Bifunctional compounds for relief of pain comprising an opioid receptor agonist moiety and a NK1 receptor antagonist moiety and methods for treating pain
A compound for treatment of pain comprising a single multivalent/multifunctional ligand with agonist activity at opioid receptors and with antagonist activity at NK-1 receptors, joined by a linker. Also disclosed is a pharmaceutical compound comprising the above compound in a pharmaceutically acceptable carrier.
1. A compound comprising an opioid receptor agonist moiety that is linked to a NK1 receptor antagonist moiety, wherein said compound is of the formula:
A-B
wherein A is said opioid receptor agonist moiety, and wherein B is said NK1 receptor antagonist moiety of the formula:
and wherein said opioid receptor agonist moiety A is a moiety of the formula:
H-Tyr′-D-NRAla-NRGly-Phe′-[AA] a -,
wherein
each of R′ is independently H, CH 3 , or CF 3 ;
X is NH or NMe;
a is 0 or 1;
AA is Nle, β-Ala, γ-Abu, Ahx, 4-Amb, 4-Abz, 4-Apac, or 4-Ampa;
Tyr′ is Tyr or Dmt;
Phe′ is N-methylated Phe, or Phe(4-F); and
R is H or methyl provided at least one of R on said opioid receptor agonist is methyl or Phe′ is N-methylated Phe.
2. The compound of according to claim 1 , wherein Tyr′ is Tyr.
3. The compound according to claim 1 , wherein Tyr′ is Dmt.
4. The compound according to claim 1 , Phe′ is N-methylated Phe.
5. The compound according to claim 1 , wherein a is 0.
6. The compound according to claim 1 , wherein a is 1.
7. The compound according to claim 6 , wherein AA is Nle.
8. The compound according to claim 6 , wherein AA is β-Ala.
9. The compound according to claim 6 , wherein AA is γ-Abu.
10. The compound according to claim 6 , wherein AA is Ahx.
11. The compound according to claim 6 , wherein AA is 4-Amb.
12. The compound according to claim 6 , wherein AA is 4-Abz.
13. The compound according to claim 1 , wherein at least one of R′ is CH 3 or CF 3 .
14. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutical-acceptable carrier.
15. A method for treating pain in a subject, said method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 .