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NEUROPHARMACOLOGY

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

Discovery Neuroscience (J.D., H.M., J.Z., S.K., E.S., S.S., L.S., S.R.-L.) and Chemical and Screening Sciences (A.L.S., R.L.V., G.S., B.L.H.), Wyeth Research, Princeton, New Jersey

The pharmacological profile of WAY-163909 [(7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole], a novel 5-hydroxytryptamine (HT)_2C (serotonin) receptor-selective agonist is presented. WAY-163909 displaced [¹²⁵I]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 intracellular calcium in CHO cells stably expressing the human 5-HT_2C receptor with an EC₅₀ 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 (EC₅₀ » 10µM) and was a 5-HT_2B receptor partial agonist (EC₅₀ 185 nM, E_max 40%). WAY-163909 exhibited negligible affinity (<50% inhibition at 1 µM) 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-HT₇ (343 nM) receptor subtypes and the 1 binding site in rat cortical membranes (665 nM). WAY-163909 produced a dose-dependent reduction in food intake in normal Sprague-Dawley rats (ED₅₀ = 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 ED₅₀ 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.

Address correspondence to: Dr. John Dunlop, Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, NJ 08543. E-mail dunlopj{at}wyeth.com

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