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

Abstract

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

Antidepressant-like effects of the novel, selective, 5-HT2C receptor agonist WAY-163909 in rodents

“…WAY-163909 effectively decreased the hyperactivity associated with BULB without affecting levels of activity in sham operated rats after both short-term and long-term treatment, consistent with rapid onset antidepressant-like effects. Moreover, as tolerance develops to some, but not all effects of 5-HT 2C receptor agonists (Freo et al 1992;Kennedy et al 1993;Rosenzweig-Lipson et al 2006;Vickers et al 2000Vickers et al , 2003McCall et al 2001; Hayashi et al 2004), it is important to note that the effects observed at 5 days in the BULB model were still present at 21 days. The lack of tolerance is consistent with other effects of WAY-163909 such as those on food intake and body weight (Dunlop et al 2005) and on the atypical antipsychotic-like neurochemical, electrophysiological, and behavioral profile that occurs after both acute and 21-day administration (Rosenzweig- .…”

Incubation of cocaine cue reactivity associates with neuroadaptations in the cortical serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system

“…An analysis of the dose-effect curve for the high affinity (K i =10.5 nM) and efficacy (90% vs. 5-HT) 5-HT 2C R agonist WAY163909 (Dunlop et al, 2005) substantiated a ~3-fold rightward shift in its potency to suppress cue reactivity in prolonged (ID 50 = 0.39 mg/kg) relative to early forced abstinence (ID 50 = 0.12 mg/kg) from cocaine self-administration. In general, a full agonist need only occupy a fraction of available receptors to activate a maximal response (Kenakin, 2002; Strange, 2008); this concept is supported here by the fact that the maximal efficacy of WAY163909 (1 mg/kg) is retained in prolonged forced abstinence.…”

Serotonin 5-HT2A and 5-HT2C Receptors as Potential Targets for Modulation of Psychostimulant Use and Dependence

“…In addition, with the recent interest in 5-HT 2C R agonists in the treatment of psychiatric, neuroendocrine and neurological disorders, several industry leaders have identified and characterized novel 5-HT 2C R agonists. WAY 163909 has been shown to be a full 5-HT 2C R agonist with no efficacy at 5-HT 2A R and a behavioral profile consistent with that of a 5-HT 2C R agonist [210][211][212]. A second compound is Ly 448100 which is reported to be a full agonist at 5-HT 2C R with 20-fold greater selectivity at the 5-HT 2C R over the 5-HT 2A R. While WAY 163909 and Ly 448100 are in the preclinical study phase, a phase IIb clinical trial demonstrated a significant weight loss following a 12-week treatment with the selective 5-HT 2C R agonist APD 356, an effect observed at doses that were well tolerated patients [213].…”

“…Several selective 5-HT 2 R ligands of interest are in Phase I, II or III studies with the hope of developing new medications for neurological and/or psychiatric disorders, thereby increasing the possibility that such compounds may [210][211][212] soon be available for studies examining their effectiveness in modulating drug use and dependence. The selective 5-HT 2A R antagonists M100907 and SR 46349B (Eplivanserin) [196,197] are currently in Phase II or III clinical trials for depression [198] and/or sleep disorders [199,200].…”