METHODS OF STIMULATING APPETITE AND/OR INCREASING BODY WEIGHT USING NON-NATURALLY OCCURRING MELANOCORTIN RECEPTOR ANTAGONIST ANALOGS

1 . A method of stimulating appetite and increasing or maintaining muscle mass of a subject in need thereof, the method comprising:

administering to the subject, for at least 1 week, a therapeutically effective amount of a non-naturally occurring melanocortin analog comprising a sequence according to Formula (I),

wherein:

R 1 is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), trans-4-guanidinyl-proline (transPro(guan)), cis-4-guanidinyl-proline (cisPro(guan)), acetylated cysteine, methylated D-phenylalanine, succinic acid, o-phthalic acid, tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, glutaric acid, CO-cis-CH═CH—CO, an n-pentanoyl group, an n-hexanoyl group, leucine, isoleucine, valine, norvaline, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, acetylated D-arginine, acetylated arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Tle), acetylated D-tert-leucine (dTle), acetylated norvaline (Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated glutamic acid, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;

R 2 is absent or is selected from the group consisting of proline, D-hydroxyproline (dHyp), hydroxyproline (Hyp), transPro(guan), cisPro(guan), aspartic acid, glutamic acid, glycine, lysine, alanine, D-alanine, tryptophan, cysteine, norleucine, arginine, succinic acid, glutaric acid, CO-cis-CH—CH—CO, an n-pentanoyl group, an n-hexanoyl group, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);

R 3 is absent or is selected from the group consisting of histidine, histidine methylated at positions 1 or 3, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), transPro(guan), cisPro(guan), alanine, D-alanine, D-methionine, valine, D-valine, glutamic acid, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), tryptylarginine (Trp-Arg), glycine, phenylalanine, D-phenylalanine, succinic acid, D-leucine, leucine, D-isoleucine, isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), beta-alanine (b-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclo-propane-1-carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Atc), 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), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), octohydroindole-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), indoline-2-carboxylic acid (Ioc), 2-aminoindone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentane carboxylic (Cpe);

R 4 is selected from the group consisting of histidine, D-phenylalanine, L-phenylalanine, D-Nal(2′), pCI-D-Phe, (o-Phe) Phe, aspartic acid, a disubstituted biphenyl(Bip), glycine, proline, cysteine, para-chloro-D-phenylalanine (p(C1)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-iodo-D-phenylalanine (p(I)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF 3 )dPhe);;

R 5 is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), lysine, D-arginine, D-ornithine, D-histidine, D-alanine, D-lysine, glycine, aspartic acid, D-aspartic acid, glutamic acid, D-glutamic acid, cysteine, and p(I)dPhe;

R 6 is absent or is selected from the group consisting of D-tryptophan, L-tryptophan, D-Nal(2′), L-Nal(2′), Tic, Bip, arginine, histidine, D-histidine, cysteine, Nal(1′), dNal(1′), Aia, phenylalanine, Aba, Ata, tyrosine, D-tyrosine, Pen, dPen, alanine, and D-alanine;

R 7 is absent or is selected from the group consisting of glycine, glutamic acid, cysteine, lysine, D-cysteine, D-lysine, 2,3-diamino-propionic acid, methionine, proline, tryptophan, D-Nal(2′), ornithine, D-ornithine, Pen, dPen, and tetrahydro-isoquinoline-3-carboxylic acid (Tic);

R 8 is absent or is lysine or arginine;

R 9 is absent or is tryptophan;

R 10 is absent or is lysine;

R 11 —R 20 are each independently absent or selected from the group consisting of cysteine, norleucine, tyrosine, aspartic acid, leucine, isoleucine, valine, norvaline, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, arginine, histidine, hydroxyproline, D-hydroxyproline, D-proline, prolylglycine (Pro-Gly), D-Nal(2′), L-Nal(2′), a disubstituted biphenyl, ornithine, and tryptophan;

wherein if R 2 is an n-pentanoyl group or an n-hexanoyl group, then R 1 , X 1 , X 2 and X 3 are absent;

X 1 is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, β-homo proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, a piperazin-2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine;

X 2 is absent or is selected from the group consisting of D-threonine, D-proline, L-proline, β-homo proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, a piperazin-2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine;

X 3 is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, β-homo proline, D-alanine, L-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, a piperazin-2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine;

Y 1 is selected from the group consisting of D-alanine, L-alanine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, D-tert-leucine, L-tert-leucine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;

Y 2 is absent or is selected from the group consisting of D-proline, L-proline, D-valine, L-valine, D-tert-leucine, L-tert-leucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;

Y 3 is absent or is selected from the group consisting of D-proline, L-proline, D-valine, and L-valine;

Y 4 is absent or is D-proline or D-valine;

Y 5 is absent or is D-proline or D-valine;

Y 6 is absent or is D-proline or D-valine;

Y 7 is absent or is D-proline or D-valine;

Y 8 is absent or is D-proline or D-valine; and

wherein the non-naturally occurring melanocortin analog comprises one or more of the following features: (i) X 2 or X 3 is present; (ii) R 1 is absent or is selected from the group consisting of dArg, dMet, dIIe, dLeu, dVal, dAla, Ala, Tle, dTle, DNle, Nva, Gly, dPro, dCys, dPhe, dTyr, dGln, dAsn, transPro(guan), cisPro(guan), dTyr, Tyr, and Dmt; (iii) R 2 is absent;

(iv) R 3 is selected from the group consisting of dPro, Pro-Gly, and dAla; (v) R 4 is selected from the group consisting of His, Trp, and Phe; (vi) R 5 is Phe; (vii) R 7 is absent; (viii) R 8 is present;

(ix) R 9 and/or R 10 is present; (x) one or more of R 11 —R 20 are present; and (xi) Y 4 is present; and

the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of:

a disulfide bond between R 1 or R 2 and R 7 or X 1 when R 1 or R 2 is cysteine and R 7 or X 1 is cysteine;

a disulfide bond between R 2 and any one of R 5 —R 20 when R 2 and the any one of R 5 —R 20 are selected from the group consisting of cysteine, Pen, and dPen;

a lactam bridge between R 1 and R 7 when R 1 is norleucine and R 7 is glutamic acid;

a side-chain lactam bridge between R 2 and R 7 when R 2 is glutamic acid, aspartic acid, or CO-cis-CH—CH—CO, and R 7 is lysine or ornithine;

a side-chain lactam bridge between R 2 and R 8 when R 2 is glutamic acid or aspartic acid, R 8 is lysine, and R 7 is proline or tryptophan;

a lactam closure between R 1 and R 7 when R 1 is succinic acid or o-phthalic acid and R 7 is lysine; and

a lactam closure between R 2 and R 7 when R 2 is succinic acid and R 7 is 2,3-diamino-propionic acid;

X 1 X 2 X 3 represents an optionally present N-terminus; and

Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 represents a C-terminus,

wherein following the administration, the muscle mass is increased or maintained for at least one week.

2 . (canceled)

3 . The method of claim 1 , wherein the N-terminus, if present, is modified by an acetyl group and the C-terminus is modified by an amide group.

4 .- 16 . (canceled)

17 . The method of claim 3 , wherein R 1 is norleucin,

and R 2 is aspartic acid.

18 .- 20 . (canceled)

21 . The method of claim 17 , wherein:

Y 1 is D-valine and Y 2 is D-proline.

22 .- 27 . (canceled)

28 . The method of claim 1 , wherein R 1 , R 2 , and R 7 are present and R 8 —R 20 are absent, and the sequence of Formula (I) is cyclized through R 2 and R 7 via a lactam bond.

29 . The method of claim 28 , wherein:

R 1 is acetylated norleucine;

R 2 is aspartic acid;

R 3 is selected from the group consisting of proline, hydroxyproline, and D-hydroxyproline;

R 4 is dNal(2′);

R 5 is arginine;

R 6 is;

R 7 is lysine;

Y 1 is selected from the group consisting of D-valine, D-arginine, and D-lysine; and/or

Y 2 , if present, is D-proline.

30 . The method of claim 28 , wherein the sequence of Formula (I) is:

(SEQ ID NO: 3)

Ac-Nle- c (Asp-Pro-dNal2′-Arg-Trp-Lys)-dVal-dPro-NH 2 ;

or

(SEQ ID NO: 4)

Ac-Nle- c (Asp-Hyp-dNal2′-Arg-Trp-Lys)-dVal-dPro-NH 2 ,

wherein c represents cyclization through R 2 and R 7 via a lactam bond.

31 .- 58 . (canceled)

59 . The method of claim 1 , wherein the non-naturally occurring melanocortin analog comprises a sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 150, SEQ ID NO: 156, and SEQ ID NO: 160.

60 . The method of claim 1 , wherein the non-naturally occurring melanocortin analog is present in a composition.

61 . (canceled)

62 . The method of claim 60 , wherein the composition further comprises a pharmaceutical carrier.

63 . The method of claim 60 , wherein the non-naturally occurring melanocortin analog is present in the composition in a concentration of 1 mg/mL to 50 mg/mL, relative to a total volume of the composition.

64 . The method of claim 63 , wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.

65 . (canceled)

66 . The method of claim 1 , wherein the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.

67 . The method of claim 66 , wherein the parenteral administration is subcutaneous administration.

68 . (canceled)

69 . The method of claim 1 , wherein the non-naturally occurring melanocortin analog crosses the blood-brain-barrier of the subject.

70 . The method of claim 1 , wherein the therapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.5 mg/kg to 25 mg/kg per body weight of the subject.

71 . (canceled)

72 . The method of claim 1 , wherein the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.5 mg/kg to 10 mg/kg per body weight of the subject.

73 .- 75 . (canceled)

76 . The method of claim 1 , wherein the non-naturally occurring melanocortin analog is administered to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

77 .- 102 . (canceled)

103 . The method of claim 1 , wherein muscle mass of the subject is increased by at least 5% to 15% after the administration.

104 . (canceled)

105 . The method of claim 103 , wherein the increased muscle mass is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after administration.

106 .- 431 . (canceled)

432 . The method of claim 1 , wherein the non-naturally occurring melanocortin analog is administered to the subject once daily, twice daily, three times daily, once weekly, once every 2 weeks, or once per month.