Composition and method for neuropeptide S receptor (NPSR) antagonists
Neuropeptide S receptor antagonists are provided that bind in functional assays to neuropeptide S receptors; methods are provided for use of these antagonists in treatment of conditions or disease states that are ameliorated by blocking of the neuropeptide S receptor, including substance abuse and substance abuse relapse; and for use of neuropeptide S receptor antagonists in the manufacture of therapeutics and pro-drugs for therapeutics useful in disease states and conditions sensitive to binding of the neuropeptide S receptor.
1. A neuropeptide S receptor antagonist comprising a compound of structure (I):
where the dotted lines denote a saturated or unsaturated bond, with the proviso that either all dotted lines denote an unsaturated bond, only the dotted line between e and f is an unsaturated bond or none of the dotted lines denote an unsaturated bond;
X 1 is either CH, CH 2 , N or N—R 3 and X 2 is CH when X 1 is N, X 2 is CH 2 when X 1 is N—R 3 , X 2 is N when X 1 is CH, and X 2 is N—R 3 when X 1 is CH 2 ;
m is 0 or 1;
the wavy lines represent bonds connected to carbons having cis- or trans-configuration;
Y 1 is O or S; Y 2 is O, N, or CH 2 ;
R 1 and R 2 are jointly structure (II):
where p is 0 or 2 if ring B is present and p is 2 if ring B is not present; or
R 1 and R 2 are each independently methyl alcohol, phenyl, straight chain or branched C 1-8 alkyl, C 3-6 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-10 aryl or heterocycle, substituted aryl, thiophene, furan, or one of the following structures:
where Y 3 may be at any position on the ring and is H, halogen, OH, C 1-4 alkyl, C 1-4 hydroxyalkyl, or CF 3 ;
and
R 3 is —C(═NH)NH 2 , —CONH(CH 2 ) 3 CH 3 , —CONH(CH 2 ) 4 CH 3 ,
where R 6 may be at any position on the ring and is H, NH 2 , NHCOCH 3 , —OCH 2 CH 3 , NHCO(CH 2 ) 4 CH 3 , N(CH 3 ) 2 , NHCOOC(CH 3 ) 3 , halogen,
or R 3 is one of the following structures:
where R 5 is C 1-8 alkyl, C 3-6 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-10 aryl, heterocycle, substituted aryl, substituted thiophene, furan, pyrrole, a natural amino acid side chain, or an unnatural amino acid side chain selected from the group consisting of Norleucine, Cyclohexylalanine, Homocyclohexylalanine, Cyclohexylglycine, 2-amino isobutyric acid, 3-Cyclopentylalanine, Norvaline, and homophenylalanine; and R 4 is C 1-8 alkyl, C 3-6 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-10 aryl, heterocycle, substituted aryl, substituted thiophene, furan, pyrrole, or H; or
where Y 4 may be O or S.
2. A compound of claim 1 wherein R 1 is phenyl.
3. A compound of claim 1 wherein R 2 is isobutyl.
4. A compound of claim 1 wherein R 1 is phenyl and R 2 is isobutyl.
5. A compound of claim 1 wherein X 2 is N—R 3 and X 1 is CH 2 .
6. The compound of claim 1 , wherein R 1 and R 2 are each independently aryl having halogens at position 3 and 4 independently, aryl having alkoxy, methoxy, ethoxy, benzyloxy, hydroxyl at positions 2 and 3 independently, aryl having trifluoromethyl at position 4, or one of the following structures:
where Y 3 may be at any position on the ring and is H, halogen, OH, C 1-4 alkyl, C 1-4 hydroxyalkyl, or CF 3 .
7. A compound of claim 1 having binding activity of Ke less than 200 nM.
8. A compound of claim 1 having binding activity of Ke less than 100 nM.
9. A pharmaceutically acceptable salt comprising a compound of claim 1 .
10. A pharmaceutical composition comprising an effective amount of a neuropeptide-S-receptor antagonist compound of claim 1 and a physiologically acceptable carrier.
11. A method for treating at least one of a disease or condition attributable to binding of an agonist to the neuropeptide-S receptor in a mammal, which comprises administering an effective amount of a compound according to claim 1 or a salt thereof to said mammal wherein the disease or condition is selected from the group consisting of substance abuse, relapse from substance abuse, panic disorders, phobias, post-traumatic stress disorder, and sleep disorders.
12. The method of claim 11 , wherein the sleep disorder is narcolepsy.
13. The method of claim 11 , wherein the substance abuse is selected from the group consisting of opiate addiction, cocaine addiction, nicotine addiction and ethanol addiction.
14. The method of claim 11 , wherein the compound is administered through an avenue selected from the group consisting of oral ingestion, injection, intravenous injection, tablet, capsule, syrup, aerosol, troche, bolus, suppository, ointment, powder, solution, dispersion, emulsion, and suspension.
15. The method of claim 11 , wherein the mammal is a human.