title: Biochemical and pharmacological characterisation of SR141716A, the first potent and selective brain cannabinoid receptor antagonist.
abstract: SR141716A is a selective, potent and orally active antagonist of the brain cannabinoid receptor with a long duration of action. This compound shows high affinity for the central cannabinoid receptor (Ki = 2 nM), displays low affinity for the peripheral cannabinoid receptor (Ki > 1000 nM). In vitro, SR141716A antagonizes the inhibitory effects of cannabinoid receptor agonists on both mouse vas deferens contractions and dopamine-stimulated adenylyl cyclase activities in rat brain membranes. After oral administration SR141716A totally inhibited the ex vivo [3H]-CP55,940 binding to cerebral membranes with a ED50 value of 3.5 mg/kg. Furthermore SR141716A antagonizes the classical pharmacological responses elicited by cannabinoid receptor agonists. In addition, SR141716A reverses the inhibitory effect of WIN55212-2 on isoniazid-induced elevation of cGMP in rat cerebellum. This compound will provide a powerful tool for studying the in vivo functions of the anandamide/cannabinoid system.
authors.affiliation: Sanofi Recherche, Montpellier, France.
authors.forename: M
authors.initials: M
authors.lastname: Rinaldi-Carmona
authors.forename: F
authors.initials: F
authors.lastname: Barth
authors.forename: M
authors.initials: M
authors.lastname: Héaulme
authors.forename: R
authors.initials: R
authors.lastname: Alonso
authors.forename: D
authors.initials: D
authors.lastname: Shire
authors.forename: C
authors.initials: C
authors.lastname: Congy
authors.forename: P
authors.initials: P
authors.lastname: Soubrié
authors.forename: J C
authors.initials: JC
authors.lastname: Brelière
authors.forename: G
authors.initials: G
authors.lastname: Le Fur
mesh_terms: D000818:Animals; D048588:Benzoxazines; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D016466:CHO Cells; D002186:Cannabinoids / Q000378:metabolism; D006224:Cricetinae; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009025:Morpholines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009281:Naphthalenes / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D011720:Pyrazoles / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077285:Rimonabant
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077285:Rimonabant