp), dLeu, D-tert-leucine (dTle), Trp, Arg, dArg, Lys, dLys, Gly, Ala, dAla, Asp, dAsp, asparagine (Asn), D-asparagine (dAsn), and D-threonine (dThr); Y2is absent or selected from the group consisting of Val, dVal, β2-Val, β3-Val, Pro, dPro, dTle, β-Pro, Hyp, dHyp, dTle, Arg, dArg, Gly, Ala, dAla, Asp, and dAsn; Y3is absent or selected from the group consisting of Val, dVal, Pro, dPro, dThr, and dLys; Y4is absent or selected from the group consisting of dVal, dPro, and dAsp; Y5is absent or dVal; Y6is absent or dVal; Y7is absent or dPro; and -20- 180092653.1Docket No.: 146316.8032.WO02 the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R1and R7when R1and R7are each independently Cys or dCys; a disulfide bond between R2and R7, when R2and R7are each independently selected from Cys, dCys, Pen, and dPen; a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp, dAsp, or Glu and R7is dLys or Orn, provided that: when R4is p(Br)dPhe, then R2is dCys; when R4is p(Cl)dPhe, then (i) R3is selected from Ata, Aia, and Aba; or (ii) R3is His, R5is Arg; R6is Trp; R7is Lys or dCys, and R1is not Ala, wherein when X1is present, then Y1is dTle and when X1is absent and Y1-Y2is dVal-dPro or dTle-dPro, then either R1is not Nle or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2and R7; when R4is p(F)dPhe, then (i) R3is selected from Pro, dGln, and dTyr, R6is Trp, and R2is not Cys; or (ii) R3is His and R6is Nal(2’) or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2and R7; when R4is dPhe and R1is Asp, then either (i) R2is selected from Trp, Phe, His, Tyr, dPhe, dHis, and dTyr, R3is selected from Pro, Ala, and Leu, R5is Arg, and R6is selected from Trp, Nal(1’), dNal(2’), and Nal(2’); or (ii) R2is selected from Ala, dAla, and Phe, and R3is His, wherein when R2is dAla, then Y1-Y7are absent and when R2is Ala, then R1is not Nle; when R4is dPhe, and R2is Asp, Glu, or dPen, then R3is not His or absent; and when R4is dPhe, R2is Asp, and R3is Pro, then R5is not dNal(2’) or Nal(2’) and Y3- Y7are absent if any of X1-X3are present. -21- 180092653.1Docket No.: 146316.8032.WO02

[0084] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein: X1is absent or selected from the group consisting of norleucine (Nle), arginine (Arg), D- arginine (dArg), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); X2is absent, phenylalanine (Phe), or Nle; X3is absent, Phe, or Nle; R1is selected from the group consisting of Nle, D-norleucine (dNle), Ala, D-alanine (dAla), Arg, dArg, Lys, dLys, His, dHis, ornithine (Orn), D-ornithine (dOrn), D-leucine (dLeu), D-tyrosine (dTyr), Phe, D-phenylalanine (dPhe), tryptophan (Trp), D-tryptophan (dTrp), aspartic acid (Asp), cysteine (Cys), and D-cysteine (dCys); R2is selected from the group consisting of Asp, proline (Pro), D-aspartic acid (dAsp), Cys, dCys, D-penicillamine (dPen), Ala, dAla, Trp, Phe, dPhe, His, dHis, Tyr, glutamic acid (Glu), and dTyr; R3is absent or selected from the group consisting of His, Ala, Pro, hydroxyproline (Hyp), leucine (Leu), D-glutamine (dGln), Phe, dPhe, Trp, dTrp, Tyr, dTyr, 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), 4-amino-1,4,5,6-tetrahydroazepino[4,3-b]indol-3(2H)-one (Aia), 2-aminotetraline-2-carboxylic acid (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), tetrahydro-isoquinoline-3- carboxylic acid (Tic), biphenylalanine (Bip), octohydroindole-2-carboxylic acid (Oic), 1- amino-1-cyclohexanecarboxylic acid (Che), indoline-2-carboxylic acid (Ioc), and 1-amino-1- cyclopentane carboxylic (Cpe); R4is selected from the group consisting of Phe, dPhe, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-fluoro-D-phenylalanine (p(F)dPhe); R5is selected from the group consisting of Arg, His, cis-4-guanidyl-proline (cisPro(guan)), and trans-4-guanidyl-proline (transPro(guan)); -22- 180092653.1Docket No.: 146316.8032.WO02 R6is selected from the group consisting of Trp, dTrp, Phe, Aia, Aba, Ata, 2’-D- naphthylalanine (dNal(2’)), 2’-naphthylalanine (Nal(2’)), and 1’-naphthylalanine (Nal(1’)); R7is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, penicillamine (Pen), dPen, and Orn; R8is absent or Lys; Y1is absent or selected from the group consisting of valine (Val), D-valine (dVal), β2- valine (β2-Val), β3-valine (β3-Val), Pro, D-proline (dPro), β-proline (β-Pro), Hyp, D- hydroxyproline (dHyp), dLeu, D-tert-leucine (dTle), Trp, Arg, dArg, Lys, dLys, Gly, Ala, dAla, Asp, dAsp, asparagine (Asn), D-asparagine (dAsn), and D-threonine (dThr); Y2is absent or selected from the group consisting of Val, dVal, β2-Val, β3-Val, Pro, dPro, dTle, β-Pro, Hyp, dHyp, dTle, Arg, dArg, Gly, Ala, dAla, Asp, and dAsn; Y3is absent or selected from the group consisting of Val, dVal, Pro, dPro, dThr, and dLys; Y4is absent or selected from the group consisting of dVal, dPro, and dAsp; Y5is absent or dVal; Y6is absent or dVal; Y7is 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 R1and R7when R1and R7are each independently Cys or dCys; a disulfide bond between R2and R7, when R2and R7are each independently selected from Cys, dCys, Pen, and dPen; a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and -23- 180092653.1Docket No.: 146316.8032.WO02 a lactam bridge between R2and R7when R2is Asp, dAsp, or Glu and R7is dLys 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(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 232); Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 233); Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 234); Ac-Nle-c[Asp-His-p(Br)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 235); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 236); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 237); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 238); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 239); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 240); Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 241); Ac-Ala-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 242); Ac-Nle-c[Asp-dPhe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 243); Ac-Nle-c[Asp-dGln-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 244); Ac-Nle-c[Asp-Trp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 245); Ac-Nle-c[Asp-dTrp-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 246); Ac-Nle-c[Asp-Tyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 247); Ac-Nle-c[Asp-dTyr-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 248); Ac-Nle-c[Asp-Pro-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 249); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 250); Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 251); -24- 180092653.1Docket No.: 146316.8032.WO02 Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 252); Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 253); Ac-dLys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 254); Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 255); Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 256); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 257); Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 258); Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 259); Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 260); Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 261); Ac-dLys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 262); Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 263); Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 264); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 265); Ac-Nle-c[Glu-His-p(Br)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 266); Ac-Nle-c[Asp-Bip-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 267); Ac-Nle-c[Asp-dHis-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 268); Ac-Nle-c[Asp-Phe-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 269); Ac-Nle-c[Asp-dGln-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 270); Ac-Nle-c[Asp-dTrp-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 271); Ac-Nle-c[Asp-dPhe-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 272); Ac-Nle-c[Asp-dTyr-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 273); Ac-Nle-c[Asp-Trp-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 274); Ac-Nle-c[Asp-Tyr-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 275); -25- 180092653.1Docket No.: 146316.8032.WO02 Ac-Nle-c[Asp-Pro-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 276); Ac-Nle-c[Asp-Pro-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 277); Ac-Nle-c[Glu-Pro-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 278); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 279); Ac-Nle-c[Glu-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 280); Ac-Nle-c[dCys-His-p(Cl)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 281); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 282); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 283); Ac-Nle-c[Cys-His-p(Cl)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 284); Ac-Ala-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 285); Ac-Nle-c[Asp-His-p(Cl)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 286); Ac-Ala-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 287); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 288); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 289); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 290); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 291); Ac-Nle-c[Asp-Phe-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 292); Ac-Nle-c[Asp-Bip-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 293); Ac-Nle-c[Asp-dHis-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 294); Ac-Nle-c[Asp-dTrp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 295); Ac-Nle-c[Asp-dPhe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 296); Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 297); Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 298); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 299); -26- 180092653.1Docket No.: 146316.8032.WO02 Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 300); Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 301); Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 302); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 303); Ac-Nle-c[Asp-Trp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 304); Ac-Nle-c[Asp-Tyr-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 305); Ac-Nle-c[Cys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 306); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 307); Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 308); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 309); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 310); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 311); Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 312); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 313); Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 314); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 315); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 316); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 317); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 318); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 319); Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 320); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 321); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 322); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 323); -27- 180092653.1Docket No.: 146316.8032.WO02 Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 324); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 325); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 326); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 327); Ac-Nle-c[Asp-Bip-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 328); Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 329); Ac-Nle-c[Asp-Phe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 330); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 331); Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 332); Ac-Nle-c[Asp-Trp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 333); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Phe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 334); Ac-dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 335); Ac-Nle-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 336); Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 337); Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 338); Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 339); Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 340); Ac-Arg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 341); Ac-dArg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 342); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 343); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 344); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 345); Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 346); Ac-Nle-c[dPen-dPhe-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 347); -28- 180092653.1Docket No.: 146316.8032.WO02 Ac-Nle-c[Asp-His-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 348); Ac-Nle-c[Asp-His-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 349); Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 350); Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 351); and Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 352).

[0085] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein R4is dPhe or p(F)dPhe. Accordingly, in some embodiments, the sequence of Formula (I) is a sequence of Formula (IA): X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4-Y5-Y6-Y7(IA), wherein: X1is absent or selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; X2is absent, Phe, or Nle; X3is absent, Phe, or Nle; R1is selected from the group consisting of Nle, dNle, Ala, dAla, Arg, dArg, Lys, dLys, His, dHis, Orn, dOrn, dLeu, dTyr, Phe, dPhe, Trp, dTrp, Asp, Cys, and dCys; R2is selected from the group consisting of Asp, dAsp, Glu, Cys, dCys, dPen, Ala, dAla, Trp, Phe, dPhe, His, dHis, Tyr, and dTyr; R3is absent or selected from the group consisting of His, Ala, Pro, Hyp, Leu, dGln, Phe, dPhe, Trp, dTrp, Tyr, dTyr, Aba, Ata, Aia, Atc, APC, APPC, Tic, Bip, Oic, Che, Ioc, and Cpe; R4is dPhe or p(F)dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is selected from the group consisting of Trp, dTrp, Phe, Aia, Aba, Ata, dNal(2’), Nal(2’), and Nal(1’); -29- 180092653.1Docket No.: 146316.8032.WO02 R7is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, and Orn; R8is absent or Lys; Y1is absent or selected from the group consisting of Val, dVal, β2-Val, β3-Val, Pro, dPro, β-Pro, Hyp, dHyp, dLeu, dTle, Trp, Arg, dArg, Lys, dLys, Gly, Ala, dAla, Asp, dAsp, Asn, dAsn, and dThr; Y2is absent or selected from the group consisting of Val, dVal, β2-Val, β3-Val, Pro, dPro, dTle, β-Pro, Hyp, dHyp, dTle, Arg, dArg, Gly, Ala, dAla, Asp, and dAsn; Y3is absent or selected from the group consisting of Val, dVal, Pro, dPro, dThr, and dLys; Y4is absent or selected from the group consisting of dVal, dPro, and dAsp; Y5is absent or dVal; Y6is absent or dVal; Y7is 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 R1and R7when R1and R7are each independently Cys or dCys; a disulfide bond between R2and R7, when R2and R7are each independently selected from Cys, dCys, Pen, and dPen; a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp, dAsp, or Glu and R7is dLys or Orn.

[0086] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA): -30- 180092653.1Docket No.: 146316.8032.WO02 X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4-Y5-Y6-Y7(IA), wherein: X1is absent or selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; X2is absent, Phe, or Nle; X3is absent, Phe, or Nle; R1is selected from the group consisting of Nle, dNle, Ala, dAla, Arg, dArg, Lys, dLys, His, dHis, Orn, dOrn, dLeu, dTyr, Phe, dPhe, Trp, dTrp, Asp, Cys, and dCys; R2is selected from the group consisting of Asp, dAsp, Glu, Cys, dCys, dPen, Ala, dAla, Trp, Phe, dPhe, His, dHis, Tyr, and dTyr; R3is absent or selected from the group consisting of His, Ala, Pro, Hyp, Leu, dGln, Phe, dPhe, Trp, dTrp, Tyr, dTyr, Aba, Ata, Aia, Atc, APC, APPC, Tic, Bip, Oic, Che, Ioc, and Cpe; R4is dPhe or p(F)dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is selected from the group consisting of Trp, dTrp, Phe, Aia, Aba, Ata, dNal(2’), Nal(2’), and Nal(1’); R7is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, and Orn; R8is absent or Lys; Y1is absent or selected from the group consisting of Val, dVal, β2-Val, β3-Val, Pro, dPro, β-Pro, Hyp, dHyp, dLeu, dTle, Trp, Arg, dArg, Lys, dLys, Gly, Ala, dAla, Asp, dAsp, Asn, dAsn, and dThr; Y2is absent or selected from the group consisting of Val, dVal, β2-Val, β3-Val, Pro, dPro, dTle, β-Pro, Hyp, dHyp, dTle, Arg, dArg, Gly, Ala, dAla, Asp, and dAsn; -31- 180092653.1Docket No.: 146316.8032.WO02 Y3is absent or selected from the group consisting of Val, dVal, Pro, dPro, dThr, and dLys; Y4is absent or selected from the group consisting of dVal, dPro, and dAsp; Y5is absent or dVal; Y6is absent or dVal; Y7is 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 R1and R7when R1and R7are each independently Cys or dCys; a disulfide bond between R2and R7, when R2and R7are each independently selected from Cys, dCys, Pen, and dPen; a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp, dAsp, or Glu and R7is dLys or Orn, provided that: when R4is p(F)dPhe, then (i) R3is selected from Pro, dGln, and dTyr, R6is Trp, and R2is not Cys; or (ii) R3is His and R6is Nal(2’) or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2and R7; when R4is dPhe and R1is Asp, then either (i) R2is selected from Trp, Phe, His, Tyr, dPhe, dHis, and dTyr, R3is selected from Pro, Ala, and Leu, R5is Arg, and R6is selected from Trp, Nal(1’), dNal(2’), and Nal(2’); or (ii) R2is selected from Ala, dAla, and Phe, and R3is His, wherein when R2is dAla, then Y1-Y7are absent and when R2is Ala, then R1is not Nle; when R4is dPhe, and R2is Asp, Glu, or dPen, then R3is not His or absent; and -32- 180092653.1Docket No.: 146316.8032.WO02 when R4is dPhe, R2is Asp, and R3is Pro, then R5is not dNal(2’) or Nal(2’) and Y3- Y7are absent if any of X1-X3are present.

[0087] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA): X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4-Y5-Y6-Y7(IA), wherein: X1is absent or selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; X2is absent, Phe, or Nle; X3is absent, Phe, or Nle; R1is selected from the group consisting of Nle, dNle, Ala, dAla, Arg, dArg, Lys, dLys, His, dHis, Orn, dOrn, dLeu, dTyr, Phe, dPhe, Trp, dTrp, Asp, Cys, and dCys; R2is selected from the group consisting of Asp, dAsp, Glu, Cys, dCys, dPen, Ala, dAla, Trp, Phe, dPhe, His, dHis, Tyr, and dTyr; R3is absent or selected from the group consisting of His, Ala, Pro, Hyp, Leu, dGln, Phe, dPhe, Trp, dTrp, Tyr, dTyr, Aba, Ata, Aia, Atc, APC, APPC, Tic, Bip, Oic, Che, Ioc, and Cpe; R4is dPhe or p(F)dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is selected from the group consisting of Trp, dTrp, Phe, Aia, Aba, Ata, dNal(2’), Nal(2’), and Nal(1’); R7is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, and Orn; R8is absent or Lys; -33- 180092653.1Docket No.: 146316.8032.WO02 Y1is absent or selected from the group consisting of Val, dVal, β2-Val, β3-Val, Pro, dPro, β-Pro, Hyp, dHyp, dLeu, dTle, Trp, Arg, dArg, Lys, dLys, Gly, Ala, dAla, Asp, dAsp, Asn, dAsn, and dThr; Y2is absent or selected from the group consisting of Val, dVal, β2-Val, β3-Val, Pro, dPro, dTle, β-Pro, Hyp, dHyp, dTle, Arg, dArg, Gly, Ala, dAla, Asp, and dAsn; Y3is absent or selected from the group consisting of Val, dVal, Pro, dPro, dThr, and dLys; Y4is absent or selected from the group consisting of dVal, dPro, and dAsp; Y5is absent or dVal; Y6is absent or dVal; Y7is 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 R1and R7when R1and R7are each independently Cys or dCys; a disulfide bond between R2and R7, when R2and R7are each independently selected from Cys, dCys, Pen, and dPen; a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp, dAsp, or Glu and R7is dLys 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-dTrp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 295); Ac-Nle-c[Asp-dPhe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 296); Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 297); -34- 180092653.1Docket No.: 146316.8032.WO02 Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 298); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 299); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 300); Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 301); Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 302); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 303); Ac-Nle-c[Asp-Trp-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 304); Ac-Nle-c[Asp-Tyr-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 305); Ac-Nle-c[Cys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 306); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 307); Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 308); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 309); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 310); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 311); Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 312); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 313); Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 314); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 315); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 316); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 317); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 318); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 319); Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 320); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 321); -35- 180092653.1Docket No.: 146316.8032.WO02 Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 322); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 323); Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 324); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 325); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 326); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 327); Ac-Nle-c[Asp-Bip-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 328); Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 329); Ac-Nle-c[Asp-Phe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 330); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 331); Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 332); Ac-Nle-c[Asp-Trp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 333); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Phe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 334); Ac-dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 335); Ac-Nle-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 336); Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 337); Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 338); Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 339); Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 340); Ac-Arg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 341); Ac-dArg-c[Asp-dAla-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 342); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 343); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 344); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 345); -36- 180092653.1Docket No.: 146316.8032.WO02 Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 346); Ac-Nle-c[dPen-dPhe-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 347); Ac-Nle-c[Asp-His-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 348); Ac-Nle-c[Asp-His-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 349); Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 350); Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 351); and Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 352).

[0088] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) or (IA), wherein R4is dPhe. In further embodiments, the sequence of Formula (I) or (IA) is cyclized between R2and R7or R8. Accordingly, in some embodiments, the sequence of Formula (I) or (IA) is a sequence of Formula (IA(i)): X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4-Y5-Y6-Y7(IA(i)), wherein: X1is absent or Nle; X2is absent or Nle; X3is absent or Nle; R1is selected from the group consisting of Nle, dNle, Ala, dAla, Arg, dArg, Lys, dLys, His, dHis, Orn, dOrn, dLeu, dTyr, Phe, dPhe, Trp, and dTrp; R2is selected from the group consisting of Asp, dAsp, Glu, Cys, dCys, and dPen; R3is absent or selected from the group consisting of Ala, Pro, Hyp, Leu, dGln, Phe, dPhe, Trp, dTrp, Tyr, dTyr, Aba, Ata, Aia, Atc, APC, APPC, Tic, Bip, Oic, Che, Ioc, and Cpe; R4is dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is selected from the group consisting of Trp, dTrp, Phe, Aia, Aba, Ata, and Nal(1’); -37- 180092653.1Docket No.: 146316.8032.WO02 R7is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, and Orn; R8is absent or Lys; Y1is absent or selected from the group consisting of Val, dVal, β2-Val, β3-Val, Pro, dPro, β-Pro, Hyp, dHyp, dLeu, dTle, Trp, Arg, dArg, Lys, dLys, Gly, Ala, dAla, Asp, dAsp, Asn, dAsn, and dThr; Y2is absent or selected from the group consisting of Val, dVal, β2-Val, β3-Val, Pro, dPro, dTle, β-Pro, Hyp, dHyp, dTle, Arg, dArg, Gly, Ala, dAla, Asp, and dAsn; Y3is absent or selected from the group consisting of Val, dVal, Pro, dPro, dThr, and dLys; Y4is absent or selected from the group consisting of dVal, dPro, and dAsp; Y5is absent or dVal; Y6is absent or dVal; Y7is 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 R2and R7, when R2and R7are each independently selected from Cys, dCys, Pen, and dPen; a lactam bridge between R2and R7or R8when R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp, dAsp, or Glu and R7is dLys or Orn.

[0089] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(i)): X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4-Y5-Y6-Y7(IA(i)), wherein: -38- 180092653.1Docket No.: 146316.8032.WO02 X1is absent or Nle; X2is absent or Nle; X3is absent or Nle; R1is selected from the group consisting of Nle, dNle, Ala, dAla, Arg, dArg, Lys, dLys, His, dHis, Orn, dOrn, dLeu, dTyr, Phe, dPhe, Trp, and dTrp; R2is selected from the group consisting of Asp, dAsp, Glu, Cys, dCys, and dPen; R3is absent or selected from the group consisting of Ala, Pro, Hyp, Leu, dGln, Phe, dPhe, Trp, dTrp, Tyr, dTyr, Aba, Ata, Aia, Atc, APC, APPC, Tic, Bip, Oic, Che, Ioc, and Cpe; R4is dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is selected from the group consisting of Trp, dTrp, Phe, Aia, Aba, Ata, and Nal(1’); R7is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, and Orn; R8is absent or Lys; Y1is absent or selected from the group consisting of Val, dVal, β2-Val, β3-Val, Pro, dPro, β-Pro, Hyp, dHyp, dLeu, dTle, Trp, Arg, dArg, Lys, dLys, Gly, Ala, dAla, Asp, dAsp, Asn, dAsn, and dThr; Y2is absent or selected from the group consisting of Val, dVal, β2-Val, β3-Val, Pro, dPro, dTle, β-Pro, Hyp, dHyp, dTle, Arg, dArg, Gly, Ala, dAla, Asp, and dAsn; Y3is absent or selected from the group consisting of Val, dVal, Pro, dPro, dThr, and dLys; Y4is absent or selected from the group consisting of dVal, dPro, and dAsp; Y5is absent or dVal; Y6is absent or dVal; Y7is absent or dPro; and -39- 180092653.1Docket No.: 146316.8032.WO02 the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R2and R7, when R2and R7are each independently selected from Cys, dCys, Pen, and dPen; a lactam bridge between R2and R7or R8when R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp, dAsp, or Glu and R7is dLys or Orn, provided that: when R2is Asp, Glu, or dPen, then R3is not absent; and when R2is Asp and R3is Pro, then Y3-Y7are absent if any of X1-X3are present.

[0090] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(i)), wherein: X1is absent or Nle; X2is absent or Nle; X3is absent or Nle; R1is selected from the group consisting of Nle, dNle, Ala, dAla, Arg, dArg, Lys, dLys, His, dHis, Orn, dOrn, dLeu, dTyr, Phe, dPhe, Trp, and dTrp; R2is selected from the group consisting of Asp, dAsp, Glu, Cys, dCys, and dPen; R3is absent or selected from the group consisting of Ala, Pro, Hyp, Leu, dGln, Phe, dPhe, Trp, dTrp, Tyr, dTyr, Aba, Ata, Aia, Atc, APC, APPC, Tic, Bip, Oic, Che, Ioc, and Cpe; R4is dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is selected from the group consisting of Trp, dTrp, Phe, Aia, Aba, Ata, and Nal(1’); -40- 180092653.1Docket No.: 146316.8032.WO02 R7is selected from the group consisting of Gly, Pro, Lys, dLys, Cys, dCys, Pen, dPen, and Orn; R8is absent or Lys; Y1is absent or selected from the group consisting of Val, dVal, β2-Val, β3-Val, Pro, dPro, β-Pro, Hyp, dHyp, dLeu, dTle, Trp, Arg, dArg, Lys, dLys, Gly, Ala, dAla, Asp, dAsp, Asn, dAsn, and dThr; Y2is absent or selected from the group consisting of Val, dVal, β2-Val, β3-Val, Pro, dPro, dTle, β-Pro, Hyp, dHyp, dTle, Arg, dArg, Gly, Ala, dAla, Asp, and dAsn; Y3is absent or selected from the group consisting of Val, dVal, Pro, dPro, dThr, and dLys; Y4is absent or selected from the group consisting of dVal, dPro, and dAsp; Y5is absent or dVal; Y6is absent or dVal; Y7is 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 R2and R7, when R2and R7are each independently selected from Cys, dCys, Pen, and dPen; a lactam bridge between R2and R7or R8when R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp, dAsp, or Glu and R7is dLys or Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence of: Ac-Nle-c[dPen-dPhe-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 347); or Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 352). -41- 180092653.1Docket No.: 146316.8032.WO02

[0091] Alternatively, in some embodiments, when the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) or (IA), wherein R4is dPhe, then the sequence of Formula (I) or (IA) is cyclized between R1and R7. Accordingly, in some embodiments, the sequence of Formula (I) or (IA) is a sequence of Formula (IA(ii)): X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IA(ii)), wherein: X1is absent or selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; X2is absent, Phe, or Nle; X3is absent or Phe; R1is selected from the group consisting of Asp, Cys, and dCys; R2is selected from the group consisting of Ala, dAla, Trp, Phe, dPhe, His, dHis, Tyr, and dTyr; R3is absent or selected from the group consisting of His, Pro, Ala, and Leu; R4is dPhe; R5is Arg; R6is selected from the group consisting of Trp, dNal(2’), Nal(2’), and Nal(1’); R7is selected from the group consisting of Lys, Cys, and dCys; Y1is absent or selected from the group consisting of dVal, dLeu, dTle, dArg, and dLys; Y2is absent or selected from the group consisting of dVal, dPro, and dHyp; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: -42- 180092653.1Docket No.: 146316.8032.WO02 a disulfide bond between R1and R7when R1and R7are each independently Cys or dCys; and a lactam bridge between R1and R7when R1is Asp and R7is Lys.

[0092] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(ii)): X1-X2-X3-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IA(ii)), wherein: X1is absent or selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; X2is absent, Phe, or Nle; X3is absent or Phe; R1is selected from the group consisting of Asp, Cys, and dCys; R2is selected from the group consisting of Ala, dAla, Trp, Phe, dPhe, His, dHis, Tyr, and dTyr; R3is absent or selected from the group consisting of His, Pro, Ala, and Leu; R4is dPhe; R5is Arg; R6is selected from the group consisting of Trp, dNal(2’), Nal(2’), and Nal(1’); R7is selected from the group consisting of Lys, Cys, and dCys; Y1is absent or selected from the group consisting of dVal, dLeu, dTle, dArg, and dLys; Y2is absent or selected from the group consisting of dVal, dPro, and dHyp; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: -43- 180092653.1Docket No.: 146316.8032.WO02 a disulfide bond between R1and R7when R1and R7are each independently Cys or dCys; and a lactam bridge between R1and R7when R1is Asp and R7is Lys, provided that: when R1is Asp, then either (i) R2is selected from Trp, Phe, His, Tyr, dPhe, dHis, and dTyr, R3is selected from Pro, Ala, and Leu, R5is Arg, and R6is selected from Trp, Nal(1’), dNal(2’), and Nal(2’); or (ii) R2is selected from Ala, dAla, and Phe, and R3is His, wherein when R2is dAla, then Y1-Y7are absent and when R2is Ala, then R1is not Nle.

[0093] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(ii)), wherein: X1is absent or selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; X2is absent, Phe, or Nle; X3is absent or Phe; R1is selected from the group consisting of Asp, Cys, and dCys; R2is selected from the group consisting of Ala, dAla, Trp, Phe, dPhe, His, dHis, Tyr, and dTyr; R3is selected from the group consisting of His, Pro, Ala, and Leu; R4is dPhe; R5is Arg; R6is selected from the group consisting of Trp, dNal(2’), Nal(2’), and Nal(1’); R7is selected from the group consisting of Lys, Cys, and dCys; Y1is absent or selected from the group consisting of dVal, dLeu, dTle, dArg, and dLys; Y2is absent or selected from the group consisting of dVal, dPro, and dHyp; Y3is absent, dVal, or dPro; -44- 180092653.1Docket No.: 146316.8032.WO02 Y4is 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 R1and R7when R1and R7are each independently Cys or dCys; and a lactam bridge between R1and R7when R1is Asp and R7is Lys, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-Trp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 333); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Phe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 334); Ac-dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 335); and Ac-Nle-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 336).

[0094] In some embodiments, when the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) or (IA), wherein R4is p(F)dPhe. Accordingly, in some embodiments, the sequence of Formula (I) or (IA) is a sequence of Formula (IA(iii)): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IA(iii)), wherein: X1is absent or Nle; R1is selected from the group consisting of Nle, Ala, Arg, dArg, Lys, dLys, His, and dHis; R2is selected from the group consisting of Asp, Glu, Cys, and dCys; R3is selected from the group consisting of His, Pro, dGln, and dTyr; R4is p(F)dPhe; R5is Arg or His; R6is Trp or Nal(2’); R7is selected from the group consisting of Lys, Cys, dCys, and Orn; -45- 180092653.1Docket No.: 146316.8032.WO02 Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is 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 R2and R7, when R2and R7are each independently Cys or dCys; a lactam bridge between R2and R7when R2is Asp and R7is Lys; and a lactam bridge between R2and R7when R2is Asp, or Glu and R7is Orn.

[0095] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(iii)): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IA(iii)), wherein: X1is absent or Nle; R1is selected from the group consisting of Nle, Ala, Arg, dArg, Lys, dLys, His, and dHis; R2is selected from the group consisting of Asp, Glu, Cys, and dCys; R3is selected from the group consisting of His, Pro, dGln, and dTyr; R4is p(F)dPhe; R5is Arg or His; R6is Trp or Nal(2’); R7is selected from the group consisting of Lys, Cys, dCys, and Orn; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; -46- 180092653.1Docket No.: 146316.8032.WO02 Y3is absent, dVal, or dPro; Y4is 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 R2and R7, when R2and R7are each independently Cys or dCys; a lactam bridge between R2and R7when R2is Asp and R7is Lys; and a lactam bridge between R2and R7when R2is Asp, or Glu and R7is Orn, provided that: when R3is selected from Pro, dGln, and dTyr, R6is Trp, then R2is not Cys; and when R3is His, then R6is Nal(2’) or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2and R7.

[0096] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(iii)), wherein: X1is absent or Nle; R1is selected from the group consisting of Nle, Ala, Arg, dArg, Lys, dLys, His, and dHis; R2is selected from the group consisting of Asp, Glu, Cys, and dCys; R3is selected from the group consisting of His, Pro, dGln, and dTyr; R4is p(F)dPhe; R5is Arg or His; R6is Trp or Nal(2’); R7is selected from the group consisting of Lys, Cys, dCys, and Orn; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; -47- 180092653.1Docket No.: 146316.8032.WO02 Y3is absent, dVal, or dPro; Y4is 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 R2and R7, when R2and R7are each independently Cys or dCys; a lactam bridge between R2and R7when R2is Asp and R7is Lys; and a lactam bridge between R2and R7when R2is Asp, or Glu and R7is Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 297); Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 298); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 299); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 300); Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 301); Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 302); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 303); Ac-Nle-c[Cys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 306); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 307); Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 308); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 309); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 310); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 311); Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 312); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 313); -48- 180092653.1Docket No.: 146316.8032.WO02 Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 314); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 315); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 316); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 317); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 318); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 319); Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 320); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 321); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 322); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 323); Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 324); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 325); Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 326); and Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 327).

[0097] In some embodiments, when the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein R4is p(Cl)dPhe or p(Br)dPhe. When R4is p(Cl)dPhe or p(Br)dPhe in the sequence of Formula (I), then R8is absent. Accordingly, in some embodiments, the sequence of Formula (I) is a sequence of Formula (IB): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IB), wherein: X1is absent or Nle; R1is selected from the group consisting of Nle, Arg, dArg, Lys, dLys, His, and dHis; R2is Asp or dCys; R3is selected from the group consisting of His, Aba, Aia, and Ata; R4is p(Cl)dPhe or p(Br)dPhe; -49- 180092653.1Docket No.: 146316.8032.WO02 R5is Arg; R6is Trp; R7is selected from the group consisting of Lys, Cys, and dCys; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is 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 R2and R7, when R2and R7are each independently Cys or dCys; and a lactam bridge between R2and R7when R2is Asp and R7is Lys.

[0098] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IB), wherein: X1is absent or Nle; R1is selected from the group consisting of Nle, Arg, dArg, Lys, dLys, His, and dHis; R2is Asp or dCys; R3is selected from the group consisting of His, Aba, Aia, and Ata; R4is p(Cl)dPhe or p(Br)dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Lys, Cys, and dCys; Y1is selected from the group consisting of dVal, dPro, and dTle; -50- 180092653.1Docket No.: 146316.8032.WO02 Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is 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 R2and R7, when R2and R7are each independently Cys or dCys; and a lactam bridge between R2and R7when R2is Asp and R7is Lys, provided that: when R4is p(Br)dPhe, then R2is dCys; and when R4is p(Cl)dPhe, then (i) R3is selected from Ata, Aia, and Aba; or (ii) R3is His, R5is Arg; R6is Trp; R7is Lys or dCys, and R1is not Ala, wherein when X1is present, then Y1is dTle and when X1is absent and Y1-Y2is dVal-dPro or dTle-dPro, then either R1is not Nle or the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between R2and R7.

[0099] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB), wherein: X1is absent or Nle; R1is selected from the group consisting of Nle, Arg, dArg, Lys, dLys, His, and dHis; R2is Asp or dCys; R3is selected from the group consisting of His, Aba, Aia, and Ata; R4is p(Cl)dPhe or p(Br)dPhe; R5is Arg; R6is Trp; R7is selected from the group consisting of Lys, Cys, and dCys; Y1is selected from the group consisting of dVal, dPro, and dTle; -51- 180092653.1Docket No.: 146316.8032.WO02 Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is 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 R2and R7, when R2and R7are each independently Cys or dCys; and a lactam bridge between R2and R7when R2is Asp and R7is Lys, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 234); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 238); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 239); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 240); Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 241); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 250); Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 251); Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 252); Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 253); Ac-dLys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 254); Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 255); Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 256); Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 257); Ac-Nle-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 258); Ac-dArg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 259); -52- 180092653.1Docket No.: 146316.8032.WO02 Ac-Arg-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 260); Ac-Lys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 261); Ac-dLys-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 262); Ac-His-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 263); Ac-dHis-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 264); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 279); Ac-Nle-c[Glu-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 280); Ac-Nle-c[dCys-His-p(Cl)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 281); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 288); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 289); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 290); and Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 291).

[0100] In some embodiments, when the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) or (IA), wherein R4is dPhe or p(F)dPhe. In further embodiments, the sequence of Formula (I) or (IA) is cyclized through a lactam bond between Asp or Glu at R2and Orn at R7. Accordingly, in some embodiments, the sequence of Formula (I) is a sequence of Formula (IC): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IC), wherein: R1is Nle; R2is Asp or Glu; R3is Pro; R4is p(F)dPhe or dPhe; R5is Arg; R6is Trp; -53- 180092653.1Docket No.: 146316.8032.WO02 R7is Orn; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7.

[0101] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IC), wherein: R1is Nle; R2is Asp or Glu; R3is Pro; R4is p(F)dPhe or dPhe; R5is Arg; R6is Trp; R7is Orn; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7, provided that: when R4is dPhe, then R2is Glu.

[0102] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC), wherein: R1is Nle; -54- 180092653.1Docket No.: 146316.8032.WO02 R2is Asp or Glu; R3is Pro; R4is p(F)dPhe or dPhe; R5is Arg; R6is Trp; R7is Orn; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7, provided that the non-naturally occurring melanocortin analog does not comprise a sequence of: Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 23).

[0103] In some embodiments, the non-naturally occurring melanocortin analog has one or more beta hairpin (β-hairpin) and / or beta turn (β-turn) structures. In some embodiments, the presence of Pro, dPro, Hyp, dHyp, transPro(guan), and / or cisPro(guan), provides the β- hairpin and / or β-turn structures of the non-naturally occurring melanocortin analog. In some embodiments, the disulfide bond of the sequence according to Formula (I), if present, provides the β-hairpin and / or β-turn structures of the non-naturally occurring melanocortin analog.

[0104] As will be appreciated by the skilled artisan, non-naturally occurring melanocortin analogs comprising a sequence of any one of Formulae (I)-(IC), have an N- terminus and a C-terminus. The melanocortin analogs of the present technology are written beginning with the N-terminus at the left-most amino acid residue and ending with the C- terminus at the right most residue. Accordingly, the N-terminus of a non-naturally melanocortin analog comprising a sequence of any one of Formulae (I)-(IC) may be at any of X1, X2, X3, and R1. Analogously, the C-terminus of a non-naturally occurring melanocortin analog comprising a sequence of any one of Formulae (I)-(IC) may be at any of R7, R8, Y1, Y2, Y3, Y4, Y5, Y6, and Y7. -55- 180092653.1Docket No.: 146316.8032.WO02

[0105] 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 ).

[0106] N-terminus of the non-naturally occurring melanocortin analog is not modified.

[0107] As discussed above, Y1Y2Y3Y4Y5Y6Y7represents a C-terminus of the non- naturally occurring melanocortin analog. In some embodiments, Y1-Y7are absent. In some embodiments, Y1is present and Y2-Y7are absent. In some embodiments, Y1and Y2are present and Y3-Y7are absent. In some embodiments, Y1-Y3are present and Y4-Y7are absent. In some embodiments, Y1-Y4are present and Y5-Y7are absent. In some embodiments, Y1-Y5are present and Y6-Y7are absent. In some embodiments, Y1-Y6are present and Y7is absent. In some embodiments, Y1-Y7are present.

[0108] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified by an amide In the sequence of any one of Formulae (I)-(ID), a non-naturallywith a C- terminus modified by an amide may be represented by a terminal -NH2.

[0109] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is not modified. In the sequence of any one of Formulae (I)-(ID), a non- naturally occurring melanocortin analog with an unmodified C-terminus may be represented by -OH.

[0110] Non-naturally occurring melanocortin analogs comprising a sequence of any one of Formulae (I)-(IC) 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 R1and R7when R1and R7are each independently Cys or dCys; a disulfide bond between R2and R7, when R2and R7are each independently selected from Cys, dCys, Pen, and dPen; a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and -56- 180092653.1Docket No.: 146316.8032.WO02 R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp, dAsp, or Glu and R7is dLys or Orn.

[0111] In some embodiments of the sequence of Formula (I), R4is Phe or dPhe. In further embodiments, R1is Nle, R3is Pro or His, R5is Arg, R6is Trp, Y1is dVal and Y2is dPro. In some embodiments, the sequence of Formulae (I) is: Ac-Nle-c[Asp-Pro-Phe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 2); Ac-Nle-c[Asp-Pro-His-Phe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 3); and Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 31), wherein c represents cyclization through R1or R2and R7via a lactam bond.

[0112] In some embodiments of the sequence of any one of Formulae (I)-(IC), R4is dPhe. In further embodiments, sequence of any one of Formulae (I)-(IC) is cyclized through a lactam bond between Asp R2and Lys at R7.

[0113] In some embodiments, X1-X3are absent. Alternatively, in some embodiments, one or more of , X1-X3is present. In some embodiments, X1is present and X2-X3are absent. In some embodiments, X1-X2are present and X3is absent. In some embodiments, X1-X3are present. In further embodiments, R1is Nle, R3is Pro, R5is Arg, R6is Trp, Y1is dVal or dTle and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 53); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 40); Ac-Nle-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 188); and Ac-Nle-Nle-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 189), wherein c represents cyclization through R2and R7via a lactam bond.

[0114] In some embodiments, R1is Nle. Alternatively, in some embodiments, R1is an amino acid other than Nle. In further embodiments, R1is selected from dLeu, dAla, Ala, dPhe, Phe, Trp, dTrp, dArg, Arg, dLys, His, dHis, Orn, and dOrn. In still further embodiments, R3is Pro, R5is Arg, and R6is Trp. In some embodiments, Y1is dVal and Y2is dPro. In some -57- 180092653.1Docket No.: 146316.8032.WO02 embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-dLeu-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 66); Ac-dAla-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 94); Phe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 144); His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 145); Trp-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 147); dPhe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 148); dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 149); dTrp-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 150); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 151); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 152); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 153); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 154); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 155); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 156); Ac-Orn-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 158); Ac-dOrn-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 159); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 187); Ac-dPhe-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 193); and Ac-dTyr-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 195), wherein c represents cyclization through R2and R7via a lactam bond.

[0115] In other embodiments, Y1is dTle and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 167); -58- 180092653.1Docket No.: 146316.8032.WO02 Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 168); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 169); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 170); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 171); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 172); and Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 173), wherein c represents cyclization through R2and R7via a lactam bond.

[0116] In still other embodiments, Y1is selected from dArg, dLys, dVal, and dTle, Y2is selected from dPro, dVal, and dHyp, Y3is absent, dVal, or dPro, and Y4is absent or dPro. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH2 (SEQ ID NO: 160); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 161); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dPro-NH2 (SEQ ID NO: 162); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 163); Ac-Orn-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 164); and Ac-dOrn-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 165), wherein c represents cyclization through R2and R7via a lactam bond.

[0117] In some embodiments, R3is Pro. Alternatively, in some embodiments, R3is an amino acid other than Pro. In further embodiments, R3is selected from Aba, Aia, Ata, APC, APPC, Ioc, Tyr, Trp, Atc, Ala, Leu, Hyp, Phe, dPhe, dGln, dTyr, dTrp, Bip, Tic, Cpe, Che, and Oic. In still further embodiments, R1is Nle, R5is Arg, R6is Trp, Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-Nle-c[Asp-Aba-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 4); -59- 180092653.1Docket No.: 146316.8032.WO02 Ac-Nle-c[Asp-Aia-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 5); Ac-Nle-c[Asp-Ata-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 6); Ac-Nle-c[Asp-APC-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 10); Ac-Nle-c[Asp-APPC-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 11); Ac-Nle-c[Asp-Ioc-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 18); Ac-Nle-c[Asp-Trp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 42); Ac-Nle-c[Asp-Tyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-Atc-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 63); Ac-Nle-c[Asp-Ala-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 88); Ac-Nle-c[Asp-Hyp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 142); Ac-Nle-c[Asp-dPhe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 174); Ac-Nle-c[Asp-dGln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 175); Ac-Nle-c[Asp-dTrp-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 176); Ac-Nle-c[Asp-dTyr-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 177); Ac-Nle-c[Asp-Cpe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 190); Ac-Nle-c[Asp-Che-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 191); Ac-Nle-c[Asp-Oic-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 192); Ac-Nle-c[Asp-Leu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 220); Ac-Nle-c[Asp-Tic-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 221); Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 222); and Ac-Nle-c[Asp-Bip-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 223), wherein c represents cyclization through R2and R7via a lactam bond.

[0118] In some embodiments, R5is Arg. Alternatively, in some embodiments, R5is an amino acid other than Arg. In further embodiments, R5is selected from transPro(guan), -60- 180092653.1Docket No.: 146316.8032.WO02 cisPro(guan), and His. In still further embodiments, when R1is Nle, R3is Pro, R6is Trp, R7is Lys, Y1is dVal, and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 12); Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 13); and Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 92), wherein c represents cyclization through R2and R7via a lactam bond.

[0119] In some embodiments, R6is Trp. Alternatively, in some embodiments, R6is an amino acid other than Trp. In further embodiments, R6is selected from Aia, Aba, Ata, dTrp, Nal(1’), and Phe. In still further embodiments, when R1is Nle, R3is Pro, R5is Arg, R7is Lys, Y1is dVal, and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)- (IC) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-dPhe-Arg-Aia-Lys]-dVal-dPro-NH2 (SEQ ID NO: 14); Ac-Nle-c[Asp-Pro-dPhe-Arg-Aba-Lys]-dVal-dPro-NH2 (SEQ ID NO: 15); Ac-Nle-c[Asp-Pro-dPhe-Arg-Ata-Lys]-dVal-dPro-NH2 (SEQ ID NO: 16); Ac-Nle-c[Asp-Pro-dPhe-Arg-dTrp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 65); Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(1’)-Lys]-dVal-dPro-NH2 (SEQ ID NO: 95); and Ac-Nle-c[Asp-Pro-dPhe-Arg-Phe-Lys]-dVal-dPro-NH2 (SEQ ID NO: 96), wherein c represents cyclization through R2and R7via a lactam bond.

[0120] In some embodiments, Y1is dVal, Y2is dPro, and the C-terminus is modified by NH2. Alternatively, in some embodiments, Y1is an amino acid other than dVal, Y2is an amino acid other than dPro, and / or the C-terminus is not modified. In further embodiments Y1is selected from dThr, dPro, Val, β-Val, Hyp, dHyp, Pro, β-Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, Lys, dLys, and dTle and Y2is selected from dThr, dVal, Val, β-Val, Hyp, dHyp, Pro, β-Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, and dTle. In still further embodiments, R1is Nle, R3is Pro, R5is Arg, and R6is Trp. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: -61- 180092653.1Docket No.: 146316.8032.WO02 Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-Hyp-NH2 (SEQ ID NO: 36); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 37); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-β2Val-βPro-NH2 (SEQ ID NO: 38); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Arg-NH2 (SEQ ID NO: 41); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-NH2 (SEQ ID NO: 44); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-Pro-Val-NH2 (SEQ ID NO: 45); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH2 (SEQ ID NO: 46); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Arg-Pro-Val-NH2 (SEQ ID NO: 47); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Arg-Val-Pro-NH2 (SEQ ID NO: 48); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 49); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 50); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 51); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 52); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Trp-NH2 (SEQ ID NO: 54); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dAsn-NH2 (SEQ ID NO: 57); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asn-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Ala-Ala-NH2 (SEQ ID NO: 59); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Gly-Gly-NH2 (SEQ ID NO: 60); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAsn-dPro-NH2 (SEQ ID NO: 61); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Val-Pro-NH2 (SEQ ID NO: 104); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Val-NH2 (SEQ ID NO: 129); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dThr-dPro-dThr-NH2 (SEQ ID NO: 130); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dThr-dPro-dThr-OH (SEQ ID NO: 131); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 132); -62- 180092653.1Docket No.: 146316.8032.WO02 Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-dPro-dVal-NH2 (SEQ ID NO: 133); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-βPro-β2Val-NH2 (SEQ ID NO: 134); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-βPro-β3Val-NH2 (SEQ ID NO: 135); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 136); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-β3Val-βPro-NH2 (SEQ ID NO: 137); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Pro-NH2 (SEQ ID NO: 138); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-βPro-βPro-NH2 (SEQ ID NO: 139); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-Arg-NH2 (SEQ ID NO: 146); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dArg-NH2 (SEQ ID NO: 157); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 166); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLys-dPro-NH2 (SEQ ID NO: 178); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-Val-Pro-NH2 (SEQ ID NO: 179); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-dVal-dPro-NH2 (SEQ ID NO: 180); Ac-dNle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 181); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 182); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 183); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 184); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 185); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 186); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-dPro-dVal-NH2 (SEQ ID NO: 197); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAla-dAla-NH2 (SEQ ID NO: 198); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asp-NH2 (SEQ ID NO: 199); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dHyp-NH2 (SEQ ID NO: 200); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-Asp-NH2 (SEQ ID NO: 201); -63- 180092653.1Docket No.: 146316.8032.WO02 Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Hyp-NH2 (SEQ ID NO: 203); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asp-dPro-NH2 (SEQ ID NO: 204); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Asn-NH2 (SEQ ID NO: 205); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAsp-NH2 (SEQ ID NO: 206); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAsn-NH2 (SEQ ID NO: 207); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-Lys-dPro-NH2 (SEQ ID NO: 208); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 209); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 17), wherein c represents cyclization through R2and R7via a lactam bond.

[0121] In some embodiments, R4is dPhe and the sequence of any one of Formulae (I)-(IC) is cyclized through a lactam bond between Glu or Asp at R2and Orn at R7. In some embodiments, the sequence of any one of Formulae (I)-(IC) is: Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 23); or Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 216), wherein c represents cyclization through R2and R7via a disulfide bond.

[0122] In some embodiments, R4is dPhe and the sequence of any one of Formulae (I)-(IC) is cyclized through a disulfide bond between R2and R7, where R2and R7are each independently selected from Cys, dCys, and dPen. In further embodiments, R1is Nle, R3is Pro or absent, R5is Arg, R6is Trp, Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-Nle-c[dCys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c[dPen-Pro-dPhe-Arg-Trp-dPen]-dVal-dPro-NH2 (SEQ ID NO: 67); Ac-Nle-c[dCys-Pro-dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 74); Ac-Nle-c[Cys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 202); and Ac-Nle-c[Cys-dPhe-Arg-Trp-Pen]-dVal-dPro-NH2 (SEQ ID NO: 210), -64- 180092653.1Docket No.: 146316.8032.WO02 wherein c represents cyclization through R2and R7via a disulfide bond.

[0123] In some embodiments, R4is dPhe and the sequence of any one of Formulae (I)-(IC) is cyclized through a lactam or disulfide bond between R1and R7. In some embodiments, R2is Trp and / or R3is Pro. In further embodiments, X1is selected from Nle, Ala, Lys, dLys, Arg, His, and dHis; R2is selected from Trp, Phe, His, Tyr, dPhe, dHis, and dTyr; R3is selected from Pro, Ala, and Leu, R5is Arg, and R6is selected from Trp, dNal(2’), Nal(2’), and Nal(1’). In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 64); Ac-Nle-c[Cys-Trp-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 99); Ac-Nle-c[dCys-Trp-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 100); Ac-Nle-c[dCys-Trp-Pro-dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 101); Ac-Ala-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 102); Ac-Lys-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 103); Ac-dLys-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 105); Ac-Arg-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 106); Ac-dArg-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 107); Ac-dHis-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 108); Ac-His-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 109); Ac-Nle-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 110); Ac-Nle-c[Asp-Trp-Ala-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 111); Ac-Nle-c[Asp-Trp-Leu-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 112); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Nal(1')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 113); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 114); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 115); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dArg-dVal-dPro-NH2 (SEQ ID NO: 116); -65- 180092653.1Docket No.: 146316.8032.WO02 Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dLys-dVal-dPro-NH2 (SEQ ID NO: 117); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dArg-dPro-NH2 (SEQ ID NO: 118); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dLys-dPro-NH2 (SEQ ID NO: 119); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dHyp-NH2 (SEQ ID NO: 120); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 121); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 122); Ac-Nle-c[Asp-Phe-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 123); Ac-Nle-c[Asp-His-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 124); Ac-Nle-c[Asp-Tyr-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 125); Ac-Nle-c[Asp-dPhe-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 126); Ac-Nle-c[Asp-dHis-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 127); and Ac-Nle-c[Asp-dTyr-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 128), wherein c represents cyclization through R1and R7via a lactam bond.

[0124] In other embodiments, R2is Ala or dAla and R3is His. In further embodiments, X1is Arg or dArg; R5is Arg, and R6is Trp, Y1is absent or dVal, and Y2is absent or dPro. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 194); Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 196); and Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 230), wherein c represents cyclization through R1and R7via a lactam bond.

[0125] In still other embodiments, R2is Phe and R3is His. In further embodiments, X1is Nle or Phe; R5is Arg, and R6is Trp, Y1is selected from dVal, dLeu, and dTle, and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-Nle-Phe-Phe-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 140); -66- 180092653.1Docket No.: 146316.8032.WO02 Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 141); Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dLeu-dPro-NH2 (SEQ ID NO: 224); and Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 225), wherein c represents cyclization through R1and R7via a lactam bond.

[0126] In some embodiments, R4is dPhe and the sequence of any one of Formulae (I)-(IC) is cyclized through a lactam or disulfide bond between R2and R8. In some embodiments, R7is Pro or Gly. In further embodiments, R1is Nle R3is Pro or Hyp, R5is Arg, and R6is Trp. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-Nle-c[Asp-Hyp-dPhe-Arg-Trp-Pro-Lys]-dVal-dPro-NH2 (SEQ ID NO: 143); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 55); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dPro-dPro-dLys-dAsp-NH2 (SEQ ID NO: 56); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dPro-dPro-Lys-Asp-NH2 (SEQ ID NO: 219); wherein c represents cyclization through R2and R8via a lactam bond.

[0127] In some embodiments of the sequence of any one of Formulae (I)-(IC), R4is p(F)dPhe. In further embodiments, sequence of any one of Formulae (I)-(IC) is cyclized through a lactam bond between Asp R2and Lys at R7.

[0128] In some embodiments, X1-X3are absent. Alternatively, in some embodiments, one or more of , X1is present and X2-X3are absent. In further embodiments, R1is Nle, R3is Pro, R5is Arg, R6is Trp, Y1is dVal or dTle and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 20); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 76); and Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 77), wherein c represents cyclization through R2and R7via a lactam bond.

[0129] In some embodiments, R1is Nle. Alternatively, in some embodiments, R1is an amino acid other than Nle. In further embodiments, R1is selected from Ala, Arg, dArg, dLys, -67- 180092653.1Docket No.: 146316.8032.WO02 His, and dHis. In still further embodiments, R3is Pro, R5is Arg, and R6is Trp. In some embodiments, Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 213); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 214); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 215); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 68); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 69); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 70); and Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 71), wherein c represents cyclization through R2and R7via a lactam bond.

[0130] In other embodiments, Y1is dTle and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 78); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 79); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 80); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 81); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 82); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 83); and Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 84), wherein c represents cyclization through R2and R7via a lactam bond.

[0131] In some embodiments, R3is Pro. Alternatively, in some embodiments, R3is an amino acid other than Pro. In further embodiments, R3is selected from His, dGln and dTyr. In still further embodiments, R1is Nle, R5is Arg, R6is Trp or dNal(2’), Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: -68- 180092653.1Docket No.: 146316.8032.WO02 Ac-Nle-c[Asp-dGln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 97); Ac-Nle-c[Asp-dTyr-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 98); and Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 226), wherein c represents cyclization through R2and R7via a lactam bond.

[0132] In some embodiments, R5is Arg. Alternatively, in some embodiments, R5is an amino acid other than Arg. In further embodiments, R5is His. In some embodiments, the sequence of any one of Formulae (I)-(IC) is: Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal- dPro-NH2 (SEQ ID NO: 21), wherein c represents cyclization through R2and R7via a lactam bond.

[0133] In some embodiments, R1is Nle, R3is Pro, R5is Arg, and R6is Trp. In further embodiments, Y1is selected from dVal, dPro and dTle, Y2is selected from dVal, dPro, and dTle, Y3is absent, dVal, or dPro, and Y4is absent or dPro. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 19); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 22); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 72); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 73); and Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 75), wherein c represents cyclization through R2and R7via a lactam bond.

[0134] In some embodiments, R4is p(F)dPhe and the sequence of any one of Formulae (I)-(IC) is cyclized through a lactam bond between Glu or Asp at R2and Orn at R7. In some embodiments, the sequence of any one of Formulae (I)-(IC) is: Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 217); or Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 218), wherein c represents cyclization through R2and R7via a disulfide bond.

[0135] In some embodiments, R4is p(F)dPhe and the sequence of any one of Formulae (I)-(IC) is cyclized through a disulfide bond between R2and R7, where R2and R7-69- 180092653.1Docket No.: 146316.8032.WO02 are each independently Cys or dCys. In further embodiments, R1is Nle, R3is Pro or His, R5is Arg, R6is Trp, Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-Nle-c[dCys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 211); Ac-Nle-c[dCys-Pro-p(F)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 212); Ac-Nle-c[dCys-His-p(F)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 93); Ac-Nle-c[Cys-His-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 227); and Ac-Nle-c[dCys-His-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 231), wherein c represents cyclization through R2and R7via a disulfide bond.

[0136] In some embodiments of the sequence of any one of Formulae (I)-(IC), R4is p(Cl)dPhe or p(Br)dPhe. In further embodiments, sequence of any one of Formulae (I)-(IC) is cyclized through a lactam bond between Asp R2and Lys at R7.

[0137] In some embodiments, R1is Nle. Alternatively, in some embodiments, R1is an amino acid other than Nle. In further embodiments, R1is selected from Arg, dArg, dLys, His, and dHis. In still further embodiments, R3is His, R4is p(Cl)dPhe, R5is Arg, and R6is Trp. In some embodiments, Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-Arg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 24); Ac-Lys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 25); Ac-His-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 26); Ac-dHis-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 27); Ac-dArg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 86); and Ac-dLys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 87), wherein c represents cyclization through R2and R7via a lactam bond.

[0138] In other embodiments, Y1is dTle and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-dArg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 33); -70- 180092653.1Docket No.: 146316.8032.WO02 Ac-Arg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 34); Ac-dHis-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 35); Ac-Lys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 228); Ac-His-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 229); and Ac-dLys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 89), wherein c represents cyclization through R2and R7via a lactam bond.

[0139] In some embodiments, R3is Pro. Alternatively, in some embodiments, R3is an amino acid other than Pro. In further embodiments, R3is selected from Aia, Aba, and Ata. In still further embodiments, R1is Nle, R5is Arg, R6is Trp, Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-Nle-c[Asp-Aba-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 7); Ac-Nle-c[Asp-Aia-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 8); an Ac-Nle-c[Asp-Ata-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 9), wherein c represents cyclization through R2and R7via a lactam bond.

[0140] In some embodiments, Y1is dVal and Y2is dPro. Alternatively, in some embodiments, Y1is an amino acid other than dVal and / or Y2is an amino acid other than dPro. In further embodiments, R1is Nle, R5is Arg, and R6is Trp. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 28); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 29); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 30); and Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 32), wherein c represents cyclization through R2and R7via a lactam bond.

[0141] In some embodiments, R4is p(Cl)dPhe or p(Br)dPhe and the sequence of any one of Formulae (I)-(IC) is cyclized through a disulfide bond between R2and R7, where R2-71- 180092653.1Docket No.: 146316.8032.WO02 and R7are each independently Cys or dCys. In further embodiments, R1is Nle, R3is Pro or His, R5is Arg, R6is Trp, Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IC) is selected from the group consisting of: Ac-Nle-c[dCys-His-p(Cl)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 85); Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 90); and Ac-Nle-c[dCys-His-p(Br)dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 91), wherein c represents cyclization through R2and R7via a disulfide bond.

[0142] 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: 2-231.

[0143] 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: 4-6, 10-23, 31, 36-84, 88, 92-227, 230, and 231.

[0144] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(i)). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 4-6, 10-18, 23, 31, 36-63, 65-67, 74, 88, 92, 94-96, 104, 129-139, 142-193, 195, 197-210, 216, and 219- 223.

[0145] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(ii)). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 64, 99-103, 105- 128, 140, 141, 194, 196, 145, 147, and 230.

[0146] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(iii)). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 19-22, 68-73, 75-84, 93, 97, 98, 211-215, 217, 218, 226, 227, and 231. -72- 180092653.1Docket No.: 146316.8032.WO02

[0147] 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: 7-9, 24-30, 32- 35, 85-87, 89-91, 228, and 229.

[0148] 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: 216-218. Non-Naturally Occurring Melanocortin Analog Synthesis

[0149] 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.

[0150] 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.

[0151] 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 -73- 180092653.1Docket No.: 146316.8032.WO02 Peptides, Analysis, Synthesis and Biology, Vol. 2, Gross E. and Meienhofer J., Eds. Academic Press 1-284 (1980).

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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)-α-[1-(9H-fluor-en-9-yl)-methoxyformamido]-2,4- dimethyloxybenzyl]-phenoxyacetic acid (Rink linker) to a benzhydrylamine (BHA) resin, or by other means well known in the art. Fmoc-Linker-BHA resin supports are commercially available and generally used when feasible. The resins are carried through repetitive cycles as necessary to add amino acids sequentially. The alpha amino Fmoc protecting groups are -74- 180092653.1Docket No.: 146316.8032.WO02 removed under basic conditions. Piperidine, piperazine, diethylamine, or morpholine (20- 40% v / v) in N,N-dimethylformamide (DMF) may be used for this purpose.

[0156] 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.

[0157] 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.

[0158] The peptide may be cyclized prior to cleavage from the peptide resin. For cyclization through reactive side chain moieties, the desired side chains are deprotected, and the peptide suspended in a suitable solvent and a cyclic coupling agent added. Suitable solvents include, for example DMF, dichloromethane (DCM) or 1-methyl-2-pyrrolidone (NMP). Suitable cyclic coupling reagents include, for example, 2-(1H-benzotriazol-1-yl)- 1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate (HBTU), benzotriazole-1-yl-oxy- tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole-1-yl-oxy- tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP), 2-(7-aza-1H-benzotriazol-1- yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TATU), 2-(2-oxo-1 (2H)-pyridyl)-1,1,3,3- tetramethyluronium tetrafluoroborate (TPTU) or N,N′-dicyclohexylcarbodiimide / 1- hydroxybenzotriazole (DCCl / HOBt). Coupling is convention initiated by use of a suitable -75- 180092653.1Docket No.: 146316.8032.WO02 base, such as N,N-diispropylethylamine (DIPEA), sym-collidine or N-methylmorpholine (NMM).

[0159] 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

[0160] 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.

[0161] 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, -76- 180092653.1Docket No.: 146316.8032.WO02 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

[0162] 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.

[0163] 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.

[0164] 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, -77- 180092653.1Docket No.: 146316.8032.WO02 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, 10- 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.

[0165] 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 -78- 180092653.1Docket No.: 146316.8032.WO02 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 Gln, 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 Gln 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.

[0166] 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.

[0167] 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. 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 Name Amino Acid SEQ ID NO-79- 180092653.1Docket No.: 146316.8032.WO02 Name Amino Acid SEQ ID NO Linker F GGSGGSGGSGG 374

[0168] In some embodiments, the non-naturally occurring melanocortin analogs of the present technology are present in a pharmaceutical composition.

[0169] 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.

[0170] In some embodiments, the non-naturally occurring melanocortin analog comprises any one of SEQ ID NOs: 31, 216, and 218, and the non-naturally occurring -80- 180092653.1Docket No.: 146316.8032.WO02 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 any one of SEQ ID NOs: 31, 216, and 218is 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 any one of SEQ ID NOs: 31, 216, and 218 is present in the pharmaceutical composition in a concentration of about 50 mg / mL, relative to a total volume of the pharmaceutical composition.

[0171] In some embodiments, the composition comprises the non-naturally occurring melanocortin analog of formula (I) 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 any one of SEQ ID NOs: 31, 216, and 218.

[0172] 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.

[0173] 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. -81- 180092653.1Docket No.: 146316.8032.WO02

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] Any pharmaceutically acceptable carriers and / or excipients known in the art may be included in the pharmaceutical composition. Non-limiting examples of -82- 180092653.1Docket No.: 146316.8032.WO02 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.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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. -83- 180092653.1Docket No.: 146316.8032.WO02

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] In some embodiments, the pharmaceutical composition includes water in an amount of at least about 1 wt% to at least about 90 wt%, at least about 10 wt% to at least about 75 wt%, or at least about 25 wt% to at least about 50 wt%, relative to a total weight of the composition.

[0191] 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 -84- 180092653.1Docket No.: 146316.8032.WO02 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.

[0192] 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.

[0193] 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.

[0194] 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.

[0195] 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.

[0196] 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 -85- 180092653.1Docket No.: 146316.8032.WO02 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.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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 -86- 180092653.1Docket No.: 146316.8032.WO02 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.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to Tris is about 1:1 to about 20:1, about 3:2 to about 15:1, about 2:1 to about 12:1, about 3:1 to about 10:1, about 4:1 to about 9:1, about 5:1 to about 8:1, or about 6:1 to about 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to Tris is about 7:1.

[0207] 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. -87- 180092653.1Docket No.: 146316.8032.WO02

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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, -88- 180092653.1Docket No.: 146316.8032.WO02 0.1 mg / mL to 10 mg / mL, or 1 mg / mL to 5 mg / mL, relative to a total volume of the composition.

[0213] The pharmaceutical composition may further comprise an emulsifier. Non- limiting examples of emulsifiers that may be included in the pharmaceutical composition include sodium carboxymethylcellulose, cetyl alcohol, glycerol monostearate, methylcellulose, and stearic acid. In some embodiments, when the pharmaceutical composition comprises an emulsifier, the emulsifier is sodium carboxymethylcellulose.

[0214] 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

[0215] 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.

[0216] 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. -89- 180092653.1Docket No.: 146316.8032.WO02

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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 -90- 180092653.1Docket No.: 146316.8032.WO02 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.

[0224] 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.

[0225] 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 -91- 180092653.1Docket No.: 146316.8032.WO02 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.

[0226] 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.

[0227] 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.

[0228] 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 -92- 180092653.1Docket No.: 146316.8032.WO02 embodiments, the pharmaceutical composition has a viscosity of at least about 1.4 cP or at least about 1.6 cP.

[0229] 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.

[0230] When the pharmaceutical composition is formulated for parenteral administration (e.g., subcutaneous administration), the active ingredient(s) (e.g., the non- naturally occurring melanocortin analog) may be dissolved or suspended in the aforementioned carrier and / or excipient. Additional aqueous or non-aqueous carriers that may facilitate dissolution of the active ingredient include, but are not limited to, ethanol, benzyl alcohol, DMSO, polyethylene glycol, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, and / or various buffers.

[0231] 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.

[0232] 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. -93- 180092653.1Docket No.: 146316.8032.WO02

[0233] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., subcutaneous administration) and comprises Tris in a concentration of about 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, or 120 mM.

[0234] 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.

[0235] In some embodiments, the pharmaceutical composition comprises a surfactant, such as a sorbitan ester.

[0236] In some embodiments, the pharmaceutical composition comprises a flavoring or scent, such as an aromatic oil.

[0237] 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%.

[0238] 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%. -94- 180092653.1Docket No.: 146316.8032.WO02

[0239] 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%.

[0240] 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.

[0241] 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 -95- 180092653.1Docket No.: 146316.8032.WO02 selected, the desired therapeutic response, the route of administration, the formulation and other factors known to those of skill in the art.

[0242] 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.

[0243] 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.

[0244] 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 1ug to 100ug per spray. In some embodiments, the spray device or nasal inhaler may be configured to deliver 1ug to 100ug, 5ug to 90ug, 10ug to 80ug, 15ug to 70ug, 20ug to 60ug, 25ug, to 50ug, or 30ug to 40ug per spray. Dosing

[0245] In some embodiments, the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) is administered hourly once a day, or twice a day. 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. 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. Methods

[0246] The non-naturally occurring melanocortin analogs of the present technology may interact with one or more ligand binding sites of a melanocortin receptor, thereby modulating melanocortin receptor activity. This may modulate melanocortin receptor signaling pathways, including, but not limited to, reward and reinforcement-type pathways, thereby reducing pain, cravings, and / or withdrawal symptoms. As such, the non-naturally -96- 180092653.1Docket No.: 146316.8032.WO02 occurring melanocortin analog of the present technology may be useful pain management, opioid and other substance addictions (e.g., alcohol or nicotine addiction), or reducing a symptom thereof.

[0247] In some embodiments, the non-naturally occurring melanocortin analogs selectively bind at least a portion of an melanocortin receptor. The portion may comprise one or more amino acids of an melanocortin receptor. In some embodiments, the non- naturally occurring melanocortin analogs selectively bind two or more amino acids of an melanocortin receptor. The melanocortin receptor may be a MC3R or a MC4R.

[0248] The non-naturally occurring melanocortin analogs may comprise one or more motifs that confer binding to a melanocortin receptor or at least a portion thereof. The motif may be selected from the group consisting of Pro-p(F)dPhe; Trp-Pro-p(F)dPhe; dAla-Pro- p(F)dPhe; dAla-Pro-dPhe; Pro-dPhe; Ioc-dPhe; dAla-Pro-dPhe; Trp-Pro-dPhe; Pro-His- dPhe; His-p(Cl)dPhe; Aba-p(Cl)dPhe; Aia-p(Cl)dPhe; Ata-p(Cl)dPhe; Oic-p(F)dPhe; Oic- dPhe; dPhe at position R4; and p(F)dPhe at position R4.

[0249] The non-naturally occurring melanocortin analogs of the present technology may have a dissociation constant (Kd) value for an melanocortin receptor or one or more amino acids thereof that is less than that of a conventional melanocortin analog. Subjects

[0250] In some embodiments, the subject has used or is using an addictive substance. In some embodiments, the subject has used or is using a medication to treat an addiction. In some embodiments, the frequency or amount of the addictive substance and / or rescue medication is reduced during or after administration of the non-naturally occurring melanocortin analog. In some embodiments, the frequency or amount of the addictive substance and / or rescue medication is reduced as the dose or dosage of the non-naturally occurring melanocortin analog increases. In some embodiments, the frequency or amount of the addictive substance and / or rescue medication comprises a downward titration during or after administration of a non-naturally occurring melanocortin analog.

[0251] 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 -97- 180092653.1Docket No.: 146316.8032.WO02 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. Controls

[0252] 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. Weight Loss Agents

[0253] The non-naturally occurring melanocortin analogs of the present technology may be administered before or after administration of a weight loss agent (e.g., a glucagon- like peptide-1 receptor agonist). In some embodiments, the non-naturally occurring melanocortin analogs are administered simultaneously to a weight loss agent. In some embodiments, the combination of the weight loss agent and the non-naturally occurring melanocortin analog enhances an effect of the non-naturally occurring melanocortin analog alone or the weight loss agent alone.

[0254] The present technology is expected to be useful for subjects that may receive, have received, or are receiving one or more doses of a weight loss agent regardless of the underlying disease or condition that the subject has or develops.

[0255] The weight loss agent may include any conventional weight loss agent known in the art. Non-limiting examples of conventional weight loss agents include antihyperglycemic agents such as metformin, sulfonylureas (e.g., glimepiride, glipizide, and glyburide), meglitinides (e.g., repaglinide and nateglinide), thiazolidinediones (e.g., pioglitazone, rosiglitazone), dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g., sitagliptin, saxagliptin, and linagliptin), sodium-glucose cotransporter-2 (SGLT-2) inhibitors (e.g., empagliflozin, ertugliflozin, dapagliflozin, and canagliflozin), alpha-glucosidase inhibitors (e.g., acarbose and miglitol), bromocriptine, and colesevelam; glucagon-like peptide 1 (GLP- -98- 180092653.1Docket No.: 146316.8032.WO02 1) receptor agonists such as semaglutide (Ozempic®, Wegovy® and Rybelsus®), danuglipron, lotiglipron, orforglipron, exenatide (Byetta® an Bydureon®), liraglutide (Victoza® and Saxenda®), dulaglutide (Trulicity®), albiglutide (Tanzeum®), taspoglutide, and lixisenatide (Lyxumia® and Adlyxin®); glucose-dependent insulinotropic polypeptide (GIP) receptor agonists such as synthetic incretin hormone and long-acting GIP receptor agonists such as LY3537021; dual GLP-1 / GIP receptor agonists such as tirzepatide (Mounjaro™ and Zepbound™); GLP-1 / glucagon receptor coagonists such as efinopegdutide (MK-6024) and mazdutide; GLP-1 / GIP / glucagon receptor trifunctional agonists such as retatrutide; amylin agonists such as amylin hormone analogue; neuregulin 4 (NRG4) agonists; peptide YY analog agonists; patatin-like phospholipase domain- containing protein 3 (PNPLA3) siRNA; lipase inhibitors such as orlistat (Xenical or Alli); norepinephrine and dopamine reuptake inhibitors such as bupropion-naltrexone (Contrave®); antiepileptics such as phentermine-topiramate (Qsymia®); and melanocortin 4 (MC4) receptor agonists such as setmelanotide (Imcivree®).

[0256] In some embodiments, the weight loss agent is in a free base form. In other embodiments, the weight loss agent is in a salt form. Any salt form of the weight loss agent known in the art may be used in the methods described herein. For example, when the weight loss agent is a salt form of setmelanotide, it may be setmelanotide acetate.

[0257] In some embodiments, the pharmaceutical combination comprises one weight loss agent. In other embodiments, the pharmaceutical combination comprises two or more weight loss agents. In some embodiments in which the pharmaceutical combination comprises two or more weight loss agents, the two or more weight loss agents are from the same class of weight loss agents, e.g., the two or more weight loss agents are GLP-1 agonists. Alternatively, in some embodiments in which the pharmaceutical combination comprises two or more weight loss agents, each of the two or more weight loss agents are from a different class of weight loss agents, e.g., one weight loss agent is a GLP-1 agonist, another is a GIP agonist, and so on.

[0258] In some embodiments, the weight loss agent is selected from GLP-1 receptor agonists, GIP receptor agonists including long-acting GIP receptor agonists, a dual GLP- 1 / GIP receptor agonists, GLP-1 / glucagon receptor coagonists, GLP-1 / GIP / glucagon -99- 180092653.1Docket No.: 146316.8032.WO02 receptor trifunctional agonists, and melanocortin 4 (MC4) receptor agonists. In some embodiments, the weight loss agent is selected from GLP-1 receptor agonists, GIP receptor agonists, a dual GLP-1 / GIP receptor agonists, GLP-1 / glucagon receptor coagonists, and GLP-1 / GIP / glucagon receptor trifunctional agonists.

[0259] In some embodiments, the weight loss agent is a GLP-1 receptor agonist. In some embodiments, the weight loss agent is a peptide GLP-1 receptor agonist. In other embodiments, the weight loss agent is a small molecule GLP-1 receptor agonist. In some embodiments, the weight loss agent is a GLP-1 receptor agonist and is one or more of semaglutide (Ozempic® and Wegovy®), danuglipron, lotiglipron, orforglipron, exenatide (Byetta® an Bydureon®), liraglutide (Victoza® and Saxenda®), dulaglutide (Trulicity®), albiglutide (Tanzeum®), taspoglutide, and lixisenatide (Lyxumia®). In some embodiments, the GLP-1 receptor agonist is one or more of semaglutide (Ozempic®, Wegovy® and Rybelsus®), exenatide (Byetta® an Bydureon®), liraglutide (Victoza® and Saxenda®), dulaglutide (Trulicity®), albiglutide (Tanzeum®), and lixisenatide (Lyxumia® and Adlyxin®). In some embodiments, the GLP-1 receptor agonist is danuglipron. In some embodiments, the GLP-1 receptor agonist is lotiglipron. In some embodiments, the GLP-1 receptor agonist is orfoglipron. In some embodiments, the GLP-1 receptor agonist is taspoglutide. In some embodiments, the GLP-1 receptor agonist is semaglutide (e.g., Ozempic® or Wegovy®). In some embodiments, the GLP-1 receptor agonist is exenatide (Byetta® an Bydureon®). In some embodiments, the GPL-1 receptor agonist is liraglutide (Victoza® and Saxenda®). In some embodiments, the GLP-1 receptor agonist is dulaglutide (Trulicity®). In some embodiments, the GLP-1 receptor agonist is albiglutide (Tanzeum®). In some embodiments, the GLP-1 receptor agonist is lixisenatide (Lyxumia® and Adlyxin®).

[0260] In some embodiments, the GLP-1 receptor agonist is a compound of Formula (IV): , 180092653.1Docket No.: 146316.8032.WO02 or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; Y is N or CR4; n is 0 or 1; R is hydrogen; R1is —C1-C6 alkylene-R5; R2is hydrogen, oxo, or C1-C6 alkyl; R3is hydrogen, oxo, or C1-C6 alkyl and R4is hydrogen, OH, or C1-C6 alkyl; or R3and R4are taken together with the carbon atoms to which they are attached to form C3-C6 cycloalkyl optionally substituted by halo or C1-C3 alkyl; R5is 5-membered heterocyclyl or 5-membered heteroaryl, each of which comprises 1, 2, or 3 heteroatoms independently selected from O, N, and S, wherein at least one heteroatom of R5is S, and further wherein R5is optionally substituted by halo, —O—C1- 6 alkyl, C1-6 alkyl, C1-6 alkenyl, or C1-C6 haloalkyl; Ring A is 5- to 12-membered heterocyclyl or 5- to 12-membered heteroaryl, each of which is independently optionally substituted by halo, CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH; L is a bond, —O—, C1-C6 alkylene, *—O—C1-C6 alkylene-**, *—C1-C6 alkylene-O— **, or *—NR6—C1-C6 alkylene-**, wherein * represents the point of attachment to ring A and ** represents the point of attachment to ring B; when L is *—O—C1-C6 alkylene-**, the C1-C6 alkylene of L is optionally substituted by RL, wherein each RLis independently C1-C6 alkyl or halo, or two RLare taken together with the carbon atom or atoms to which they are attached to form C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl; and when L is C1-C6 alkylene, the C1-C6 alkylene is optionally substituted by RL1, wherein each RL1is independently halo, OH, oxo, or C1-C6 alkyl, or two RL1are taken -101- 180092653.1Docket No.: 146316.8032.WO02 together with the carbon atom or atoms to which they are attached to form C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl; R6is hydrogen or C1-C6 alkyl; and Ring B is C3-C10 cycloalkyl, C6-C14 aryl, 4- to 12-membered heterocyclyl, or 5- to 12- membered heteroaryl, each of which is independently optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1- C6 alkyl, C1-C6 haloalkyl, —COCH3, —CONH2, —S(O)2CH3, and phenyl.

[0261] In further embodiments, the GLP-1 receptor agonist is a compound of Formula (IVa):

[0001] ,R7is hydrogen, chloro, bromo, fluoro, methyl, or vinyl; and R8is:Docket No.: 146316.8032.WO02 . agonist is a compound of: .agonist is a compound of any one of Formulae (IV), (IVa), and (IVb), in the form of a salt. In some embodiments, the salt is a meglumine salt.

[0004] Various other GLP-1 receptor agonists which may be employed as a weight loss agent in the present technology include, but are not limited to, peptides and small molecules disclosed in WO2006 / 134340, WO2007 / 100535, WO2008 / 10101, WO2008 / 152403, WO2009 / 155257, WO2009 / 155258, WO2010 / 070252, WO2010 / 070253, WO2010 / 070255, WO2010 / 070251, WO2011 / 006497, WO2011 / 160630, WO2011 / 160633, WO2013 / 092703, WO2014 / 041195, WO2015 / 055802, WO2015149627, WO2015 / 155139, WO2015 / 155140, WO2015 / 155141, WO2015 / 155151, WO2015 / 193378, WO2015 / 193381, WO2016 / 0154014, WO2016 / 046753, US2022 / 0089578, and US2023 / 0150998, which are incorporated herein by reference in their entireties.

[0005] In some embodiments, the weight loss agent is a GIP receptor agonist, such as a long-acting GIP receptor agonist. In some embodiments, the weight loss agent is LY3537021. -103- 180092653.1Docket No.: 146316.8032.WO02

[0006] In other embodiments, the pharmaceutical combination comprises a first weight loss agent which is a long-acting GIP receptor agonist and a second weight loss agent which is a GLP-1 receptor agonist. The long-acting GIP receptor agonist may be LY3537021 and the GLP-1 receptor agonist may be any one of semaglutide (Ozempic® and Wegovy®), danuglipron, lotiglipron, orforglipron, exenatide (Byetta® an Bydureon®), liraglutide (Victoza® and Saxenda®), dulaglutide (Trulicity®), albiglutide (Tanzeum®), taspoglutide, and lixisenatide (Lyxumia®). In some embodiments, the GLP-1 receptor agonist is one or more of semaglutide (Ozempic®, Wegovy® and Rybelsus®), exenatide (Byetta® an Bydureon®), liraglutide (Victoza® and Saxenda®), dulaglutide (Trulicity®), albiglutide (Tanzeum®), and lixisenatide (Lyxumia® and Adlyxin®). In some embodiments, the first weight loss agent is LY3537021, and the second weight loss agent is liraglutide.

[0007] In some embodiments, the weight loss agent is a bifunctional or trifunctional GLP-1 agonist, e.g., a GLP-1 agonist that also has agonist activity at one or two other receptors. In some embodiments, the weight loss agent is a dual GLP-1 / GIP receptor agonist. In some embodiments, the weight loss agent is tirzepatide (Mounjaro™ and Zepbound™). In some embodiments, the weight loss agent is a dual GIP / GLP-1 receptor agonist of a Formula (II) Specific dual GLP-1 / GIP receptor agonists according to Formula (II) that may be used in the presently described combination therapy and methods are disclosed in US 2023 / 0293638, which is incorporated herein by reference in its entirety.

[0008] In some embodiments, the weight loss agent is a GLP-1 / glucagon receptor coagonist. In some embodiments, the weight loss agent is efinopegdutide or mazdutide. In some embodiments, the weight loss agent is a GLP-1 / GIP / glucagon receptor trifunctional agonist. In some embodiments, the weight loss agent is retatrutide.

[0009] In some embodiments, the weight loss agent is an MC4 receptor agonist. In some embodiments, the weight loss agent is setmelanotide (e.g., Imcivree®). Weight Loss Agent Combination Therapy Dosing

[0010] The present technology comprises combination therapies including the non- naturally occurring melanocortin analog and the weight loss agent in a single composition or as distinct compositions. For example, the weight loss agent may be present in a first -104- 180092653.1Docket No.: 146316.8032.WO02 pharmaceutical composition and the non-naturally occurring analog may be present in a second pharmaceutical composition. As will be described in more detail below, the first and second pharmaceutical compositions may be administered concurrently, sequentially, or cyclically. Alternatively, pharmaceutical combinations of the present technology may be formulated as a single pharmaceutical composition comprising a non-naturally occurring melanocortin analog and a weight loss agent.

[0011] In some embodiments of the combination therapy, the weight loss agent is present in a first pharmaceutical composition and the non-naturally occurring melanocortin analog is present in a second pharmaceutical composition. The weight loss agent may be formulated with one or more pharmaceutically acceptable carriers and / or excipients to form the first pharmaceutical composition. Similarly, the non-naturally occurring melanocortin analog may be formulated with one or more pharmaceutically acceptable carriers and / or excipients to form the second pharmaceutical composition. In some embodiments, the first and the second pharmaceutical compositions are different.

[0012] In some embodiments, the first pharmaceutical composition comprising the weight loss agent and the second pharmaceutical composition comprising the non-naturally occurring melanocortin analog are administered concurrently.

[0013] In other embodiments, the first pharmaceutical composition and the second pharmaceutical composition are administered sequentially. In sequential administration, the first pharmaceutical composition may be administered before the second pharmaceutical composition, after the second pharmaceutical composition, or both. Likewise, the second pharmaceutical composition may be administered before the first pharmaceutical composition, after the first pharmaceutical composition, or both.

[0014] In still other embodiments, the first pharmaceutical composition and the second pharmaceutical composition may be administered cyclically.

[0015] In some embodiments, the weight loss agent is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, the weight loss agent is present in the first pharmaceutical composition in a concentration of 0.001 -105- 180092653.1Docket No.: 146316.8032.WO02 mg / mL to 1,000 mg / mL, 0.005 mg / mL to 750 mg / mL, 0.01 mg / mL to 500 mg / mL, 0.05 mg / mL to 250 mg / mL, 0.1 mg / mL to 100 mg / mL, 0.2 mg / mL to 80 mg / mL, 0.3 mg / mL to 60 mg / mL, 0.4 mg / mL to 50 mg / mL, 0.5 mg / mL to 40 mg / mL, 0.5 mg / mL to 30 mg / mL, or 1 mg / mL to 30 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0016] In some embodiments, the weight loss agent is a GLP-1 receptor agonist and is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, the GLP-1 receptor agonist is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, 0.005 mg / mL to 750 mg / mL, 0.01 mg / mL to 500 mg / mL, 0.05 mg / mL to 250 mg / mL, 0.08 mg / mL to 50 mg / mL, 0.1 mg / mL to 50 mg / mL, 0.2 mg / mL to 10 mg / mL, 0.3 mg / mL to 8 mg / mL 0.5 mg / mL to 5 mg / mL, or 1 mg / mL to 3.5 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0017] In some embodiments, the weight loss agent is semaglutide and is present in the first pharmaceutical composition in a concentration of 0.5 mg / mL to 5.0 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, semaglutide is present in the first pharmaceutical composition in a concentration of 0.5 mg / mL to 5.0 mg / mL, 0.5 mg / mL to 4.0 mg / mL, 0.6 mg / mL to 3.5 mg / mL, 0.65 mg / mL to 3.2 mg / mL, 0.65 mg / mL to 3.0 mg / mL, 0.8 mg / mL to 2.8 mg / mL, 1.0 mg / mL to 3.0 mg / mL, 1.0 mg / mL to 2.8 mg / mL, 1.2 mg / mL to 3.0 mg / mL, 1.2 mg / mL to 2.8 mg / mL, 0.6 mg / mL to 2.3 mg / mL, 0.6 mg / mL to 2.0 mg / mL, 0.6 mg / mL to 1.8 mg / mL, 0.6 mg / mL to 1.5 mg / mL, or 1.3 mg / mL to 2.8 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, semaglutide is present in the first pharmaceutical composition in a concentration of about 0.68 mg / mL, 1 mg / mL, 1.34 mg / mL, 2.0 mg / mL, 2.26 mg / mL, 2.68 mg / mL, or 3.2 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0018] In some embodiments, the weight loss agent is Ozempic®. In some embodiments, the weight loss agent is Wegovy®.

[0019] In some embodiments, the weight loss agent is semaglutide and is present in the first pharmaceutical composition in an amount of about 0.5 mg to about 40 mg. In some embodiments, semgalutide is present in the first pharmaceutical composition in an amount of 0.5 mg to 40 mg, 0.5 mg to 30 mg, 1 mg to 30 mg, 0.5 mg to 20 mg, 1 mg to 20 mg, 2 mg -106- 180092653.1Docket No.: 146316.8032.WO02 to 20 mg, 0.5 mg to 15 mg, 1 mg to 15 mg, 2 mg to 15 mg, 3 mg to 15 mg, 5 mg to 15 mg, 0.5 mg to 10 mg, 1 mg to 10 mg, or 5 mg to 10 mg. In some embodiments, semaglutide is present in the first pharmaceutical composition in an amount of about 3 mg or less, 7 mg or less, or 14 mg or less.

[0020] In some embodiments, the weight loss agent is Rybelsus®.

[0021] In some embodiments, the weight loss agent is exenatide and is present in the first pharmaceutical composition in a concentration of 5 µg / mL to 1000 µg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, exenatide is present in the first pharmaceutical composition in a concentration of 5 µg / mL to 1000 µg / mL, 10 µg / mL to 900 µg / mL, 20 µg / mL to 800 µg / mL, 50 µg / mL to 700 µg / mL, 70 µg / mL to 600 µg / mL, 90 µg / mL to 550 µg / mL, 100 µg / mL to 500 µg / mL, 110 µg / mL to 450 µg / mL, 120 µg / mL to 400 µg / mL, 130 µg / mL to 350 µg / mL, 140 µg / mL to 350 µg / mL, 150 µg / mL to 300 µg / mL, 200 µg / mL to 300 µg / mL, or 200 µg / mL to 250 µg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, exenatide is present in the first pharmaceutical composition in a concentration of about 250 µg / mL, relative to a total volume of the first pharmaceutical composition.

[0022] In some embodiments, the weight loss agent is Byetta®.

[0023] In some embodiments, the weight loss agent is exenatide and is present in the first pharmaceutical composition in a concentration of 0.1 mg / mL to 5.0 mg / mL, 0.25 mg / mL to 4.5 mg / mL, 0.5 mg / mL to 4.5 mg / mL, 0.75 mg / mL to 4.0 mg / mL, 1.0 mg / mL to 3.75 mg / mL, 1.25 mg / mL to 3.5 mg / mL, 1.5 mg / mL to 3.25 mg / mL, 1.75 mg / mL to 3.0 mg / mL, 2.0 mg / mL to 2.75 mg / mL, or 2.25 mg / mL to 2.5 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, exenatide is present in the first pharmaceutical composition in a concentration of about 2.35 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0024] In some embodiments, the weight loss agent is Bydureon®.

[0025] In some embodiments, the weight loss agent is dulaglutide and is present in the first pharmaceutical composition in a concentration of 0.01 mg / mL to 100 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, dulaglutide is -107- 180092653.1Docket No.: 146316.8032.WO02 present in the first pharmaceutical composition in a concentration of 0.01 mg / mL to 100 mg / mL, 0.05 mg / mL to 90 mg / mL, 0.1 mg / mL to 80 mg / mL, 0.2 mg / mL to 70 mg / mL, 0.3 mg / mL to 60 mg / mL, 0.5 mg / mL to 50 mg / mL,0.6 mg / mL to 45 mg / mL, 0.7 mg / mL to 40 mg / mL, 0.8 mg / mL to 35 mg / mL, 0.9 mg / mL to 30 mg / mL, 1.0 mg / mL to 25 mg / mL, 1.1 mg / mL to 20 mg / mL, 1.2 mg / mL to 15 mg / mL, or 1.5 mg / mL to 10 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, dulagultide is present in the first pharmaceutical composition in a concentration of about 1.5 mg / mL, 3.0 mg / mL, 6.0 mg / mL, or 9.0 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0026] In some embodiments, the weight loss agent is Trulicity®.

[0027] In some embodiments, the weight loss agent is orforglipron and is present in the first pharmaceutical composition in an amount of about 0.01 mg to about 100 mg. In some embodiments, orforglipron is present in the first pharmaceutical composition in an amount of 0.01 mg to 100 mg, 0.05 mg to 90 mg, 0.1 mg to 80 mg, 0.2 mg to 70 mg, 0.3 mg to 60 mg, 0.4 mg to 50 mg, 0.5 mg to 45 mg, 0.6 mg to 40 mg, 0.7 mg to 35 mg, 0.8 mg to 30 mg, 0.9 mg to 25 mg, 1.0 mg to 20 mg, 1.1 mg to 18 mg, 1.2 mg to 16 mg, 1.3 mg to 14 mg, 1.4 mg to 12 mg, or 1.5 mg to 10 mg. In some embodiments, orforglipron is present in the first pharmaceutical composition in an amount of about 2 mg or less, 4 mg or less, 5 mg or less, 6 mg or less, 8 mg or less, 12 mg or less, 16 mg or less, or 24 mg or less.

[0028] In some embodiments, the weight loss agent is a long-acting GIP receptor agonist and is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, the long-acting GIP receptor agonist is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, 0.01 mg / mL to 750 mg / mL, 0.05 mg / mL to 500 mg / mL, 0.1 mg / mL to 250 mg / mL, 0.5 mg / mL to 100 mg / mL, 1 mg / mL to 90 mg / mL, 1.5 mg / mL to 80 mg / mL, 2 mg / mL to 70 mg / mL, 2.5 mg / mL to 60 mg / mL, 3 mg / mL to 50 mg / mL, 3.5 mg / mL to 45 mg / mL, 4 mg / mL to 40 mg / mL, 4.5 mg / mL to 35 mg / mL, or 5 mg / mL to 30 mg / mL, relative to a total volume of the first pharmaceutical composition. -108- 180092653.1Docket No.: 146316.8032.WO02

[0029] In some embodiments, the weight loss agent is a dual GLP-1 / GIP receptor agonist and is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, the dual GLP-1 / GIP receptor agonist is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, 0.01 mg / mL to 750 mg / mL, 0.05 mg / mL to 500 mg / mL, 0.1 mg / mL to 250 mg / mL, 0.5 mg / mL to 100 mg / mL, 1 mg / mL to 90 mg / mL, 1.5 mg / mL to 80 mg / mL, 2 mg / mL to 70 mg / mL, 2.5 mg / mL to 60 mg / mL, 3 mg / mL to 50 mg / mL, 3.5 mg / mL to 45 mg / mL, 4.0 mg / mL to 40 mg / mL, 4.5 mg / mL to 35 mg / mL, or 5 mg / mL to 30 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0030] In some embodiments, the weight loss agent is tirzepatide and is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, tirzepatide is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, 0.01 mg / mL to 750 mg / mL, 0.05 mg / mL to 500 mg / mL, 0.1 mg / mL to 250 mg / mL, 0.5 mg / mL to 100 mg / mL, 1 mg / mL to 90 mg / mL, 1.5 mg / mL to 80 mg / mL, 2 mg / mL to 70 mg / mL, 2.5 mg / mL to 60 mg / mL, 3 mg / mL to 50 mg / mL, 3.5 mg / mL to 45 mg / mL, 4.0 mg / mL to 40 mg / mL, 4.5 mg / mL to 35 mg / mL, or 5 mg / mL to 30 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, tirzepatide is present in the first pharmaceutical composition in a concentration of about 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, or 30 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0031] In some embodiments, the weight loss agent is Mounjaro™. In some embodiments, the weight loss agent is Zepbound™.

[0032] In some embodiments, the weight loss agent is a GLP-1 / glucagon receptor coagonist and is present in the first pharmaceutical composition in an amount of about 0.5 mg to about 50 mg. In some embodiments, the GLP-1 / glucagon receptor coagonist is present in the first pharmaceutical composition in an amount of 0.5 mg to 50 mg, 1 mg to 50 mg, 5 mg to 50 mg, 0.5 mg to 40 mg, 1 mg to 40 mg, 5 mg to 40 mg, 0.5 mg to 30 mg, 1 mg to 30 mg, 5 mg to 30 mg, 0.5 mg to 20 mg, 1 mg to 20 mg, 2 mg to 20 mg, 5 mg to 20 mg, -109- 180092653.1Docket No.: 146316.8032.WO02 0.5 mg to 15 mg, 1 mg to 15 mg, 2 mg to 15 mg, 3 mg to 15 mg, 5 mg to 15 mg, 0.5 mg to 10 mg, 1 mg to 10 mg, or 5 mg to 10 mg.

[0033] In some embodiments, the weight loss agent is mazdutide and is present in the first pharmaceutical composition in an amount of about 0.5 mg to about 50 mg. In some embodiments, mazdutide is present in the first pharmaceutical composition in an amount of 0.5 mg to 50 mg, 1 mg to 50 mg, 5 mg to 50 mg, 0.5 mg to 40 mg, 1 mg to 40 mg, 5 mg to 40 mg, 0.5 mg to 30 mg, 1 mg to 30 mg, 5 mg to 30 mg, 0.5 mg to 20 mg, 1 mg to 20 mg, 2 mg to 20 mg, 5 mg to 20 mg, 0.5 mg to 15 mg, 1 mg to 15 mg, 2 mg to 15 mg, 3 mg to 15 mg, 5 mg to 15 mg, 0.5 mg to 10 mg, 1 mg to 10 mg, or 5 mg to 10 mg. In some embodiments, mazdutide is present in the first pharmaceutical composition in an amount of about 5 mg or less, 6 mg or less, 7 mg or less, 8 mg or less, 9 mg or less, or 10 mg or less.

[0034] In some embodiments, the weight loss agent is a GLP-1 / GIP / glucagon receptor trifunctional agonist and is present in the first pharmaceutical composition in an amount of about 0.5 mg to about 50 mg. In some embodiments, the GLP-1 / GIP / glucagon receptor trifunctional agonist is present in the first pharmaceutical composition in an amount of 0.5 mg to 50 mg, 1 mg to 50 mg, 5 mg to 50 mg, 0.5 mg to 40 mg, 1 mg to 40 mg, 5 mg to 40 mg, 0.5 mg to 30 mg, 1 mg to 30 mg, 5 mg to 30 mg, 0.5 mg to 20 mg, 1 mg to 20 mg, 2 mg to 20 mg, 5 mg to 20 mg, 0.5 mg to 15 mg, 1 mg to 15 mg, 2 mg to 15 mg, 3 mg to 15 mg, 5 mg to 15 mg, 0.5 mg to 10 mg, 1 mg to 10 mg, or 5 mg to 10 mg.

[0035] In some embodiments, the weight loss agent is retatrutide and is present in the first pharmaceutical composition in an amount of about 0.5 mg to about 50 mg. In some embodiments, retatrutide is present in the first pharmaceutical composition in an amount of 0.5 mg to 50 mg, 1 mg to 50 mg, 5 mg to 50 mg, 0.5 mg to 40 mg, 1 mg to 40 mg, 5 mg to 40 mg, 0.5 mg to 30 mg, 1 mg to 30 mg, 5 mg to 30 mg, 0.5 mg to 20 mg, 1 mg to 20 mg, 2 mg to 20 mg, 5 mg to 20 mg, 0.5 mg to 15 mg, 1 mg to 15 mg, 2 mg to 15 mg, 3 mg to 15 mg, 5 mg to 15 mg, 0.5 mg to 10 mg, 1 mg to 10 mg, or 5 mg to 10 mg. In some embodiments, retatrutide is present in the first pharmaceutical composition in an amount of about 0.5 mg or less, 1.5 mg or less, 3 mg or less, 6 mg or less, 9 mg or less, or 12 mg or less. -110- 180092653.1Docket No.: 146316.8032.WO02

[0036] In some embodiments, the weight loss agent is an MC4 receptor agonist and is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, the MC4 receptor agonist is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, 0.01 mg / mL to 900 mg / mL, 0.05 mg / mL to 800 mg / mL, 0.1 mg / mL to 700 mg / mL, 0.5 mg / mL to 600 mg / mL, 1 mg / mL to 500 mg / mL, 2.5 mg / mL to 400 mg / mL, 5 mg / mL to 300 mg / mL, 7.5 mg / mL to 200 mg / mL, 10 mg / mL to 100 mg / mL, 25 mg / mL to 90 mg / mL, or 50 mg / mL to 75 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0037] In some embodiments, the weight loss agent is setmelanotide, and setmelanotide is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, setmelanotide is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, 0.005 mg / mL to 500 mg / mL, 0.01 mg / mL to 250 mg / mL, 0.05 mg / mL to 100 mg / mL, 0.1 mg / mL to 80 mg / mL, 0.5 mg / mL to 60 mg / mL, 1 mg / mL to 50 mg / mL, 2 mg / mL to 40 mg / mL, 2.5 mg / mL to 35 mg / mL, 3 mg / mL to 30 mg / mL, 3.5 mg / mL to 25 mg / mL, 4 mg / mL to 20 mg / mL, 4.5 mg / mL to 20 mg / mL, or 5 mg / mL to 15 mg / mL, relative to a total volume of the first pharmaceutical composition. In some embodiments, setmelanotide is present in the first pharmaceutical composition in a concentration of about 10 mg / mL, relative to a total volume of the first pharmaceutical composition. Pharmacokinetics and Pharmacodynamics

[0038] 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.

[0039] In some embodiments, the pK and / or pD of the non-naturally occurring melanocortin analogs may be assessed using concentration and / or temporal measurements -111- 180092653.1Docket No.: 146316.8032.WO02 (e.g., Tfinal, Cmax, T ½ (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. Clearance

[0040] “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 (λz) or an inter-compartmental clearance (Q).

[0041] 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.

[0042] 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. Concentration

[0043] In some embodiments, the non-naturally occurring melanocortin analogs of the present technology comprise an increased tissue, plasma, and / or serum 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. -112- 180092653.1Docket No.: 146316.8032.WO02

[0044] 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).

[0045] 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).

[0046] 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).

[0047] In some embodiments, the increased concentration is reflected by a reduction in time to reach Cmax (Tmax). A reduced Tmax may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control.

[0048] In some embodiments, the increased concentration is reflected by a final measurable concentration (Tfinal). An increased Tfinal may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control.

[0049] 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 -113- 180092653.1Docket No.: 146316.8032.WO02 analogs, relative to a control. The AUC measurement may comprise an Area Under the Curve for Concentration of Drug in Non-Compartmental Analysis (DNAUC).

[0050] 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.

[0051] 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.

[0052] 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.

[0053] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement during administration of the non-naturally occurring melanocortin analogs.

[0054] 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.

[0055] 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.

[0056] In some embodiments, the non-naturally occurring melanocortin analog is administered to the subject until the concentration of the non-naturally occurring -114- 180092653.1Docket No.: 146316.8032.WO02 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. Distribution

[0057] 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. -115- 180092653.1Docket No.: 146316.8032.WO02

[0058] In some embodiments, the measurement of distribution comprises measuring a volume of distribution at the terminal phase (Vd or Vdß), a central volume of distribution (V), a peripheral volume of distribution (V2), an apparent volume of distribution (Vz), or a measurement of distribution comprises measuring a volume of distribution at steady state (Vss). A high or increased Vd, Vdß, Vz, and / or Vss may suggest large distribution beyond the tissue, plasma, and / or serum compartment, relative to the control.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] In some embodiments, the increase in distribution comprises a measurement during administration of the non-naturally occurring melanocortin analogs.

[0063] In some embodiments, the increase in distribution comprises a measurement at the completion of administration of the non-naturally occurring melanocortin analogs. Additional pD and pK Embodiments

[0064] In some embodiments, the non-naturally occurring melanocortin analog of the present technology exhibits one or more of the following: (a) an increase in half-life relative to a control; (b) a reduction in clearance relative to a control; (c) an increase in tissue concentration relative to a control; -116- 180092653.1Docket No.: 146316.8032.WO02 (d) an increase in plasma concentration relative to a control; (e) an increase in serum concentration relative to a control; (f) an increase in distribution relative to a control; (g) an increase in an AUC measurement relative to a control; (h) an increase in a DNAUC measurement relative to a control; (i) an increase in Tfinal relative to a control; (j) an increase in Cmax relative to a control; (k) an increase in Cmin relative to a control; (l) an increase in DNCmin relative to a control; (m) an increase in MRT relative to a control; (n) an increase in Cavg relative to a control; (o) an increase in Ctrough relative to a control; (p) an increase in CT relative to a control; (q) an increase in Vd relative to a control; (r) a reduction in Tmax relative to a control; or (s) a reduction in Q relative to a control.

[0065] In some embodiments, the non-naturally occurring melanocortin analog of the present technology exhibits one or more of the following, relative to a control: (a) an increase in half-life by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (b) a reduction in clearance by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to a control; -117- 180092653.1Docket No.: 146316.8032.WO02 (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; (d) an increase in plasma concentration by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (e) an increase in serum concentration by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (f) an increase in distribution by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (g) an increase in an AUC by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% measurement relative to a control; (h) an increase in a DNAUC measurement by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (i) an increase in Tfinal by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (j) an increase in Cmax by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (k) an increase in Cmin by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; -118- 180092653.1Docket No.: 146316.8032.WO02 (l) an increase in DNCmin by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (m) an increase in MRT by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (n) an increase in Cavg by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (o) an increase in Ctrough by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (p) an increase in CT by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (q) an increase in Vd by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (r) a reduction in Tmax by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to a control; or (s) a reduction in Q by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to a control. EXAMPLES

[0066] 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 -119- 180092653.1Docket No.: 146316.8032.WO02 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

[0067] The non-naturally occurring melanocortin analogs of the present technology were synthesized by conventional procedures (e.g., solution-phase procedure, solid-phase synthesis) for the formation of a peptide linkage between amino acids. The solution-phase procedure involved a condensation between the free alpha amino group of an amino acid or derivative thereof having the carboxyl group or other reactive groups protected and the free primary carboxyl group of another amino acid or derivative thereof having the amino group or other reactive groups protected. The solid-phase synthesis utilized a variety of resins and reagents and may involve additional purification steps.

[0068] 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.

[0069] 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.

[0070] 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 -120- 180092653.1Docket No.: 146316.8032.WO02 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 amide bond between the carboxyl group of the amino acid and a reactive handle on the solid-phase resin For example, an amino acid residue may be coupled to a benzhydrylamine (BHA) resin through an Fmoc-linker such as, for example, p- [(R,S)-α-[1-(9H-fluor-en-9-yl)-methoxyformamido]-2,4-dimethyloxybenzyl]-phenoxyacetic acid (Rink linker) via an amide linkage.

[0071] 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

[0072] 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.

[0073] 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 -121- 180092653.1Docket No.: 146316.8032.WO02 place at that site. Specific protecting groups for solid phase synthesis methods and solution phase synthesis methods are known to those having ordinary skill in the art. Alpha amino groups were protected by a suitable protecting group, including a urethane-type protecting group, such as benzyloxycarbonyl (Z) and substituted benzyloxycarbonyl, such as p- chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p- biphenyl-isopropoxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc) and p- methoxybenzyloxycarbonyl (Moz); aliphatic urethane-type protecting groups, such as t- butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropoxycarbonyl, and allyloxycarbonyl. Fmoc was also used for alpha amino protection. Guanidino groups, if present, were protected by a suitable protecting group, such as nitro, p-toluenesulfonyl (Tos), Z, pentamethylchromanesulfonyl (Pmc), adamantyloxycarbonyl, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) and Boc. Pmc was used as a protecting group for Arg.

[0074] 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

[0075] 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.

[0076] Additionally, the cyclized peptide structures were obtained prior to cleavage from the peptide resin. For cyclization through reactive side chain moieties, the desired side chains were deprotected, and the peptide suspended in a suitable solvent and a cyclic coupling agent added. Suitable solvents, for example DMF, dichloromethane (DCM) or 1- methyl-2-pyrrolidone (NMP), were used for the cyclization. Suitable cyclic coupling reagents (e.g., 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H- benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), benzotriazole- -122- 180092653.1Docket No.: 146316.8032.WO02 1-yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole-1-yl- oxy-tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP), 2-(7-aza-1H-benzotriazol- 1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TATU), 2-(2-oxo-1 (2H)-pyridyl)-1,1,3,3- tetramethyluronium tetrafluoroborate (TPTU), N,N′-dicyclohexylcarbodiimide / 1- hydroxybenzotriazole (DCCl / HOBt)) were also used for the cyclization. Coupling was initiated by a suitable base, such as N,N-diispropylethylamine (DIPEA), sym-collidine or N- methylmorpholine (NMM). Example 4: Biological Data

[0077] The agonist and antagonist activity of exemplary non-naturally occurring melanocortin analogs at the melanocortin receptors (e.g., MC1R, MC3R, MC4R, and MC5R) were measured via cAMP accumulation assay, according to the following procedure. Experimental design and execution were conducted by Epics Therapeutics S.A. EuroscreenFast (Bruxelles, Belgium). Compound Handing

[0078] Compounds were delivered as powder (1 mg) or 10 mM solutions (100 μl) in 100% DMSO. Powders were solubilized in 100% DMSO at a concentration of 10 mM (master solution) in a solvent volume defined. Serial dilutions were performed from master solution in 100% DMSO to obtain intermediate concentrations 200-, 300- or 400-fold higher than the concentrations to be tested, depending on the assay. Each sample was diluted 100- fold in the assay buffer and dispensed in a test plate. Amounts, solvents, and dilutions were estimated based on standard small-molecule drugs. Cell lines used for functional assays are shown in Table 1. Table 1. Cell lines Receptor Cell Line Reference agonist Reference t-123- 180092653.1Docket No.: 146316.8032.WO02 Compound Testing

[0079] Compounds were tested for (i) agonist and / or antagonist activity at the human MC3 (FAST-0232C) and MC4 (FAST-0233C) receptors, (ii) agonist activity at the human MC1 (FAST-0230C) receptor, and / or (iii) agonist activity at the human MC5 (FAST-0233C) receptor at the following nanomolar concentrations, in duplicate: 0.0001, 0.001, 0.01, 0.03, 0.1, 0.3, 1, 10, 100, and 1,000. Testing Protocol

[0080] Cyclic AMP (cAMP) Homogenous Time-Resolved Fluorescence (HTRF) assay for Gs coupled receptor:

[0081] CHO-K1 cells expressing recombinant human receptor grown prior to the test in media without antibiotic were detached by gentle flushing with PBS-EDTA (5 mM EDTA), recovered by centrifugation and resuspended in assay buffer (KRH: 5 mM KCl, 1.25 mM MgSO4, 124 mM NaCl, 25 mM HEPES, 13.3 mM Glucose, 1.25 mM KH2PO4, 1.45 mM CaCl2, 0.5 g / l BSA, supplemented with 1mM IBMX or 25μM Rolipram).

[0082] Dose response curves were performed in parallel with the reference compounds.

[0083] For agonist test (384well): 5 μl of cells were mixed with 5 μl of the test compound at increasing concentrations and then incubated 30 min at room temperature. After addition of the lysis buffer containing cAMP-d2 and anti-cAMP cryptate detection reagents, plates were incubated 1-hour at room temperature, and fluorescence ratios were measured according to the manufacturer specification, with the HTRF kit.

[0084] For antagonist test (384well): 5 μl of cells were mixed in the wells of an assay plate with 5 μl of a mix of test compound at increasing concentrations and reference agonist for a final concentration corresponding to the historical EC80. The plates were then incubated 30 min at room temperature. After addition of the lysis buffer containing cAMP-d2 and anti-cAMP cryptate detection reagents, plates were incubated 1-hour at room temperature, and fluorescence ratios were measured according to the manufacturer specification, with the HTRF kit. -124- 180092653.1Docket No.: 146316.8032.WO02 Quality Control for Compound Testing

[0085] 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.

[0086] Reference values thus obtained for the test were compared to historical values obtained from the same receptor and used to validate the experimental session.

[0087] 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.

[0088] 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

[0089] Group A included non-naturally occurring melanocortin analogs A1 to A3, all of which are cyclic peptides comprising the motif Pro-dPhe-Arg-Trp (SEQ ID NO: 353) or Pro- Phe-Arg-Trp (SEQ ID NO: 358) and cyclized through a lactam bond between Asp and Lys. Group A non-naturally occurring melanocortin analogs are provided in Table 2. Table 2. Group A non-naturally occurring melanocortin analogs Melanocortin SEQ ID Sequence analo NOl of which are cyclic peptides comprising the motif Pro-dPhe-Arg-Trp (SEQ ID NO: 353) and cyclized through a lactam bond between Asp and Lys. Group B melanocortin analogs include an N-terminal extension. Group B non-naturally occurring melanocortin analogs are provided in Table 3. Table 3. Group B non-naturally occurring melanocortin analogs Melanocortin SEQ ID Se uence-125- 180092653.1Docket No.: 146316.8032.WO02 A1 53 Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 2 - allof which are cyclic peptides comprising the motif Pro-dPhe-Arg-Trp (SEQ ID NO: 353) and cyclized through a lactam bond between Asp and Lys. Group C melanocortin analogs include an N-terminal amino acid other than Nle. Group C non-naturally occurring melanocortin analogs are provided in Table 4. Table 4. Group C non-naturally occurring melanocortin analogs Melanocortin SEQ ID Sequence analog NO-126- 180092653.1Docket No.: 146316.8032.WO02 C18 187 Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 -all of which are cyclic peptides comprising a derivative of the motif Pro-dPhe-Arg-Trp (SEQ ID NO: 353) and cyclized through a lactam bond between Asp and Lys. Derivatives of the motif of SEQ ID NO: 353 included in Group D melanocortin analogs include substitution of Pro for another amino acid. Group D non-naturally occurring melanocortin analogs are provided in Table 5. Table 5. Group D non-naturally occurring melanocortin analogs Melanocortin SEQ ID Se uence-127- 180092653.1Docket No.: 146316.8032.WO02 D4 10 Ac-Nle-c[Asp-APC-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2, l of which are cyclic peptides comprising a derivative of the motif Pro-dPhe-Arg-Trp (SEQ ID NO: 353) and cyclized through a lactam bond between Asp and Lys. Derivatives of the motif of SEQ ID NO: 353 included in Group E melanocortin analogs include substitution of Arg for another amino acid or substitution of Trp for another amino acid. Group E non-naturally occurring melanocortin analogs are provided in Table 6. Table 6. Group E non-naturally occurring melanocortin analogs Melanocortin SEQ ID --128- 180092653.1Docket No.: 146316.8032.WO02 E2 13 Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2l of which are cyclic peptides comprising the motif Pro-dPhe-Arg-Trp (SEQ ID NO: 353) and cyclized through a lactam bond between Asp and Lys. Group F melanocortin analogs include a C-terminal extension other than dVal-dPro. Group F non-naturally occurring melanocortin analogs are provided in Table 7. Table 7. Group F non-naturally occurring melanocortin analogs Melanocortin SEQ ID Sequence l N-129- 180092653.1Docket No.: 146316.8032.WO02 F1350 Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2F14-130- 180092653.1Docket No.: 146316.8032.WO02 F43184 Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 F44185 Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2l of which are cyclic peptides comprising a derivative of the motif Pro-dPhe-Arg-Trp (SEQ ID NO: 353) and cyclized through a lactam bond between Asp and Lys. Group G melanocortin analog include a Pro or Gly after the Trp residue. Group G non-naturally occurring melanocortin analogs are provided in Table 8. Table 8. Group G non-naturally occurring melanocortin analogs Melanocortin SEQ ID Sequence -

[0096] Group H included non-naturally occurring melanocortin analogs H1 to H5, all of which are cyclic peptides comprising a derivative of the motif Pro-dPhe-Arg-Trp (SEQ ID -131- 180092653.1Docket No.: 146316.8032.WO02 NO: 353) and cyclized through a disulfide bond. Group H non-naturally occurring melanocortin analogs are provided in Table 9. Table 9. Group H non-naturally occurring melanocortin analogs Melanocortin SEQ ID analog NO Sequenceof which are cyclic peptides comprising a derivative of the motif Trp-Pro-dPhe-Arg-Trp (SEQ ID NO: 354) or a derivative thereof. Derivatives of the motif of SEQ ID NO: 354 may include substitution of Trp for another amino acid or substitution of Pro for another amino acid. Group I non-naturally occurring melanocortin analogs are provided in Table 10. Table 10. Group D non-naturally occurring melanocortin analogs Melanocortin SEQ ID Sequence-132- 180092653.1Docket No.: 146316.8032.WO02 I13 110Ac-Nle-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2222, of which are cyclic peptides comprising a derivative of the motif Ala-His-dPhe-Arg-Trp (SEQ ID NO: 355) or a derivative thereof. Derivatives of the motif of SEQ ID NO: 355 may include substitution of Ala for another amino acid, for example dAla. Group J non-naturally occurring melanocortin analogs are provided in Table 11. Table 11. Group J non-naturally occurring melanocortin analogs Melanocortin SEQ ID S-133- 180092653.1Docket No.: 146316.8032.WO02 J3 230Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-NH2l ofwhich are cyclic peptides comprising a derivative of the motif Phe-His-dPhe-Arg-Trp (SEQ ID NO: 356). Group K non-naturally occurring melanocortin analogs are provided in Table 12. Table 12. Group K non-naturally occurring melanocortin analogs Melanocortin SEQ ID Sequence analog NO o-l of which are cyclic peptides comprising a derivative of the motif His-p(Cl)dPhe-Arg-Trp (SEQ ID NO: 357), or a derivative thereof. Derivatives of the motif of SEQ ID NO: 357 may include substitutions of His for another amino acid, for example, Aba, Aia, and Ata, or substitutions of p(Cl)dPhe for another amino acid, for example, p(Br)dPhe. Group L non-naturally occurring melanocortin analogs are provided in Table 13. Table 13. Group L non-naturally occurring melanocortin analogs Melanocortin SEQ ID Sequence-134- 180092653.1Docket No.: 146316.8032.WO02 L8 28 Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal- 2 2 2all of which are cyclic peptides comprising a derivative of the motif Pro-p(F)dPhe-Arg-Trp (SEQ ID NO: 359), or a derivative thereof. Derivatives of the motif of SEQ ID NO: 359 may include substitutions of Pro for another amino acid, for example, His, dGln, and dTyr, or substitutions of Trp for another amino acid, for example, dNal(2’). Group M non-naturally occurring melanocortin analogs are provided in Table 14. Table 14. Group M non-naturally occurring melanocortin analogs Melanocortin SEQ ID Se uence 2-135- 180092653.1Docket No.: 146316.8032.WO02 M5 68Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2222o--136- 180092653.1Docket No.: 146316.8032.WO02

[0102] Group O included non-naturally occurring melanocortin analogs O1, O2, O7, O11, all of which are cyclic peptides comprising the motif Pro-dPhe-Arg-Trp (SEQ ID NO: 353) or Pro-p(F)dPhe-Arg-Trp (SEQ ID NO: 359), and are cyclized through a lactam bond between Asp or Glu and Orn. Group O non-naturally occurring melanocortin analogs are provided in Table 15. Table 15. Group O non-naturally occurring melanocortin analogs Melanocortin SEQ ID Sequence analog NO

[0103] Administration of some non-naturally occurring melanocortin analogs activated melanocortin 1 receptor (MC1R) and / or melanocortin 5 receptor (MC5R) activity, as measured by cAMP levels (Table 16). Table 16. Dose-response results of melanocortin analogs and control against the melanocortin 1 receptor (MC1R) and melanocortin 5 receptor (MC5R) MC1R MC5R n-137- 180092653.1Docket No.: 146316.8032.WO02 193 C19 0.58 101.44 1.58 102.54 195 C20 8.77 101.34 51.43 100.24-138- 180092653.1Docket No.: 146316.8032.WO02 221 D21 0.01 103.06 0.02 104.44 142 D12 0.03 100.86 0.28 100.84-139- 180092653.1Docket No.: 146316.8032.WO02 118 I21 2.08 102.23 27.61 101.25 119 I22 2.31 102.04 45.73 103.66-140- 180092653.1Docket No.: 146316.8032.WO02 72 M9 0.49 100.42 0.35 102.49 73 M10 0.01 100.40 0.01 103.78-141- 180092653.1Docket No.: 146316.8032.WO02 33 L12 0.01 102.27 0.18 103.84 34 L13 0.01 101.88 0.08 102.90-142- 180092653.1Docket No.: 146316.8032.WO02 183 F42 0.18 101.47 0.53 103.92 51 F14 0.03 102.57 0.10 103.54-143- 180092653.1Docket No.: 146316.8032.WO02 136 F30 0.07 101.38 0.45 101.42 38 F4 0.02 101.95 0.13 102.11 Agonist activity of melanocortin analogs on melanocortin 3 and 4 receptors -144- 180092653.1Docket No.: 146316.8032.WO02

[0104] 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 17). Table 17. Dose-response results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) MC3R MC4R M x M x n-145- 180092653.1Docket No.: 146316.8032.WO02 159 C17 11.92 20.65 0.74 103.53 202 H4 — n.c. — 2.78 86.97-146- 180092653.1Docket No.: 146316.8032.WO02 101 I4 — n.c. — 589.92 100.00 102 I6 — n.c. — 1.61 100.03-147- 180092653.1Docket No.: 146316.8032.WO02 141 K2 4.18 69.29 0.24 103.06 225 K4 4.42 62.02 0.27 100.60-148- 180092653.1Docket No.: 146316.8032.WO02 231 M31 344.26 100.00 1.69 100.23 93 M21 — n.c. — 134.09 89.34-149- 180092653.1Docket No.: 146316.8032.WO02 138 F32 — n.c. — 1.06 95.09 146 F34 — n.c. — 0.69 93.12-150- 180092653.1Docket No.: 146316.8032.WO02 203 F51 — n.c. — 1.05 95.26 59 F19 4.20 21.20 0.76 92.22-151- 180092653.1Docket No.: 146316.8032.WO02 165 C34 — n.c. — 0.27 102.96 40 A2 6.30 36.37 0.27 97.54 n.Antagonist activity of melanocortin analogs on melanocortin 3 or 4 receptor

[0105] 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 18). Table 18. Dose-response results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) MC3R MC4R n-152- 180092653.1Docket No.: 146316.8032.WO02 156 C15 309.36 81.42 — n.c. — 181 F40 49.90 82.70 — n.c. —-153- 180092653.1Docket No.: 146316.8032.WO02 191 D18 — n.c. — — n.c. — 192 D19 — n.c. — — n.c. —-154- 180092653.1Docket No.: 146316.8032.WO02 115 I18 — n.c. — — n.c. — 116 I19 — n.c. — — n.c. —-155- 180092653.1Docket No.: 146316.8032.WO02 71 M8 153.54 93.16 — n.c. — 20 M2 15.10 81.16 — n.c. —-156- 180092653.1Docket No.: 146316.8032.WO02 29 L9 1.21 56.49 — n.c. — 30 L10 4.80 61.69 — n.c. —-157- 180092653.1Docket No.: 146316.8032.WO02 49 F12 55.62 83.59 — n.c. — 50 F13 48.28 82.75 — n.c. —-158- 180092653.1Docket No.: 146316.8032.WO02 133 F27 — n.c. — — n.c. — 134 F28 — n.c. — — n.c. —-159- 180092653.1Docket No.: 146316.8032.WO02 n.c. = not calculated Comparison of agonist and antagonist activity of O7 and O11 to similar melanocortin analogs

[0106] To determine the impact that certain features of the melanocortin analogs of the present technology had on agonist activity at the different melanocortin receptors, the agonist and antagonist activity of O7 and O11 was compared to the agonist and antagonist activity of similar sequences. Specifically, O7 and O11 were compared to sequences with different lactam cyclization types, different residues at the R4and R3positions, and different C-terminal residues. The agonist and antagonist activity of O7 and comparative sequences is provided in Table 19 and Table 20 and the agonist and antagonist activity of O11 and comparative sequences is provided in Table 21 and 22. Table 19. Agonist activity of O7 and melanocortin analogs with point mutations relative to O7 MC3R MC4R Feature Sequence SEQ EC50 Max EC50 Max n-160- 180092653.1Docket No.: 146316.8032.WO02 MC3R MC4R Feature Sequence SEQ ID NO EC50 Max EC50 Max nTable 21. Agonist activity of O11 and melanocortin analogs with point mutations relative to O11 MC3R MC4R F t S SEQ n-161- 180092653.1Docket No.: 146316.8032.WO02 Ac-Nle-c[Glu-Pro-dPhe- Arg-Trp-Lys]-dVal-dPro- 367 3.941 42 0.235 98 NH211 MC3R MC4R F t SEQ n-162- 180092653.1Docket No.: 146316.8032.WO02 Ac-Nle-c[Asp-Pro-dPhe- Arg-Trp-Lys]-dVal-dPro- 31 21.116 81 n.c. NH2, , 11 clearly impacts the agonism on MC3R, however, the cyclization does not appear to have the same impact on agonism of MC4R and antagonism of MC3R and MC4R. Even more stark is the difference in agonism / antagonism of MC3R and MC4R observed when p(F)dPhe or dPhe is substituted for a larger residue, such as p(Br)dPhe or p(I)dPhe. For example, SEQ ID NOs: 216 and 218, which have smaller p(F)dPhe and dPhe at the R4position, are full agonists on MC4R, whereas SEQ ID NOs: 249 and 364, which have larger p(Br)dPhe and p(I)dPhe at the R4position, are full antagonists on MC4R. Additionally, a substantial change in agonist activity on the MC3 receptor was observed when His was substituted for Pro at position R3in the melanocortin analogs. Specifically, SEQ ID NOs: 216 and 218, which have Pro at R3, exhibited moderate binding and partial agonism on MC3R, whereas SEQ ID NOs: 326 and 363, which have His at R3, exhibited strong binding and full agonism on MC3R. -163- 180092653.1Docket No.: 146316.8032.WO02 Residual binding of melanocortin analogs on melanocortin 1 receptor

[0108] The residual binding of some of the non-naturally occurring melanocortin analogs was measured on the melanocortin 1 receptor (MC1R) by RLB assay (Table 23). Table 23. Dose-response binding results of melanocortin analogs and control against the melanocortin 1 receptor (MC1R) Synthetic Max Residual EC50 (nM)* Hill Top (%) Pe tide Bindin % Coefficient Re

[0109] The residual binding of some of the non-naturally occurring melanocortin analogs was measured on the melanocortin 3 receptor (MC3R) by RLB assay (Table 24). Table 24. Dose-response binding results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) Synthetic Max Residual EC50 (nM)* Hill Top (%) Re

[0110] The residual binding of some of the non-naturally occurring melanocortin analogs was measured on the melanocortin 4 receptor (MC4R) by RLB assay (Table 25). -164- 180092653.1Docket No.: 146316.8032.WO02 Table 25. Dose-response binding results of melanocortin analogs and control against the melanocortin 4 receptor (MC4R) Synthetic Max Residual EC50 (nM)* Hill Top (%) Peptide Binding % Coefficient Re

[0111] The residual binding of some of the non-naturally occurring melanocortin analogs was measured on the melanocortin 5 receptor (MC5R) by RLB assay (Table 26). Table 26. Dose-response binding results of melanocortin analogs and control against the melanocortin 5 receptor (MC5R) Synthetic Max Residual EC50 (nM)* Hill Top (%) Ag

[0112] The agonist activity of some of the non-naturally occurring melanocortin analogs was measured on GPR54 by Aequorin assay. Results from this assay are provided in Table 27. Table 27. Dose-response results of melanocortin analogs and control against GPR54 Synthetic Max EC50 (nM)* Hill Top (%)-165- 180092653.1Docket No.: 146316.8032.WO02 LY2112688 trifluoroacetate 1.75 >2000 - - An

[0113] The antagonist activity of some of the non-naturally occurring melanocortin analogs was measured on GPR54 by Aequorin assay. Results from this assay are provided in Table 28. Table 28. Dose-response results of melanocortin analogs and control against GPR54 Synthetic Max IC50 (nM)* Hill Top (%) Ag

[0114] The agonist activity of some of the non-naturally occurring melanocortin analogs was measured on QRFP by Aequorin assay. Results from this assay are provided in Table 29. Table 29. Dose-response results of melanocortin analogs and control against QRFP Synthetic Max EC50 (nM)* Hill Top (%)-166- 180092653.1Docket No.: 146316.8032.WO02 O11 1.57 >2000 - - An

[0115] The antagonist activity of some of the non-naturally occurring melanocortin analogs was measured on QRFP by Aequorin assay. Results from this assay are provided in Table 30. Table 30. Dose-response results of melanocortin analogs and control against QRFP Synthetic Max IC50 (nM)* Hill Top (%) P tid I hibiti % C ffi i t Ag

[0116] The agonist activity of some of the non-naturally occurring melanocortin analogs was measured on PrRP by Aequorin assay. Results from this assay are provided in Table 31. Table 31. Dose-response results of melanocortin analogs and control against PrRP Synthetic Max EC50 (nM)* Hill Top (%) An-167- 180092653.1Docket No.: 146316.8032.WO02

[0117] The antagonist activity of some of the non-naturally occurring melanocortin analogs was measured on PrRP by Aequorin assay. Results from this assay are provided in Table 32. Table 32. Dose-response results of melanocortin analogs and control against PrRP Synthetic Max IC50 (nM)* Hill Top (%) Peptide Inhibition % Coefficient Ag

[0118] The agonist activity of some of the non-naturally occurring melanocortin analogs was measured on NPFF2S by Aequorin assay. Results from this assay are provided in Table 33. Table 33. Dose-response results of melanocortin analogs and control against NPFF2S Synthetic Max EC50 (nM)* Hill Top (%) An

[0119] The antagonist activity of some of the non-naturally occurring melanocortin analogs was measured on NPFF2S by Aequorin assay. Results from this assay are provided in Table 34. -168- 180092653.1Docket No.: 146316.8032.WO02 Table 34. Dose-response results of melanocortin analogs and control against NPFF2S Synthetic Max IC50 (nM)* Hill Top (%) Peptide Inhibition % Coefficient Ag

[0120] The agonist activity of some of the non-naturally occurring melanocortin analogs was measured on NPY1 by cAMP assay. Results from this assay are provided in Table 35. Table 35. Dose-response results of melanocortin analogs and control against NPY1 Synthetic Max EC50 (nM)* Hill Top (%) An

[0121] The antagonist activity of some of the non-naturally occurring melanocortin analogs was measured on NPY1 by cAMP assay. Results from this assay are provided in Table 36. Table 36. Dose-response results of melanocortin analogs and control against NPY1 Synthetic Max IC50 (nM)* Hill Top (%)-169- 180092653.1Docket No.: 146316.8032.WO02 Agonist activity on NPFF1

[0122] The agonist activity of some of the non-naturally occurring melanocortin analogs was measured on NPFF1 by cAMP assay. Results from this assay are provided in Table 37. Table 37. Dose-response results of melanocortin analogs and control against NPFF1 Synthetic Max EC50 (nM)* Hill Top (%) Pe tide Activation % Coefficient An

[0123] The antagonist activity of some of the non-naturally occurring melanocortin analogs was measured on NPFF1 by cAMP assay. Results from this assay are provided in Table 38. Table 38. Dose-response results of melanocortin analogs and control against NPFF1 Synthetic Max IC50 (nM)* Hill Top (%)Example 5: Pharmacokinetic Assessment of Non-Naturally Occurring Melanocortin Analogs Following Oral Administration to Rats and Cynomolgus Monkeys Study Objective

[0124] The objective of this study is to determine the pharmacokinetics of non-naturally occurring melanocortin analogs of the present technology following oral gavage administration in male rats and single oral administration to non-naïve male cynomolgus monkeys. In rats, the test article will be monitored in plasma for up to 24 hours post each -170- 180092653.1Docket No.: 146316.8032.WO02 dose. Study design and sample collection will be conducted as outlined in Table 39 and Table 40. -171- 180092653.120 OetW.2308.613641:.o Ntekco D te gra T n igste e Dgry a d T utS.9 3 leba Tdnuop mo C B D D B B B D D D D D D D D D N 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 su s llu s g u olglga y o o m e ye ye1.3 mio k m n o k m n o k 5 nt t t t t t t t62 n ny o ny o ny o a a a a a a a atatatata 90 A C M C M C M R R R R R R R R R R R R 08120 OW.C C 2 S S 308.6136 e n e 4 ini1l:.als as olalNt ica giceklog l cioo oioioioioi ioo s D y s s s s s s h y p h y y y y y p h p h p h p h p h p)r4 h P P P P P P P P 1 3 1 1 1 33 3 3 3 3 3 3 A A A A A A A 38*0.P PC / P P P P P 0 P e)g g ask / 0 0 1 3 0 5 0 0 o g 1 3 1 1 3 6 F F F F F F F Dm(3 3 3 3 3 3 6 su s pulgy u o elgyet t t t trk o k a ato m n m n a a a a G o o R R R R R R n o o n1.3 atatatatataty M M 5 t y 6 a C C 290 R R R R R R R 081Docket No.: 146316.8032.WO02 E: Anticoagulant: Potassium (K2) EDTA; P: plasma C: cerebrospinal fluid *Sampled only for certain compounds

[0125] Dose Solution Analysis Samples: After each dose preparation, remove approximately 0.5 mL aliquots from the formulations, transfer the aliquots into amber HPLC vials and stored at -60°C or lower until assayed in duplicate for dose validation.

[0126] Disposition of Remaining Test Article Formulations: Remaining formulations will be stored at -60°C or lower.

[0127] Disposition of Remaining Test Article (dry powder or solid): Remaining test article will be stored at room temperature desiccated, and protected from light until shipment or discard.

[0128] Animals will be fasted overnight through 4 hours post dosing. Vehicle and Formulation Preparation:

[0129] Appropriate amount of test article will be accurately weighed and mixed with appropriate volume of vehicle to get a clear solution or suspension.

[0130] Formulation samples will be removed from each of the formulation solutions, transferred into 1.5 mL of polypropylene microcentrifuge tubes and run dose validation by LC / UV or LC-MS / MS.

[0131] Compounds to be assessed are outlined in Table 41. Table 41. Compounds Compound Animal MW Exact Purity Storage FW ( / mol) CF n-174- 180092653.1Docket No.: 146316.8032.WO02 B (M1) Cynomolgus 1198.41 1258.46 N / A 95 N / A -20°C MonkeysAnimal Specifications: Cynomolgus Monkeys

[0132] Cynomolgus Monkey specifications are outlined in Table 42. Table 42. Cynomolgus Monkey Specifications Species Cynomolgus Monkeys K in e or al ff g-175- 180092653.1Docket No.: 146316.8032.WO02 Selected animals will be acclimated at the Acclimation Period testing facility prior to the study.

[0133] Environmental Conditions: Environment controls will be set to maintain a temperature range of 20-26°C, a relative humidity range of 40 to 70%, and a 12-hour light / 12-hour dark cycle. The light / dark cycle may be interrupted for study-related activities.

[0134] Housing: Animals will be group-housed (up to four animals / sex / cage) in polysulfone cages with certified aspen shaving bedding or corncob bedding during acclimation and study period. While animals may be individually housed after surgery or when there is special requirement in protocol, as well as, for behavioral or health reasons or due to cage mate death.

[0135] Diet and Feeding: Animals were offered certified rodent breeding and growth diet ad libitum every day, unless fasted for study procedures. Each lot of the diet is analyzed for nutrients, chemical contaminant and microorganisms, the results are reviewed and evaluated by veterinarians before provided to animals.

[0136] Drinking Water: Autoclaved RO (reverses osmosis) water will be available to all animals, ad libum.

[0137] Feed and Water Analyses: Autoclaved RO water will be provided ad libitum via water bottle. Water samples are periodically analyzed by a certified laboratory for specified microorganisms and environment contaminants. The diet is routinely analyzed by the manufacturer for specified microorganisms, nutritional components and environmental contaminants.

[0138] Environmental Enrichment: Enrichment toys will be provided.

[0139] Dose Administration: The dose volume will be determined by the animals' body weight collected on the morning of dosing day. Animal Specifications: Rats

[0140] Rat specifications are outlined in Table 43. -176- 180092653.1Docket No.: 146316.8032.WO02 Table 43. Rat Specifications Species Rat Strain SD in o e e is Observ

[0141] Clinical Observations: All animals will be observed at dosing and each scheduled collection. All abnormalities will be recorded.

[0142] Body Weight: All animals will be weighed on the dosing day prior to dosing to determine the dose volume to be administered. Sample Collection and Processing

[0143] Blood Sample Collection and Process: At least 0.1 mL blood will be collected at each time point. All blood samples will be collected via jugular vein. All blood samples will be transferred into low binding EP tube with anticoagulant (0.5 M Potassium (K2) EDTA will be pre-added as a ratio of 50:1 for blood: anticoagulant), 0.05% Triton X-100 (e.g., 100uL Blood+2uL 2.5% Triton X-100) will be used for desorption the blood samples will be placed on wet ice. -177- 180092653.1Docket No.: 146316.8032.WO02

[0144] Blood samples will be centrifuged within 1hr of collection at 3,200 g 4°C for 10 minutes. Following centrifugation, plasma samples will be transferred into their respective pre-labeled low binding EP tube and immediately frozen over dry ice. The plasma samples will be stored lower than -60°C until bioanalysis.

[0145] LC-MS / MS method development:

[0146] A LC-MS / MS method for the quantitative determination of test compound in biological matrix will be developed.

[0147] N in 1 cassette LC-MS / MS method may be developed for samples coming from different studies as long as these studies belong to the same sponsor.

[0148] Cassette administration assay could be performed if the mass difference (ΔMass) among different analytes is ≥4 Da. In this case, interference evaluation is not necessary.

[0149] If ΔMass among different analytes is less than 4 Da, there is a potential risk that interference would occur during LC-MS / MS analysis. If such kind of cassette assay is still requested by client, interference among analytes will not be evaluated but the LC separation of those analytes by using a generic method will be attempted.

[0150] Sample analysis:

[0151] A calibration curve with at least 6 non-zero calibration standards will be applied for each batch including LLOQ.

[0152] If sample number within a batch is ≤ 12, at least one set of standard curve separated with two parts through begin and end of the sequence should be included in the run and QCs are not required. The recommended injection order is C8, C6, C4, C2, study samples, C7, C5, C3, C1.

[0153] If sample number within a batch is > 12, one standard curve and two sets of QCs with low, middle and high concentrations will be applied for bioanalysis. Meanwhile, QCs number should be more than 5% of study sample number. -178- 180092653.1Docket No.: 146316.8032.WO02

[0154] Samples, coming from one client with the same type of matrix in different studies, are allowed to be quantified in one analysis run by using the developed N in 1 cassette LC-MS / MS method.

[0155] Acceptance criteria:

[0156] (1) Linearity: At least 75% of the calibration standards should fall within ±20% of their nominal values for biofluid and within ±25% of their nominal values for tissue and feces samples. If the endpoints, such as LLOQ and ULOQ, on the calibration curve are eliminated, the calibration curve will be truncated. The truncated calibration curve should consist of at least 75% of the initial STDs.

[0157] (2) Accuracy: At least 67% of QCs should fall within ±20% of their nominal values for biofluid and within ±25% of their nominal values for tissue and feces samples. At least half of QCs at each concentration should be passed.

[0158] (3) Specificity: The mass response of analyte in the double blank and blank should be ≤ 50% LLOQ.

[0159] (4) Sensitivity: The LLOQ will be tried to target ≤ 3 ng / mL. Any adjustment of LLOQ will be informed to client in advance.

[0160] (5) Carryover: The mean calculated carryover peak area in the double blanks or blanks immediately after the highest standard injection should be less than that of LLOQ. If the carryover couldn’t meet the criteria, the impact of the carryover on unknown samples should be re-evaluated according to the below procedure:

[0161] Carryover should be re-evaluated based on absolute carryover. Absolute carryover is calculated by carryover contribution multiplies carryover impact, where the carryover contribution is calculated by the area ratio of the double blank or blank with the highest carryover (Area max of carryover blank) to the ULOQ with the minimum calculated value (Area min of ULOQ), and the carryover impact is calculated by the area ratio of one injection (Area of one injection) to the following injection (Area of the following injection). The absolute carryover should be below the acceptable accuracy of the studies (e.g., 20% or 25%). -179- 180092653.1Docket No.: 146316.8032.WO02

[0162] Carryover contribution = Areamax of carryover blank / Areamin of ULOQ Carryover impact = Area of one injection / Area of the following injection Absolute carryover = Carryover contribution * Carryover impact Data Analysis

[0163] Plasma concentration versus time data for Compounds A-C in Rats and Cynomolgus Monkeys will be plotted in graph and analyzed by non-compartmental approaches. Related PK parameters will be calculated according to dosing route, e.g., Cl, Vdss and C0 for intravenous administration, Cmax, Tmax or %F for extravascular administration, and T½, AUC(0-t), AUC(0-inf), MRT(0-t), MRT(0-inf) for all routes. Preliminary plasma results after 24 hours for 60 mg / kg oral administration in Rats and 30mg / kg of Compounds A-C in Cynomolgus Monkeys are shown in Table 44 and FIG.1. Table 44. Plasma Pharmacokinetic Results of Compounds A-C after 24 hours 30 mg / kg PO plasma Cynomolgus Com- 60 mg / kg PO plasma Rat Data 24 h M k t 24 h / 2 ) 13C) in Cynomolgus Monkeys was plotted in graphs and analyzed by non-compartmental approaches. Related PK parameters were calculated according to dosing route, e.g., Cl, Vdss and C0 for intravenous administration, Cmax, Tmax or %F for extravascular administration, and T½, AUC(0-t), AUC(0-inf), MRT(0-t), MRT(0-inf) for all routes. Preliminary plasma results after 24 hours of 3 mg / kg, 10 mg / kg, 30 mg / kg, or 60 mg / kg PO administration of Compound D (Ac- -180- 180092653.1Docket No.: 146316.8032.WO02 Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; O7) in Cynomolgus Monkeys are shown in Table 45. Table 45. Plasma Pharmacokinetic Results of Compound (O7) in Cynomolgus Monkeys after 24 hours Dose Cmax AUC0-lastAUC0-infMRT Comp. Tmax T1 / 2 MRT0- AUCEX AUMCEX (mg / kg (ng / mL Tfinal (ng.h / mL (ng.h / mL0-infofadministration of Compound D (Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; O7) and Compound F (Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2) in Rats are shown in Table 46 and Table 47. Graphs of plasma concentration and CSF concentration in Rats are shown in FIGS 3A-3D (SC administration), FIGS. 4A-4D (IP administration), and FIGS.5A-5C (PO administration).

[0166] Plasma and CSF concentrations over 24 hours after administration of Compound D (O7) or setmelanotide were also assessed (FIGS.4H-4K). It was predicted -181- 180092653.120 X n O E w CW.M 23 U 0 A8.6 X 1 E 3 C 64sU A1ru:.o ohfni-N 4 0t2 T erR k e ctM ofDasttsa al-0 R T inR ) M 7 O(fniD-0 d C.n U g 70 88 40 51 18 231.32.5DCh.m 7 d u An(1 3 1 1 4 1 2 35 11 d U g D 2 D o n An(N 5ap u Nlmt ) )es o al- C 0 f C o U s A ltuse2 / R 1 c T itelh ina - 0 h 1 0 h c -1-6 ita O e nifh h D(- k nifh h0 h4 h4 h h h4 - 0 0D2 o T 6 1 2 2 4 6 h h hinT 1 1 N d 8 c 2 4 4 8 k n1a o - c x u mrxa 7 0 0 7 33 0 05 38 38 a a)0 0 op ah m)h6.0.0.4.8.0.2.5.0.mrm Th(0.80.D 2 N mo P T(1 2 2 0 0 1 0 0 0 ah aP)Cfm)s x L F x Lolaam / 7 1 S am / 1 4 9 7 19.0.m g6.y 9 DtilP m g . Cn(92 0 8 1 3 2 1 9 3 7 6 6 3 065.9 22 4 C 9.Cn7(23 11 N an 64io4in ein ettrlemt leu o d uo C b md o C P d p b C C a A R S S SPIPIPIO O O P P P a T A R SPIO eorT )) in pmes.g gro 0 esk / esk / etD5- o g o g 0 0 0 0 0m(0 0 0 ed 8 Dm(1 3 1 1 3 1 1 3 6 D 1 1 6t4s p e.o p eN] le 1.3 m 7 b 5 a 62 o ma mo ma=61 90 C N D D D D D D D D D C N D D D DT0 N0[ in812f0oshPIOts p(W.al-2 0 3 C 0 U8.A 61 n 3 o 6it4 a1 rt:. isoina 6 77 66 art lua a 0 0rt lua da rtNtmdVts 6 8 0is V02 21 18is Vn 1 a5ise a 03 / 1 / ts 1ints5.5.5. inka l-1 / 5 5ina1 / 4 / a 9 Clec C o DSleg insaretfastxtfReRe a a 0 7 6axtat9 6 7fxafstG8 0aaIR m4.3.6.stm5.6.6.am8 8.1 FniC 3 1 4 C 4 7 1stC.2 11.4 slt RniEdn aDsdnuopmofC C efa -]s nif s o oit0 3 a0 0 oe oi0 3oe oi0 0iny n - o D R.33. .3 0 y 1tilsota a D R0.33.0.3 0 y 1ts ilot0 a D R0.30.60.psL- o 2it38 yorpra1ti n an bT-rt -laiontr io ergrne iotr )otro e g 0 o0.0 0 0 p 0or )g 0 0 0 p o)c A- c g0.0.0.d e n h o c pk / g 1.1.3P k / 0.0.0. rg 1 1 3k / 0 0 0 n g 1 1 3 P F orm e mPe ma da - S P(s sr r ro(sr r rso(sr r rmorCe e s s ev ev ev D.es ev ev ev D es ev ev e sP- d vlp n o o O O O 9 o.oas Da.D8er4lDO O O 0DO O Ope er5 e yrA[no 4 alerp b ap b ap ac-le ita le.0.a m 00T m 00 0a m0 0 0in N rtb o0.0 0 o0. .0.0 T o. . .mil -c n a C 3 1 1 C 3 1 1 C 03 06 06 Tee r A P(cn.)F o no d d dc itn n d n a a u u nurtop e op e op e]uo mis 1.3 8 p si56 mo ma mo ma mo ma 6la n2 1 m 9 o p m 0 C N D D D C N D D D C N D D D0[Cfo d 0 a 8120 avytOiliW.2308.613641:.o e.tm c Nitn r o ek e C c v o DostF a S R C f oF 4 D D2S 2 N N.D D 7 N N7.1 niR(ts0.2.6.0.1.4.F Mla3 3 5 1 1 1 C d d nfL 7 5 n n ah 4.9.3 57 D D4.ui-0m / 7 a 6 5 2 6 5 4 ms lapniFdnuop mo Cfo noitarto n5.0 52 63 63 86 71 25 h h eC P (c a a xa 3 3 n m h m 0 0 7 6 7 6 3 3 3 5 o s 5 7 9 m. . . .8.7.Cal2.82 30 47 41 66 2 s 6laT 1 1 2 0 0 0 . 1 P 0 2 3 2 7 1 4 P 5) . )L leg 2 xam / 9 7 42 8 1 b ek / 5lem g Cn(13 46 3 3 1 4 7 7 7 9 1 5 a s T o g 5 Dm(1 3 01 1 3 0 b 1 a Tin emtu nietd d o A R C C CPIP Pm u e S S SI Id onie A R C C CkS S SPIPIPImre s / to g Dm( )0 0 e g 1 3 1 1 3 1 . dt .1.p e o p e 35 m mn6 m m 2 o a=o a 90 C N F F F F F F D 0 N C N F F F F F F 8120 E O C M)W.U 23 A 0 E8).C 6 U 1 A 36 -041T)46:.R h(f4.D o Min0 N Nt-e 0 T)h 7 k(ot8 c R M s la 3.D 0 N D fn L i-0m / Ch.3 U g 6 D An( )11 N t)sa L l-0m / Ch.8 U g 04.An(11 71 i m / )lL g k3.Cm( / n 41 - s)g 9 sk / 9 d VL(3.0 - 2 / 2 1)5 Th(3.D - 0 N 68 l1- anif0 T5.0 15.1 xa m)Th( -5.0 ) x L am / m g0.Cn( -12 ) 0 L Cm / d g 4 e n(32in3 -mrete a dt1.o 3 m 5 s 6 l FN2 a S=90 P C D 0 N 81Docket No.: 146316.8032.WO02

[0171] FIG. 9 illustrates the average plasma concentration of Compound F over time in rats following SC, IP, and IV bolus administration. Plasma Concentration

[0172] Plasma pharmacokinetic measurements using 30 mg / kg were assessed in Cynomolgus monkey plasma up to 24 hours. Results are detailed in Table 57. Table 57: Pharmacokinetic Data Compound30 mg / kgName PO Cynomolgus Monkey

[0173] The antagonist activity of exemplary non-naturally occurring melanocortin analogs at specific ion channels was measured using the Qube electrophysiological platform. The non-naturally occurring melanocortin analogs and specific ion channel targets are provided in Table 58. Table 58. Ion channel targets and melanocortin analogs Melanocortin Ion channel targets MW + Saly Condition-187- 180092653.1Docket No.: 146316.8032.WO02 Voltage-Gated Potassium: CHO- Dry powder O2 1183.63 hERG

[0174] The non-naturally occurring melanocortin analogs identified above were tested for antagonist activity at various ion channels at concentrations ranging from 0.1 µM to 30 µM. In each experiment and if applicable, the respective reference compounds were tested concurrently with the test compounds, and the data were compared with known historical values. hNav1.5 Sodium Channel Assay – Qube APC

[0175] Onset and steady state block of peak Nav1.5 current is measured using a pulse pattern, repeated every 5 sec, consisting of a hyperpolarizing pulse to -120mV for a 200ms duration, depolarization to -15mV amplitude for a 40ms duration, followed by step to 40mV for 200ms and finally a 100ms ramp (1.2 V / s) to a holding potential of -80mV. Peak current is measured during the step to -15mV.

[0176] The parameters measured were difference between the peak inward current on stepping to -15mV (i.e., peak of the current) and the leak current. All data were filtered for seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition and the amount of block was assessed by dividing the Test compound current amplitude by the Control current amplitude. Control is the mean Nav1.5 current amplitude collected 10 seconds at the end of the vehicle control; Test Compound is the mean Nav1.5 current amplitude collected 10 seconds at the end of test concentration application for each concentration. hKv4.3 / hKChIP2 Potassium Channel Assay – Qube APC

[0177] After whole cell configuration is achieved, the cells are held at -80mV. Onset and steady state block of hKv4.3 current is measured using a pulse pattern from -80mV to 40mV amplitude for a 110ms duration, and finally a 100ms ramp (1.2 V / s) to -80mV. This paradigm is delivered once every 5s to monitor the current amplitude. -188- 180092653.1Docket No.: 146316.8032.WO02

[0178] The parameters measured were the maximum outward current evoked on stepping to 40mV from holding potential of -80mV. All data were filtered for seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition and the amount of block was assessed by dividing the Test compound current amplitude by the Control current amplitude. Control data is the mean Kv4.3 / KChIP2 current amplitude collected 10 seconds at the end of the vehicle control period; Test compound data is the mean Kv4.3 / KChIP2 current amplitude collected 10 seconds at the end of test concentration application for each concentration. hCav1.2 (L-type) CiPA Calcium Channel Assay – Qube APC

[0179] Onset and steady state block of peak hCav1.2 current is measured using a pulse pattern, repeated every 15 sec. Cells were held at -80mV for a 50ms before stepping to -90mV for 100ms to measure leak current and then stepped back to -80mV for 50ms, depolarization to 0mV amplitude for a 40ms duration, followed by step to 40mV for 200ms and finally a 100ms ramp (1.2 V / s) to a holding potential of -80 mV. Peak current is measured during the step to 0mV. Each concentration is applied for 5 minutes.

[0180] The calcium current amplitude is calculated by measuring the difference between the peak inward current on stepping to 0mV or the peak inward current at the ramp (i.e. peak of the current) and the leak current. The calcium current is assessed in vehicle control conditions and at the end of each five (5) minute compound application. hNav1.5 Late Current Sodium Channel Assay – Qube APC

[0181] Onset and steady state block of Late Nav1.5 current is measured using a pulse pattern, repeated every 5 sec, consisting of a hyperpolarizing pulse to -120mV for a 200ms duration, depolarization to -15mV amplitude for a 40ms duration, followed by step to 40mV for 200ms and finally a 100ms ramp (1.2 V / s) to a holding potential of -80mV. Late current is measured as charge current elicited during the ramp with 50nM ATXII.

[0182] The parameters measured were the ramp current charge (AUC) evoked on ramping back to -80mV from 40mV test pulse in the presence of 50nM ATXII. All data were filtered for seal quality, seal drop, and current. The peak and ramp current amplitude was calculated before and after compound addition and the amount of current was assessed by -189- 180092653.1Docket No.: 146316.8032.WO02 dividing the Test compound current by the Control current. Control data is the mean hNav1.5 late current collected 15 seconds at the end of 50nM ATXII application (50nM ATXII control); Test compound data is the mean ramp hNav1.5 current collected 15 seconds at the end of test concentration application for each concentration. hERG Potassium Channel Assay - Qube APC

[0183] After whole cell configuration is achieved, the cells are held at -80mV. Cells are held at this voltage for 50ms to measure the leak current, which is subtracted from the tail current on-line. The cells are depolarized to +40mV for 500ms and then to -80 mV over a 100ms ramp to elicit the hERG tail current. This paradigm is delivered once every 8s to monitor the current amplitude. All compounds were tested in the presence of 0.1% Pluronic F-68 Non-Ionic Surfactant and at approximately room temperature.

[0184] The parameters measured were the maximum tail current evoked ramping back to -80mV from the test pulse of 40mV. All data were filtered for seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition and the amount of block was assessed by dividing the Test compound current amplitude by the Control current amplitude. Control data is the mean hERG current amplitude collected for three pulses (24 seconds) at the end of the vehicle control; Test compound data is the mean hERG current amplitude collected for three pulses (24 seconds) at the end of test concentration application for each concentration. hKCNQ1 / hminK Potassium Channel Assay – Qube APC

[0185] After whole cell configuration is achieved, the cells are held at -80mV. KCNQ1 / minK currents are evoked by a 1000ms pulse from -80mV to 60mV followed by a ramp from 60mV to -80mV over 115ms with the outward peak currents measured upon depolarization of the cell membrane. This paradigm is delivered once every 15s to monitor the current amplitude.

[0186] The parameters measured were the maximum outward current evoked on stepping to +60mV from a holding potential of -80mV. All data were filtered for seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition and the amount of block was assessed by dividing the Test -190- 180092653.1Docket No.: 146316.8032.WO02 compound current amplitude by the Control current amplitude. Control data is the mean hKCNQ1 / hminK current amplitude collected 30 seconds at the end of vehicle control period; Test compound data is the mean hKCNQ1 / hminK current amplitude collected 30 seconds at the end of test concentration application for each concentration. hKir2.1 Potassium Channel Assay – Qube APC

[0187] After whole cell configuration is achieved, the cells are held at -30mV. Kir2.1 currents are evoked by a single 500ms pulse to -120mV before returning to the holding potential of -30mV. This paradigm is delivered once every 20s to monitor the current amplitude.

[0188] The parameters measured were the maximum inward current elicited on stepping to -120mV for 500ms from a holding potential of -30 mV. All data were filtered for seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition. Residual non-Kir2.1 current was eliminated via normalization to residual current after application of 100uM Barium Chloride. The amount of Test compound effect was then assessed by dividing the Test compound current amplitude by the Control current amplitude. Control data is the mean Kir2.1 current amplitude collected 40 seconds at the end of the vehicle control; Test compound data is the mean Kir2.1 current amplitude collected 30 seconds at the end of test concentration application for each concentration. Results

[0189] Where presented, IC50 values were determined by a non-linear, least squares regression analysis. Reference standards were run as an integral part of each assay to ensure the validity of the results obtained. Results from the ion channel assessment of non- naturally occurring melanocortin analogs are provided in Table 59. Table 59. Dose-response results of melanocortin analogs and reference compounds against ion channels. Compound Ion channel target Max Estimated IC50-191- 180092653.1Docket No.: 146316.8032.WO02 Flecainide Kv4.3 / ChIP2 96.97 7.60 Nifedipine Cav1.2 88.16 0.127Example 7: Assessment of physical biological properties of non-naturally occurring melanocortin analogs

[0190] Physical biological properties including solubility, in vitro absorption and in vitro metabolism of nine exemplary non-naturally occurring melanocortin analogs were assessed according to the following procedures. In each experiment and if applicable, the respective reference compound was tested concurrently with the test compounds, and the data were compared with known values. Stock solutions of the tested compounds were prepared at a concentration of 0.01M in DMSO. Solution Properties

[0191] Solution properties of non-naturally occurring melanocortin analogs and reference compounds in various biological media were assessed according to the conditions provided in Table 60. -192- 180092653.1Docket No.: 146316.8032.WO02 Table 60. Assay conditions for in vitro absorption assessment Assay Technique Incubation Detection Method Aqueous solubility (simulated shake-flask 24h RT HPLC-UV / Vis

[0192] Aqueous solubility (μM) was determined by comparing the peak area of the principal peak in a calibration standard (200 μM) containing organic solvent (methanol / water, 60 / 40, v / v) with the peak area of the corresponding peak in a buffer sample. In addition, chromatographic purity (%) was defined as the peak area of the principal peak relative to the total integrated peak area in the HPLC chromatogram of the calibration standard. A chromatogram of the calibration standard of each test compound, along with a UV / VIS spectrum with labeled absorbance maxima, was generated.

[0193] A chromatogram of the test compound (200 μM) along with a UV / VIS spectrum with labeled absorbance maxima, was generated. Protein Binding

[0194] The peak areas of the test compound in the buffer and test samples were used to calculate percent binding and recovery according to the following formulas: Protein binding(%) = ((Areap-Areab) / Areap) x 100 -193- 180092653.1Docket No.: 146316.8032.WO02 Recovery(%) = ((Areap-Areab) / Areac) x 100 where: Areap = peak area of analyte in protein matrix; Areab = peak area of analyte in buffer; and Areac = peak area of analyte in control sample. Partition Coefficient

[0195] The total amount of compound was determined as the peak area of the principal peak in a calibration standard (100 μM) containing organic solvent (methanol / water, 60 / 40, v / v). The amount of compound in buffer was determined as the combined, volume-corrected, and weighted areas of the corresponding peaks in the aqueous phases of three organic- aqueous samples of different composition. An automated weighting system was used to ensure the preferred use of raw data from those samples with well quantifiable peak signals. The amount of compound in organic was calculated by subtraction. Subsequently, Log D was calculated as the Log10 of the amount of compound in the organic phase divided by the amount of compound in the aqueous phase. Half-Life Determination

[0196] 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.

[0197] Results of the solubility assessment detailed above are provided in Tables 61- 64. Table 61. Protein binding of melanocortin analogs in plasma Compound Test Average % Average %-194- 180092653.1Docket No.: 146316.8032.WO02 Quinidine_02 1.0E-5 66.10 114.10 Sertraline 01 1.0E-5 97.52 64.76Table 62. Half-life of melanocortin analogs in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) Compound Test Average Half-life (min)Table 63. Aqueous solubility of melanocortin analogs in plasma (PBS), simulated gastric fluid (SGF), and simulated intestinal fluid (SIF) Compound Test Concentration (M)Average Solubility (µM)-195- 180092653.1Docket No.: 146316.8032.WO02 Metoprolol 2.0E-4 190.93 - - Phenytoin 2.0E-4 89.72 - -Table 64. Partition coefficient of melanocortin analogs and reference compounds Compound Test Concentration (M) Partition Coefficient*In Vitro Absorption

[0198] In vitro absorption of non-naturally occurring melanocortin analogs was determined using permeability assays. Assay conditions are provided in Table 65. Table 65. Assay conditions for in vitro absorption assessment Assay Source pH Incubation Detection Method-196- 180092653.1Docket No.: 146316.8032.WO02 A-B permeability Caco-2 cell line 6.5 / 7.4 0 and 60 min, HPLC-MS / MS 37°C

[0199] The apparent permeability coefficient (Papp) of the test compound was calculated as follows: Papp(cm / s) = (VR*CR,end / ∆t) x (1 / A*(CD,mid-CR,mid) where VR is the volume of the receiver chamber; CR,end is the concentration of the test compound in the receiver chamber at the end time point; Δt is the incubation time; A is the surface area of the cell monolayer; CD,mid is the calculated mid-point concentration of the test compound in the donor side, which is the mean value of the donor concentration at time 0 minute and the donor concentration at the end time point; and CR,mid is the mid-point concentration of the test compound in the receiver side, which is one half of the receiver concentration at the end time point. Concentrations of the test compound were expressed as peak areas of the test compound. Recovery of the Test Compound from the Permeability Assay

[0200] The recovery of the test compound was calculated as follows:

[0201] Recovery(%) = ((VD*CD,end+VR*CR,end) / VD*CD0) x 100

[0202] where VD and VR are the volumes of the donor and receiver chambers, respectively; CD,end is the concentration of the test compound in the donor sample at the end time point; CR,end is the concentration of the test compound in the receiver sample at the end time point; and CD0 is the concentration of the test compound in the donor sample at time zero. Concentrations of the test compound are expressed as peak areas of the test compound. Fluorescein assessment for Permeability assays

[0203] 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 -197- 180092653.1Docket No.: 146316.8032.WO02 permeability of less than 1.5 x 10-6cm / s for Caco-2 and MDR1-MDCKII cells and 2.5 x 10-6cm / s for MDCKII cells was considered intact, and the permeability result of the test compound from intact cell monolayer is reported.

[0204] Results of the in vitro absorption assessments described above are provided in Table 66. Table 66. In vitro absorption of melanocortin analogs and reference compounds Compound Test A-B permeability B-A permeability C n ntr ti n y

[0205] In vitro metabolism of non-naturally occurring melanocortin analogs was determined using the assay conditions provided in Table 67. Table 67. Assay conditions for in vitro metabolism assessment Assay Source Incubation Detection Methodng, was calculated by comparing the peak area of the compound at the time point relative to that at time-0. The half-life (T1 / 2) was estimated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) vs. time, assuming the first-order kinetics. -198- 180092653.1Docket No.: 146316.8032.WO02 The apparent intrinsic clearance (CLint, in μL / min / pmol, μL / min / mg or μL / min / Mcell) was calculated according to the following formula: CLint= 0.693 / (T1 / 2*(mg protein / μL or million cells / μL or pmol CYP isoyme / μL)).

[0207] Results from the intrinsic clearance assay are provided in Table 68. Table 68. In vitro metabolism of melanocortin analogs and reference compounds Compound Test Concentration (M) Half-life Clint (uL / mi / mg) Exa

[0208] 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, O7, and comparator non-naturally occurring melanocortin analog Ac- Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 368) were tested at concentrations ranging from 0.1 µM to 100 µM 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 of O7 at 10 µM are shown in Table 69 and the results of the comparator CYP inhibition assays including IC50 values at each of the CYP enzymes are shown in Table 70. Table 69. CYP Inhibition Studies of O7 -199- 180092653.1Docket No.: 146316.8032.WO02 Assay Substrate NADPH+ / - O7 µm TaCYP Marker Substrate Isoform-Catalyzed TCMCB07 IC50 Values IC50 t b-200- 180092653.1Docket No.: 146316.8032.WO02 3A Midazolam (2 µM) 1’ -Hydroxylation >100 >100 NA 3A Testosterone (50 µM) 6ß’ Hydroxylation >100 >100 NA

[0209] Weight and food intake were assessed in Sprague-Dawley rats after administration of 3 mg / kg (3mg / kg) A3, O7, and O11 for three or four days are shown in FIGS.10A (weight) a...

Claims

Docket No.: 146316.8032.WO02 CLAIMS I / We claim:

1. A non-naturally occurring melanocortin analog comprising a sequence according to Formula (IC): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IC), wherein: R1is Nle; R2is Asp or Glu; R3is Pro; R4is p(F)dPhe or dPhe; R5is Arg; R6is Trp; R7is Orn; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7, provided that: when R4is dPhe, then R2is Glu.

2. The non-naturally occurring melanocortin analog of claim 2, comprising a sequence according to Formula (IC), wherein: R1is Nle; R2is Asp or Glu; -285- 180092653.1Docket No.: 146316.8032.WO02 R3is Pro; R4is p(F)dPhe or dPhe; R5is Arg; R6is Trp; R7is Orn; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7, provided that the non-naturally occurring melanocortin analog does not comprise a sequence of: Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 23).

3. The non-naturally occurring melanocortin analog of claim 1 or 2, wherein the sequence of Formula (IC) is selected from the group consisting of: Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 216); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 217); and Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 218), wherein c represents cyclization through R2and R7via a lactam bond.

4. The non-naturally occurring melanocortin analog of any one of claims 1-3, wherein the sequence of Formula (IC) is cyclized through a lactam bond between Glu at R2and Orn at R7.

5. The non-naturally occurring melanocortin analog of claim 4, wherein the sequence of Formula (IC) is: Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 216); or Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 218), -286- 180092653.1Docket No.: 146316.8032.WO02 wherein c represents cyclization through R2and R7via a lactam bond.

6. The non-naturally occurring melanocortin analog of any one of claims 1-3, wherein R4is p(F)dPhe.

7. The non-naturally occurring melanocortin analog of claim 6, wherein the sequence of Formula (IC) is: Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 217); Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 218), wherein c represents cyclization through R2and R7via a lactam bond.

8. The non-naturally occurring melanocortin analog of claim 7, wherein the sequence of Formula (IC) is: Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 218), wherein c represents cyclization through R2and R7via a lactam bond.

9. The non-naturally occurring melanocortin analog of any one of claims 1-3, wherein R4is dPhe.

10. The non-naturally occurring melanocortin analog of claim 4, wherein the sequence of Formula (IC) is: Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 216), wherein c represents cyclization through R2and R7via a lactam bond.

11. The non-naturally occurring melanocortin analog of any one of claims 1-10, wherein the non-naturally occurring melanocortin analog binds at least a portion of a melanocortin receptor.

12. The non-naturally occurring melanocortin analog of claim 11, wherein the non- naturally occurring melanocortin analog binds one or more amino acids of the melanocortin receptor. -287- 180092653.1Docket No.: 146316.8032.WO02 13. The non-naturally occurring melanocortin analog of claim 12, wherein the non- naturally occurring melanocortin analog binds two or more amino acids of the melanocortin receptor.

14. The non-naturally occurring melanocortin analog of any one of claims 11-13, wherein the non-naturally occurring melanocortin analog comprises a dissociation constant (Kd) value for the melanocortin receptor or the one or more amino acids thereof that is less than that of a conventional melanocortin analog 15. The non-naturally occurring melanocortin analog of any one of claims 11-14, wherein the melanocortin receptor is a melanocortin 3 receptor or a melanocortin 4 receptor.

16. The non-naturally occurring melanocortin analog of any one of claims 1-15, wherein the non-naturally occurring melanocortin analog is administered to a subject in need thereof before, during, or after administration of a weight loss agent. -288- 180092653.1

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