WAY-163909 [(7bR,10aR)-1,2,3,4,8,9,10,1 Oa-Octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole],a Novel 5-Hydroxytryptamine 2C Receptor-Selective Agonist with Anorectic Activity

摘要

The pharmacological profile of WAY-163909 [(7bR,-10aR)-1,2,3,4,8,9,10,1 Oa-octahydro-7bH-cyclopenta-[b][1,4]diaze-pino[6,7,1hi]indole],a novel 5-hydroxytryptamine (HT)_(2C) (serotonin) receptor-selective agonist is presented.WAY-163909 displaced [~(125)l]2,5-dimethoxy-4-iodoamphetamine binding from human 5-HT_(2C) receptor sites,in Chinese hamster ovary (CHO) cell membranes,with a K_i value of 10.5 +- 1.1 nM.Binding affinities determined for the human 5-HT_(2A_ and 5-HT_(2B) receptor subtypes were 212 and 485 nM,respectively.In functional studies,WAY-163909 stimulated the mobilization of in-tracellular calcium in CHO cells stably expressing the human 5-HT_(2C) receptor with an EC_(50) value of 8 nM,and E_(max) relative to 5-HT of 90%.WAY-163909 failed to stimulate calcium mobilization in cells expressing the human 5-HT_(2A) receptor subtype (EC_(50)10 muM) and was a 5-HT_(2B) receptor partial agonist (EC_(50) 185 nM,Emax 40%).WAY-163909 exhibited negligible affinity (<50% inhibition at 1 muM) for other receptor sites examined,including human 5-HT_(1A),D2,and D3 receptors,and the 5-HT transporter binding site in rat cortical membranes.WAY-163909 exhibited weak affinity for the human D4 (245 nM) and 5-HT_7 (343 nM) receptor subtypes and the alpha1 binding site in rat cortical membranes (665 nM).WAY-163909 produced a dose-dependent reduction in food intake in normal Sprague-Dawley rats (ED_(50) = 2.93 mg/kg),an effect blocked by a 5-HT_(2C) receptor antagonist but not by a 5-HT_(2A) or 5-HT_(2B) receptor antagonist.In addition,WAY-163909 decreased food intake in obese Zucker rats and diet-induced obese mice with ED_(50) values of 1.4 and 5.19 mg/kg i.p.,respectively,consistent with the potential utility of 5-HT_(2C) receptor agonists as anti-obesity agents.