RT Journal Article SR Electronic T1 Lorcaserin, a Novel Selective Human 5-Hydroxytryptamine2C Agonist: in Vitro and in Vivo Pharmacological Characterization JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 577 OP 587 DO 10.1124/jpet.107.133348 VO 325 IS 2 A1 William J. Thomsen A1 Andrew J. Grottick A1 Frederique Menzaghi A1 Hazel Reyes-Saldana A1 Stephen Espitia A1 Diane Yuskin A1 Kevin Whelan A1 Michael Martin A1 Michael Morgan A1 Weichao Chen A1 Hussien Al-Shamma A1 Brian Smith A1 Derek Chalmers A1 Dominic Behan YR 2008 UL http://jpet.aspetjournals.org/content/325/2/577.abstract AB 5-Hydroxytryptamine (5-HT)2C receptor agonists hold promise for the treatment of obesity. In this study, we describe the in vitro and in vivo characteristics of lorcaserin [(1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3 benzazepine], a selective, high affinity 5-HT2C full agonist. Lorcaserin bound to human and rat 5-HT2C receptors with high affinity (Ki = 15 ± 1 nM, 29 ± 7 nM, respectively), and it was a full agonist for the human 5-HT2C receptor in a functional inositol phosphate accumulation assay, with 18- and 104-fold selectivity over 5-HT2A and 5-HT2B receptors, respectively. Lorcaserin was also highly selective for human 5-HT2C over other human 5-HT receptors (5-HT1A, 5-HT3, 5-HT4C, 5-HT55A, 5-HT6, and 5-HT7), in addition to a panel of 67 other G protein-coupled receptors and ion channels. Lorcaserin did not compete for binding of ligands to serotonin, dopamine, and norepinephrine transporters, and it did not alter their function in vitro. Behavioral observations indicated that unlike the 5-HT2A agonist (±)-1-(2,5-dimethoxy-4-phenyl)-2-aminopropane, lorcaserin did not induce behavioral changes indicative of functional 5-HT2A agonist activity. Acutely, lorcaserin reduced food intake in rats, an effect that was reversed by pretreatment with the 5-HT2C-selective antagonist 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-yl-carbamoyl]indoline (SB242,084) but not the 5-HT2A antagonist (R)-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (MDL 100,907), demonstrating mediation by the 5-HT2C receptor. Chronic daily treatment with lorcaserin to rats maintained on a high fat diet produced dose-dependent reductions in food intake and body weight gain that were maintained during the 4-week study. Upon discontinuation, body weight returned to control levels. These data demonstrate lorcaserin to be a potent, selective, and efficacious agonist of the 5-HT2C receptor, with potential for the treatment of obesity. The American Society for Pharmacology and Experimental Therapeutics