Selective melanin-concentrating hormone type-1 receptor agonists
View Patent ↗The present invention features truncated hMCH analogs selectively active at MCH-1R over MCH-2R. Using amino acid numbering provided in hMCH, the featured analogs contain an X 6 which is either a D-amino acid, 5-guanidinopropionic acid or its lower or higher homolog, or a derivative thereof; and a X 10 which is either asparagine, glutamine, alanine, leucine, isoleucine, valine, norleucine, cyclohexylalanine, phenylalanine, (2′)-naphthylalanine, tyrosine, histidine, tryptophan, lysine, serine, threonine, methionine, or a derivative thereof.
1. A peptide consisting of the structure:
wherein X 6 is selected from the group consisting of: D-arginine, D-alanine, D-norleucine, D-α-aminobutyric acid, D-valine, D-leucine, D-isoleucine, D-proline, D-methionine, D-phenylalanine, D-asparagine, D-glutamine, D-serine, D-threonine, D-glutamic acid, D-aspartic acid, D-lysine, D-histidine, D-tryptophan, D-tyrosine, D-cyclohexylalanine, D-(2′)naphthylalanine, D-ornithine, D-homoarginine, D-nitroarginine, D-norarginine and D-citrulline,
X 7 is cysteine,
X 8 is either methionine, norleucine, or N-methyl norleucine,
X 9 is leucine,
X 10 is either asparagine, glutamine, leucine, isoleucine, valine, norleucine, cyclohexylalanine, phenylalanine, (2′)-naphthylalanine, tyrosine, histidine, tryptophan, lysine, serine, threonine, methionine, or citrulline,
X 11 is arginine,
X 12 is valine,
X 13 is phenylalanine, (2′)napthylalanine, p-fluoro-phenylalanine, tyrosine, or cyclohexylalanine,
X 14 is arginine or alanine,
X 15 is either proline or sarcosine,
X 16 is cysteine or D-cysteine,
X 17 is an optionally present amino acid that, if present, is either tryptophan or tyrosine,
Z 1 is an optionally present protecting group that, if present, is covalently joined to the N-terminal amino group,
Z 2 is an optionally present protecting group that, if present, is covalently joined to the C-terminal carboxy group, and
wherein said peptide optionally contains a detectable label, or a pharmaceutically acceptable salt of said peptide.
2. The peptide of claim 1 , wherein said detectable label is a luminescent label, an enzymatic label or a radiolabel.
3. The peptide of claim 2 , wherein X 6 is either D-arginine, D-alanine, D-norleucine, D-proline, D-phenylalanine, D-asparagine, D-serine, D-glutamic acid, D-lysine, or D-citrulline.
4. The peptide of claim 3 , wherein X 10 is glutamine.
5. The peptide of claim 4 , wherein said peptide is substituted with a radiolabel.
6. The peptide of claim 4 , wherein said peptide is not substituted with a radiolabel.
7. The peptide of claim 4 , wherein X 17 is not present, Z 1 is —C(O)CH 3 and Z 2 is —NH 2 .
8. The peptide of claim 1 , wherein said detectable label is not present.
9. The peptide of claim 8 , wherein X 17 is not present, Z 1 is —C(O)CH 3 and Z 2 is —NH 2 .
10. The peptide of claim 1 , wherein said peptide consists of a sequence selected from the group consisting of: SEQ ID NOs: 29, 30, 31, 32, 33, and 34.
11. The peptide of claim 1 , wherein said peptide consists of SEQ ID NO: 30.
12. A method of screening for a compound able to bind MCH-1R comprising the step of measuring the ability of said compound to inhibit binding of a peptide of claim 1 to MCH-1R, wherein said compound that inhibits binding of the peptide to MCH-1R is identified as able to bind MCH-1R.
13. The method of claim 12 , wherein said peptide is radiolabeled.