Taken together, these results demonstrate that the novel 5-HT2C receptor agonist WAY-163909 produces rapid onset antidepressant-like effects in animal models and may be a novel treatment for depression.

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Serotonin-2C (5-HT 2C ) receptor antagonists and agonists have been shown to affect dopamine (DA) neurotransmission, with agonists selectively decreasing mesolimbic DA. As antipsychotic efficacy is proposed to be associated with decreased mesolimbic DA neurotransmission by virtue of DA D 2 receptor antagonism, the 5-HT 2C -selective receptor agonist, WAY-163909 [(7bR,10aR)-1,2, 3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino [6,7, 1hi]indole], was evaluated in animal models of schizophrenia and in vivo microdialysis and electrophysiology to determine the effects on mesolimbic and nigrostriatal DA neurotransmission. Similar to clozapine, WAY-163909 (1.7-30 mg/kg i.p.) decreased apomorphine-induced climbing with little effect on stereotypy and no significant induction of catalepsy. WAY-163909 (0.3-3 mg/kg s.c.) more potently reduced phencyclidine-induced locomotor activity compared with d-amphetamine with no effect on spontaneous activity. WAY-163909 (1.7-17 mg/kg i. . WAY-163909 (10 mg/kg s.c.) selectively decreased extracellular levels of DA in the nucleus accumbens without affecting the striatum. Likewise, in vivo electrophysiological recordings showed a decrease in the number of spontaneously firing DA neurons in the ventral tegmental area but not in the substantia nigra with both acute and chronic (21-day) administration of WAY-163909 (1-10 mg/kg i.p.). Thus, the profile of the 5-HT 2C selective receptor agonist WAY-163909 is similar to that of an atypical antipsychotic and additionally may have rapid onset properties.

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 [125 I]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 Ϯ 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 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 Ͼ Ͼ 10 M) and was a 5-HT 2B receptor partial agonist (EC 50 185 nM, E max 40%). WAY-163909 exhibited negligible affinity (Ͻ50% inhibition at 1 M) 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 ␣1 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 ϭ 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 antiobesity agents.At least 14 distinct 5-HT receptor subtypes have been cloned, and their classification has been based on both sequence similarity and common signal transduction pathways (for review, see Barnes and Sharp, 1999). The 5-HT 2 receptor subfamily currently accommodates three subtypes designated 5-HT 2A , 5-HT 2B , and 5-HT 2C , and these receptors belong to the large family of seven transmembrane domain G protein-coupled receptors. They display high sequence homology with each other and common signal transduction (Baxter et al., 1995), principally via the activation of phospholipase C. Alterations or dysfunction of the 5-HT 2C receptor has been implicated in a variety of conditions, including obesity, anxiety, depression, obsessive compulsive disorder, schizophrenia, migraine, and erectile dysfunction (Fozard and Gray, 1989;Kennett and Curzon, 1991;Sanders-Bush Article, publication date, and citation information can be found at

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