BIOCHEMICAL AND PHARMACOLOGICAL CHARACTERIZATION OF SR141716A, THE FIRST POTENT AND SELECTIVE BRAIN CANNABINOID RECEPTOR ANTAGONIST

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 (K-i=2 nM), displays low affinity for the peripheral cannabinoid receptor (K-i>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 [H-3]-CP55,940 binding to cerebral membranes with a ED(50) 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.