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S. CHO, N. H. JENSEN, A. M. SVENNEBRING, T. KUROME, S. KADARI, M. L. MANZANO, J. E. MALBERG, B. J. CALDARONE, L. ABDALLAH, L. H. TECOTT, B. L. ROTH, A. P. KOZIKOWSKI

The 5-HT2C, a prominent central serotonin receptor subtype, is widely distributed throughout the central nervous system and is thought to play a role in regulating a wide variety of behavioral process such as mood, appetite, and sexual behavior. 5-HT2C agonists have demonstrated efficacy in preclinical models of depression, obesity, and psychosis. Due to the serious side effects caused by the activation of the pharmacologically and structurally closely related subtypes, it is essential that 5-HT2C agonists developed for clinical use have a high specificity and subtype selectivity. We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine, which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from tranylcypromine, which shows modest activity as a 5-HT2C agonist, a series of 1-aminomethyl-2-phenylcyclopropanes was investigated as 5-HT2C agonists through iterative structural modifications. Among the tested compounds, several were potent and highly selective 5-HT2C receptor agonists over both 5-HT2A and 5-HT2B receptors in functional assays. The most promising compound CHO-V-52 (racemic) does not activate 5-HT2A and 5-HT2B receptors and has an EC50 of 19 nM at the 5-HT2C receptor. Indeed selected compounds demonstrated efficacy in several animal models of CNS related disorders such as depression, obesity, addiction, and psychosis.