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 ϭ 15 Ϯ 1 nM, 29 Ϯ 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-HT 3 , 5-HT 4C , 5-HT5 5A , 5-HT 6 , and 5-HT 7 ), 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 (Ϯ)-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)-(ϩ)-␣-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (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.Serotonin mediates its physiological effects through at least 14 different receptors. The serotonin 5-HT 2 receptor subfamily contains three distinct receptor subtypes, 5-HT 2A , 5-HT 2B , and 5-HT 2C , all of which share considerable sequence homology (Ͼ80% in transmembrane spanning regions) and activate common signaling pathways, including G q ␣-mediated stimulation of phospholipase-C, elevation of intracellular inositol phosphates, and elevation of intracellular calcium (Roth et al., 1998). Human 5-HT 2C receptors are predominately expressed in the CNS, and they are highly enriched in choroid plexus, prefrontal cortex, hippocampus, basal ganglia, and other brain regions associated with the control of mood, cognition, and appetite (Roth et al., 1998). Thus, 5-HT 2C receptors have been proposed as a therapeutic target for the treatment of CNS disorders, including epilepsy, obsessive compulsive disorder, Parkinson's disease, schizophrenia, depression and anxiety, sleep disorders, and drug abuse (Tecott et al
