PEPTIDES COMPRISING OPIOID RECEPTOR AGONIST AND NK1 RECEPTOR ANTAGONIST ACTIVITIES
The present invention relates generally to a compound having both agonist activity at opioid receptor(s) and antagonist activity at NK1 receptor, and methods for producing and using the same. This combination of activities provides several synergistic and/or beneficial effects such as enhanced potency in analgesic effect and reduction or inhibition of tolerance.
1 . An oligopeptide of the formula:
AA 1 -Q-Pro-AA 2 -AA 3
where
AA 1 is Tyr or Dmt;
AA 2 is Leu or methylate Leu;
AA 3 is Trp or methylated Trp each of which is covalently linked to optionally substituted benzyl amine or (optionally substituted phenyl)ethan-1-amine; and
Q is a moiety of the formula:
-(D)-NRAla-Phe′-NRGly-Tyr′-Pro-Ser-, or
-Pro-[Z] b -Phe′-Pro-;
-AA 4 -AA 5 -AA 6 -AA 7 -Pro-Ser- (i)
AA 4 is (D)-Ala or methylated (D)-Ala;
AA 5 is Phe, Phe(4-F), methylated Phe, or methylated Phe(4-F);
AA 6 is Gly or methylated Gly; and
AA 7 is Tyr or Dmt; or
-Pro-(AA 8 ) a -AA 9 -Pro- (ii)
a is 0 or 1;
AA 8 is Phe or Trp; and
AA 9 is Phe, Phe(4-F), methylated Phe, or methylated Phe(4-F), provided at least one of AA 2 , AA 3 , AA 5 , or AA 9 is methylated.
2 . The oligopeptide of claim 1 , wherein AA 3 is covalently linked to benzyl amine, 3,5-di(trifluoromethyl)benzylamine, 1-phenylethan-1-amine, or 1-(3,5-di(trifluoromethyl)phenyl)ethan-1-amine.
3 . The oligopeptide of claim 2 , wherein AA3 is covalently linked to 3,5-di(trifluoromethyl)benzylamine or 1-(3,5-di(trifluoromethyl)phenyl)ethan-1-amine.
4 . The oligopeptide of claim 1 , wherein Q is a moiety of the formula:
-AA 4 -AA 5 -AA 6 -AA 7 -Pro-Ser-
wherein AA 4 , AA 5 , AA 6 , and AA 7 are as defined in claim 1 .
5 . The oligopeptide of claim 1 , wherein Q is a moiety of the formula:
-Pro-(AA 8 ) a -AA 9 -Pro-
wherein a, AA 8 , and AA 9 are as defined in claim 1 .
6 . A method for treating pain comprising administering a subject in need of such a treatment a therapeutically effective amount of a compound of an oligopeptide of the formula:
AA 1 -Q-Pro-AA 2 -AA 3
where
AA 1 is Tyr or Dmt;
AA 2 is Leu or methylate Leu;
AA 3 is Trp or methylated Trp each of which is covalently linked to optionally substituted benzyl amine or (optionally substituted phenyl)ethan-1-amine; and
Q is a moiety of the formula:
-(D)-NRAla-Phe′-NRGly-Tyr′-Pro-Ser-, or
-Pro-[Z] b -Phe′-Pro-;
-AA 4 -AA 5 -AA 6 -AA 7 -Pro-Ser- (i)
AA 4 is (D)-Ala or methylated (D)-Ala;
AA 5 is Phe, Phe(4-F), methylated Phe, or methylated Phe(4-F);
AA 6 is Gly or methylated Gly; and
AA 7 is Tyr or Dmt; or
-Pro-(AA 8 ) a -AA 9 -Pro- (ii)
a is 0 or 1;
AA 8 is Phe or Trp; and
AA 9 is Phe, Phe(4-F), methylated Phe, or methylated Phe(4-F), provided at least one of AA 2 , AA 3 , AA 5 , or AA 9 is methylated.
7 . The method of claim 6 , wherein pain is an acute pain.
8 . The method of claim 6 , wherein pain is a chronic pain.
9 . The method of claim 6 , wherein AA 3 is covalently linked to benzyl amine, 3,5-di(trifluoromethyl)benzylamine, 1-phenylethan-1-amine, or 1-(3,5-di(trifluoromethyl)phenyl)ethan-1-amine.
10 . The method of claim 9 , wherein AA 3 is covalently linked to 3,5-di(trifluoromethyl)benzylamine or 1-(3,5-di(trifluoromethyl)phenyl)ethan-1-amine.
11 . The method of claim 6 , wherein Q is a moiety of the formula:
-AA 4 -AA 5 -AA 6 -AA 7 -Pro-Ser-
wherein AA 4 , AA 5 , AA 6 , and AA 7 are as defined in claim 6 .
12 . The method of claim 6 , wherein Q is a moiety of the formula:
Pro(AA 8 ) a AA 9 Pro-
wherein a, AA 8 , and AA 9 are as defined in claim 6 .
13 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and an oligopeptide of the formula:
AA 1 -Q-Pro-AA 2 -AA 3
where
AA 1 is Tyr or Dmt;
AA 2 is Leu or methylate Leu;
AA 3 is Trp or methylated Trp each of which is covalently linked to optionally substituted benzyl amine or (optionally substituted phenyl)ethan-1-amine; and
Q is a moiety of the formula:
-(D)-NRAla-Phe′-NRGly-Tyr′-Pro-Ser-, or
-Pro-[Z] b -Phe′-Pro-;
-AA 4 -AA 5 -AA 6 -AA 7 -Pro-Ser- (i)
AA 4 is (D)-Ala or methylated (D)-Ala;
AA 5 is Phe, Phe(4-F), methylated Phe, or methylated Phe(4-F);
AA 6 is Gly or methylated Gly; and
AA 7 is Tyr or Dmt; or
-Pro-(AA 8 ) a -AA 9 -Pro- (ii)
a is 0 or 1;
AA 8 is Phe or Trp; and
AA 9 is Phe, Phe(4-F), methylated Phe, or methylated Phe(4-F), provided at least one of AA 2 , AA 3 , AA 5 , or AA 9 is methylated.