title: AM630, a competitive cannabinoid receptor antagonist.
abstract: AM630 (iodopravadoline), a novel aminoalkylindole, has been found to attenuate the ability of a number of cannabinoids to inhibit electrically-evoked twitches of the mouse isolated vas deferens. It did not block the inhibitory effects of morphine or clonidine on the twitch response. AM630 behaved as a competitive antagonist of CP 55,940, WIN 55,212-2, anandamide and (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide (AM356), producing rightward shifts in the log concentration response curves of these cannabinoid receptor agonists that were concentration-dependent, essentially parallel and not accompanied by any decrease in the size of maximal response. AM630 also produced concentration-dependent, parallel rightward shifts in the log concentration-response curve of delta 9-THC. However, these shifts were accompanied by a decrease in the maximal response. AM630 was markedly more potent as an antagonist of delta 9-THC and CP 55,940 (Kd = 14.0 and 17.3 nM respectively) than as an antagonist of WIN 55,212-2, AM356 or anandamide (Kd = 36.5, 85.9 and 278.8 nM respectively). These differences in dissociation constant imply that the mouse vas deferens may contain more than one type of cannabinoid receptor. The data also indicate that the receptors for which AM630 has the highest affinity may not be CB1 cannabinoid receptors as the CB1 selective antagonist, SR141716A, is known to be equally potent in attenuating the inhibitory effects of CP 55,940 and anandamide on the twitch response of the mouse vas deferens.
authors.affiliation: Department of Biomedical Sciences, University of Aberdeen, Scotland.
authors.forename: R
authors.initials: R
authors.lastname: Pertwee
authors.forename: G
authors.initials: G
authors.lastname: Griffin
authors.forename: S
authors.initials: S
authors.lastname: Fernando
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.forename: A
authors.initials: A
authors.lastname: Hill
authors.forename: A
authors.initials: A
authors.lastname: Makriyannis
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D048588:Benzoxazines; D001667:Binding, Competitive; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D003511:Cyclohexanols / Q000037:antagonists & inhibitors / Q000494:pharmacology; D063388:Endocannabinoids; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009025:Morpholines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009281:Naphthalenes / Q000037:antagonists & inhibitors / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D048588:Benzoxazines; D002186:Cannabinoids; D003511:Cyclohexanols; D063388:Endocannabinoids; D007211:Indoles; D009025:Morpholines; D009281:Naphthalenes; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C088155:methanandamide; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C094023:iodopravadoline; C078814:anandamide