Nociceptin-based analgesics
The invention relates to a family of hexapeptide compounds exhibiting activity with regard to the ORL-1 receptor. The compounds share a general formula of Arg-Tyr-Tyr-Arg-Trp-Arg, and may be constructed having modifications or substitutions at any position, and may include modifications of the amino- and carboxy-termini of the hexapeptide. These compounds include agents exhibiting agonist activity and antagonist activity when exposed to the human ORL-1 receptor. As such, the hexapeptides may be useful as analgesics, anxiolytics, diuretics, and anti-cancer agents.
1. A hexapeptide of the formula:
Arg-Xaa-Tyr-Arg-Trp-Arg (SEQ ID NO: 17), wherein the hexapeptide binds with the ORL-1 receptor, wherein Xaa is selected from the group consisting of Phe (4-Me), Phe (4-COOH), Phe (4-NO 2 ), Phe (4-F), Phe (4-CN), Tyr (4-Me), Tyr (3-Cl), and Tyr (BN, 3-Cl), the hexapeptide having an amino terminus and a carboxy terminus, either or both of which may optionally be modified.
2. The hexapeptide of claim 1 , having the formula of SEQ ID NO: 1.
3. The hexapeptide of claim 1 , having the formula of SEQ ID NO: 2.
4. The hexapeptide of claim 1 , having the formula of SEQ ID NO: 3.
5. The hexapeptide of claim 1 , having the formula of SEQ ID NO: 4.
6. The hexapeptide of claim 1 , having the formula of SEQ ID NO: 6.
7. The hexapeptide of claim 1 , having the formula of SEQ ID NO: 5.
8. The hexapeptide of claim 1 , having the formula of SEQ ID NO: 7.
9. The hexapeptide of claim 1 , having the formula of SEQ ID NO: 23.
10. The hexapeptide of claim 1 , wherein the amino terminus of the peptide is acetylated.
11. The hexapeptide of claim 1 , wherein the amino terminus of the peptide is modified to include a moiety selected from the group consisting of straight-chain alkyls, substituted straight-chain alkyls, branched-chain alkyls, substituted branched-chain alkyls, aralalkyls, cycloalkyls, or alkylcycloalkyls containing from about 1 to about 12 carbon atoms.
12. The hexapeptide of claim 1 , wherein the carboxy terminus is aminated.
13. The hexapeptide of claim 1 , wherein the carboxy terminus is aminated and the amino terminus is modified to include a moiety selected from the group consisting of straight-chain alkyls, substituted straight-chain alkyls, branched-chain alkyls, substituted branched chain alkyls, aralalkyls, cycloalkyls, or alkylcycloalkyls containing from about 1 to about 12 carbon atoms.
14. A pharmaceutical composition comprising a hexapeptide of claim 1 and a pharmaceutically acceptable diluent or excipient.
15. A method of treating pain comprising administering a compound comprising the peptide of claim 1 to a cell.
16. The hexapeptide of claim 1 wherein Xaa is Tyr (3-Cl).
17. A method of treating pain comprising administering a compound comprising the peptide of claim 16 to a cell.