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 [125I]2,5-dimethoxy-4-iodoamphetamine binding from human 5-HT2C receptor sites, in Chinese hamster ovary (CHO) cell membranes, with a Ki value of 10.5 ± 1.1 nM. Binding affinities determined for the human 5-HT2A and 5-HT2B 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-HT2C receptor with an EC50 value of 8 nM, and Emax relative to 5-HT of 90%. WAY-163909 failed to stimulate calcium mobilization in cells expressing the human 5-HT2A receptor subtype (EC50 » 10μM) and was a 5-HT2B receptor partial agonist (EC50 185 nM, Emax 40%). WAY-163909 exhibited negligible affinity (<50% inhibition at 1 μM) for other receptor sites examined, including human 5-HT1A, 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 α1 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-HT2C receptor antagonist but not by a 5-HT2A or 5-HT2B 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-HT2C receptor agonists as anti-obesity agents.
Footnotes
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doi:10.1124/jpet.104.075382.
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ABBREVIATIONS: 5-HT, 5-hydroxytryptamine (serotonin); mCPP, 1-(m-chlorophenyl)piperazine; Ro 60-0175, (S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine; WAY-161503, (4aR)-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one; VER-3323, ((2S)-1-[6-bromo-2,3-dihydroindolyl)]-2-propylamine, PNU-22394, 6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole; YM348, (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine; WAY-629, 1,2,3,4,8,9,10,11-octahydro[1,4]diazepino[6,5,4-jk]cabazole; CHO, Chinese hamster ovary; DOI, 2,5-dimethoxy-4-iodoamphetamine; FLIPR, fluorometric imaging plate reader; ANOVA, analysis of variance; WAY-163909, (7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole; SB-242084, 6-chloro-5-methyl-1-[2-(2-methylpyridyl 3-oxy)pyrid-5-yl carbamoyl]indoline; SB-215505, 6-chloro-5-methyl-1-(5-quinolyl carbamoyl) indoline; MDL100907, (±)-2,3-dimethoxyphenyl-1-[2-4-(piperidine)-methanol]; CI, confidence interval; Org 37684, 3-(5-methoxy-indan-4-yloxy)-pyrrolidine.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received August 2, 2004.
- Accepted September 20, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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