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NEUROPHARMACOLOGY

Lorcaserin, a Novel Selective Human 5-Hydroxytryptamine_2C Agonist: in Vitro and in Vivo Pharmacological Characterization

Arena Pharmaceuticals, Inc., San Diego, California

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-HT_2C full agonist. Lorcaserin bound to human and rat 5-HT_2C receptors with high affinity (K_i = 15 ± 1 nM, 29 ± 7 nM, respectively), and it was a full agonist for the human 5-HT_2C receptor in a functional inositol phosphate accumulation assay, with 18- and 104-fold selectivity over 5-HT_2A and 5-HT_2B receptors, respectively. Lorcaserin was also highly selective for human 5-HT_2C over other human 5-HT receptors (5-HT_1A, 5-HT₃, 5-HT_4C, 5-HT5_5A, 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-HT_2A agonist (±)-1-(2,5-dimethoxy-4-phenyl)-2-aminopropane, lorcaserin did not induce behavioral changes indicative of functional 5-HT_2A agonist activity. Acutely, lorcaserin reduced food intake in rats, an effect that was reversed by pretreatment with the 5-HT_2C-selective antagonist 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-yl-carbamoyl]indoline (SB242,084) but not the 5-HT_2A antagonist (R)-(+)--(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (MDL 100,907), demonstrating mediation by the 5-HT_2C 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-HT_2C receptor, with potential for the treatment of obesity.

Address correspondence to: Dr. William J. Thomsen, Arena Pharmaceuticals, Inc., 6166 Nancy Ridge Dr., San Diego, CA 92121. E-mail: bthomsen{at}arenapharm.com