Peptide compositions

1. A method of treating a disorder responsive to modulation of the melanocortin-4 receptor (MC4R) in a subject in need thereof, the method comprising administering to said subject an effective amount of a polypeptide of structural formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is —H, or a C1-C6 acyl;

R 2 is —NR 3 R 4 , or —OR 5 wherein R 3 , R 4 , and R 5 are each independently is H or a C1-C6 alkyl;

A 1 is an amino acid residue selected from Arg, Lys, Orn, His, Phe, Val, Leu, Trp, Tyr, Ala, Ser, Thr, Gln, Asn, Asp, Glu, or TzAla; or

A 1 is a moiety selected from an optionally substituted C1-C12 alkyl, an optionally substituted C6-C18 aryl, an optionally substituted C5-C18 heteroaryl, an aralkyl wherein the aryl portion is an optionally substituted C6-C18 aryl, and the alkyl portion is an optionally substituted C1-C12 alkyl, or a heteroaralkyl, wherein the heteroaryl portion is an optionally substituted C5-C18 heteroaryl, and the alkyl portion is an optionally substituted C1-C12 alkyl; or

A 2 and A 8 is each independently an amino acid residue selected from Cys, hCys, Pen, Asp, Glu, Lys, Orn, Dbu, or Dpr, wherein A 2 and A 8 are pairwise selected so as to be able to form covalent bond between their respective side chains;

A 3 is an amino acid residue selected from Ala, Tle, Val, Leu, Ile, Cha, Pro, Ser, Thr, Lys, Arg, His, Phe, Gln, Sar, Gly, Asn, Aib, or

A 3 is absent, or

A 3 is residue Y, wherein Y is an amino acid selected from amino acids represented by the following structural formulas

wherein:

R 11 and R 12 , each independently, is H, —CH 3 , phenyl, or benzyl;

R 21 , R 22 , R 23 , and R 24 , each independently is H, —CH 3 , —CF 3 , phenyl, benzyl, F, Cl, Br, I, —OCH 3 , or —OH;

R 31 , R 32 , R 33 , R 34 , R 41 , R 42 , and R 43 , each independently is H, —CH 3 , —CF 3 , phenyl, benzyl, F, Cl, Br, I, —OCH 3 , or —OH;

A 4 is absent or is an amino acid residue selected from Atc, Ala, QAla, Aib, Sar, Ser, Thr, Pro, Hyp, Asn, Gln, Trp, Tyr, Lys, Arg, sChp, or residue X, where the X is an amino acid selected from amino acids represented by the following structural formulas:

wherein:

R 51 and R 52 , each independently, is H, —CH 3 , phenyl, or benzyl;

R 61 , R 62 , R 63 , and R 64 , each independently is H, —CH 3 , —CF 3 , phenyl, benzyl, F, Cl, Br, I, —OCH 3 , or —OH;

R 71 , R 72 , R 73 , R 74 , R 81 , R 82 , and R 83 , each independently is H, —CH 3 , —CF 3 , phenyl, benzyl, F, Cl, Br, I, —OCH 3 , or —OH;

A 5 is an optionally substituted Phe, an optionally substituted 1-Nal, or an optionally substituted 2-Nal;

A 6 is Arg; and

A 7 is Trp,

wherein any amino acid residue is either in L- or in D-configuration, provided that:

1) A 3 and A 4 are not both absent;

2) when A 4 is an amino acid, A 3 is not Aib or Gly;

3) when A 2 and A 8 each is selected from Cys, hCys or Pen and:

when A 4 is absent, then A 3 is not L-His;

5) when A 2 is Asp, Glu, Lys, or Orn, then A 8 is not Asp, Glu, Lys, or Orn.

2. The method of claim 1 , wherein the disorder responsive to modulation of the MC4R is type 2 diabetes, obesity, insulin resistance, a metabolic syndrome, an inflammatory disease, a feeding disorder, Prader-Willi Syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, a cardiovascular disease, a pulmonary disease, a dermatological disease, or a disorder of substance abuse.

3. The method of claim 1 , wherein the disorder responsive to modulation of the MC4R is type 2 diabetes.

4. The method of claim 1 , wherein the disorder responsive to modulation of the MC4R is a metabolic syndrome.

5. The method of claim 4 , wherein the metabolic syndrome is selected from anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia and wasting in frail elderly.

6. The method of claim 1 , wherein the disorder responsive to modulation of the MC4R is Prader-Willi Syndrome.

7. The method of claim 1 , wherein the disorder responsive to the modulation of the MC4R is a feeding disorder.

8. The method of claim 1 , wherein A 2 and A 8 is each independently selected from Cys, hCys, and Pen.

9. The method of claim 1 , wherein A 4 is an L-amino acid or is absent.

10. The method of claim 1 , wherein A 4 is an amino acid residue selected from Atc, Ala, QAla, Aib, Sar, Ser, Thr, Pro, Hyp, Asn, Gln, Trp, Tyr, Lys, Arg, sChp, or residue X.

11. The method of claim 1 , wherein A 5 is an optionally substituted D-Phe.

12. The method of claim 1 , represented by any one of the following structural formulas:

or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 , represented by any one of the following structural formulas:

or a pharmaceutically acceptable salt thereof.

14. The method of claim 1 , represented by any one of the following structural formulas:

or a pharmaceutically acceptable salt thereof.

15. The method of claim 1 , represented by any one of the following structural formulas:

(SEQ ID NO: 36)

Ac-Arg-cyclo[Cys-D-Ala-His(3-Me)-D-Phe-Arg-Trp- 

Cys]-NH 2 ;

(SEQ ID NO: 37)

Ac-Arg-cyclo[Cys-D-Ala-His(1-Me)-D-Phe-Arg-Trp- 

Cys]-NH 2 ;

(SEQ ID NO: 9)

Ac-Arg-cyclo[Cys-D-Ala-Trp-D-Phe-Arg-Trp-Cys]-NH 2 ;

(SEQ ID NO: 8)

Ac-Arg-cyclo[Cys-D-Ala-Gln-D-Phe-Arg-Trp-Cys]-NH 2 ;

(SEQ ID NO: 7)

Ac-Arg-cyclo[Cys-D-Ala-Asn-D-Phe-Arg-Trp-Cys]-NH 2 ;

(SEQ ID NO: 38)

Ac-Arg-cyclo[Cys-D-Ala-Arg-D-Phe-Arg-Trp-Cys]-NH 2 ;

(SEQ ID NO: 39)

Ac-Arg-cyclo[Cys-D-Ala-Tyr-D-Phe-Arg-Trp-Cys]-NH 2 ;

(SEQ ID NO: 40)

Ac-Arg-cyclo[Cys-D-Ala-D-Pro-D-Phe-Arg-Trp-

Cys]-NH 2 ;

(SEQ ID NO: 2)

Ac-Arg-cyclo[Cys-D-Ala-Pro-D-Phe-Arg-Trp-Cys]-NH 2 ;

(SEQ ID NO: 4)

Ac-Arg-cyclo[Cys-D-Ala-Pro-D-Phe(p-F)-Arg-Trp-

Cys]-NH 2 ;

(SEQ ID NO: 41)

Ac-Arg-cyclo[Cys-D-Ala-Atc-D-Phe-Arg-Trp-Cys]-NH 2 ;

(SEQ ID NO: 42)

Ac-Arg-cyclo[Cys-D-Ala-QAla-D-Phe-Arg-Trp-Cys]-

NH 2 ;

(SEQ ID NO: 43)

Ac-Arg-cyclo[Cys-D-Ala-sChp-D-Phe-Arg-Trp-Cys]-

NH 2 ;

or

(SEQ ID NO: 44)

Ac-Arg-cyclo[Cys-D-Ala-X-D-Phe-Arg-Trp-Cys]-NH 2 ,

or a pharmaceutically acceptable salt thereof.

16. The method of claim 1 , represented by any one of the following structural formulas:

(SEQ ID NO: 15)

Ac-Arg-cyclo[hCys-Ala-D-Phe-Arg-Trp-Cys]-NH 2 ;

(SEQ ID NO: 14)

Ac-Arg-cyclo[hCys-D-Ala-D-Phe-Arg-Trp-Cys]-NH 2 ;

(SEQ ID NO: 45)

Ac-Arg-cyclo[hCys-D-Ala-D-Phe-Arg-Trp-Pen]-NH 2 ;

(SEQ ID NO: 26)

Ac-Arg-cyclo[Glu-D-Ala-D-Phe-Arg-Trp-Dpr]-NH 2 ;

(SEQ ID NO: 27)

Ac-Arg-cyclo[Glu-Ala-D-Phe-Arg-Trp-Dpr]-NH 2 ;

(SEQ ID NO: 46)

Ac-Arg-cyclo[hCys-Aib-D-Phe-Arg-Trp-Cys]-NH 2 ;

(SEQ ID NO: 47)

Ac-Arg-cyclo[hCys-Sar-D-Phe-Arg-Trp-Cys]-NH 2 ;

(SEQ ID NO: 48)

Ac-Arg-cyclo[hCys-Val-D-Phe-Arg-Trp-Cys]-NH 2 ;

(SEQ ID NO: 49)

Ac-Arg-cyclo[hCys-D-Val-D-Phe-Arg-Trp-Cys]-NH 2 ;

(SEQ ID NO: 50)

Ac-Arg-cyclo[hCys-Gln-D-Phe-Arg-Trp-Cys]-NH 2 ;

(SEQ ID NO: 51)

Ac-Arg-cyclo[hCys-D-Gln-D-Phe-Arg-Trp-Cys]-NH 2 ;

(SEQ ID NO: 52)

Ac-Arg-cyclo[hCys-Ala-D-Phe-Arg-Trp-Pen]-NH 2 ;

(SEQ ID NO: 53)

Ac-Arg-cyclo[D-Pen-D-Ala-D-Phe-Arg-Trp-hCys]-NH 2 ;

(SEQ ID NO: 17)

Ac-Arg-cyclo[Cys-D-Ala-D-Phe-Arg-Trp-hCys]-NH 2 ;

(SEQ ID NO: 54)

Ac-Arg-cyclo[Pen-D-Ala-D-Phe-Arg-Trp-hCys]-NH 2 ;

(SEQ ID NO: 55)

Ac-Arg-cyclo[D-hCys-D-Ala-D-Phe-Arg-Trp-Cys]-NH 2 ;

(SEQ ID NO: 20)

Ac-Arg-cyclo[hCys-Pro-D-Phe-Arg-Trp-Cys]-NH 2 ;

or

(SEQ ID NO: 56)

Ac-Arg-cyclo[hCys-D-Pro-D-Phe-Arg-Trp-Cys]-NH 2 ,

or a pharmaceutically acceptable salt thereof.

17. The method of claim 1 , wherein:

A 3 is an amino acid residue selected from Tle, Val, Leu, Ile, Cha, Pro, Ser, Thr, Lys, Arg, His, Phe, Gln, Sar, Gly, Asn, or Aib; and

A 4 is an amino acid residue selected from Atc, Ala, QAla, Aib, Sar, Ser, Thr, Pro, Hyp, Asn, Gln, Trp, Tyr, Lys, Arg, sChp, or residue X.

18. The method of claim 1 , represented by any one of the following structural formulas:

(SEQ ID NO: 57)

Ac-Arg-cyclo[Cys-Val-Gln-D-Phe-Arg-Trp-Cys]-NH 2 ;

(SEQ ID NO: 11)

Ac-Arg-cyclo[Cys-D-Val-Gln-D-Phe-Arg-Trp-Cys]-NH 2 ;

or

(SEQ ID NO: 58)

Ac-Arg-cyclo[Cys-D-Val-His(1-Me)-D-Phe-Arg-Trp-

Cys]-NH 2 ,

or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 , wherein the disorder responsive to modulation of the MC4R is obesity.

20. The method of claim 1 , wherein the disorder responsive to modulation of the MC4R is insulin resistance.