Novel modulators of melanocortin receptors

Abstract

Modulators of melanocortin receptors (MCR) are provided herein. An MC5R peptide ligand is represented by to Formula 1: R 1 -Nle 4 - c [Xaa 5 -Yaa 6 -(NMe)D-Nal(2′) 7 -Arg 8 -Trp 9 -(NMe)Zaa 10 ]-R 2 . R 1 can be an acetyl, a glycosylated amino acid, —CO—(CH 2 ) n —CH 3 , or −CO—(CH 2 ) n CF 3 with n ranging from 1 to 6. R 2 can be an —CONH 2 , —COOH, or —CH 2 OH. Xaa, Yaa, and Zaa can each be a natural amino acid or an unnatural amino acid.

What is claimed is: 
     
         1 . A melanocortin 5 receptor (MC5R) peptide ligand according to Formula 1:
   R 1 -Nle 4 - c [Xaa 5 -Yaa 6 -(NMe)D-Nal(2′) 7 -Arg 8 -Trp 9 -(NMe)Zaa 10 ]-R 2  
   wherein R 1  is an acetyl, a glycosylated amino acid, or —CO—(CH 2 ) n CH 3 , wherein n ranges from 1 to 6,   wherein R 2  is an —CONH 2 , —COOH, or —CH 2 OH, and   wherein Xaa, Yaa, and Zaa are each a natural amino acid or an unnatural amino acid.   
     
     
         2 . The MC5R peptide ligand of  claim 1 , wherein the glycosylated amino acid comprises a saccharide O-linked to a natural amino acid, wherein the natural amino acid is Ser, Thr, or Tyr, wherein the saccharide is a monosaccharide, a disaccharide, or an oligosaccharide. 
     
     
         3 . The MC5R peptide ligand of  claim 1 , wherein the glycosylated amino acid comprises a saccharide N-linked to a natural amino acid, wherein the natural amino acid is Asn or Lys, wherein the saccharide is a monosaccharide, a disaccharide, or an oligosaccharide. 
     
     
         4 . The MC5R peptide ligand of  claim 1 , wherein Xaa is a natural amino acid, wherein Xaa is Asp or Glu. 
     
     
         5 . The MC5R peptide ligand of  claim 1 , wherein Xaa is an unnatural amino acid, wherein Xaa is Abu. 
     
     
         6 . The MC5R peptide ligand of  claim 1 , wherein Yaa is a natural amino acid, wherein Yaa is His or Pro. 
     
     
         7 . The MC5R peptide ligand of  claim 1 , wherein Yaa is an unnatural amino acid, wherein Yaa is selected from a group consisting of Oic, Ioc, Tic, Cpe, Che, Aic, and Acpc. 
     
     
         8 . The MC5R peptide ligand of  claim 1 , wherein Zaa is a natural amino acid, wherein Zaa is Lys. 
     
     
         9 . The MC5R peptide ligand of  claim 1 , wherein Zaa is an unnatural amino acid, wherein Zaa is Orn or Dab. 
     
     
         10 . The MC5R peptide ligand of  claim 1 , wherein Xaa is linked to Zaa via a carba, lactam, disulfide, thioether, or succinic linker. 
     
     
         11 . The MC5R peptide ligand of  claim 1 , wherein the MC5R peptide ligand is a 23 to 27-membered ring. 
     
     
         12 . A melanocortin 5 receptor (MC5R) peptide ligand according to Formula 2:
   Ac-Nle 4 - c [Asp 5 -His 6 -(NMe)D-Nal(2′) 7 -Arg 8 -Trp 9 -(NMe)Lys 10 ]-NH 2   (PEPTIDE 9)
   
     
     
         13 . A melanocortin 5 receptor (MC5R) peptide ligand according to Formula 3:
   R 1 -Nle 4 - c [Asp 5 -His 6 -(NMe)D-Nal(2′) 7 -Arg 8 -Trp 9 -(NMe)Lys 10 ]-R 2 ,
   wherein R 1  is an acetyl, a glycosylated amino acid, or —CO—(CH 2 ) n CH 3 , wherein n ranges from 1 to 6, and   wherein R 2  is an —CONH 2 , —COOH, or —CH 2 OH.   
     
     
         14 . The MC5R peptide ligand of  claim 13 , wherein the glycosylated amino acid comprises a saccharide O-linked to a natural amino acid, wherein the natural amino acid is Ser, Thr, or Tyr, wherein the saccharide is a monosaccharide, a disaccharide, or an oligosaccharide. 
     
     
         15 . The MC5R peptide ligand of  claim 13 , wherein the glycosylated amino acid comprises a saccharide N-linked to a natural amino acid, wherein the natural amino acid is Asn or Lys, wherein the saccharide is a monosaccharide, a disaccharide, or an oligosaccharide.