Discovery of N-Substituted (2-Phenylcyclopropyl)methylamines as Functionally Selective Serotonin 2C Receptor Agonists for Potential Use as Antipsychotic Medications

5 years ago

Discovery of N-Substituted (2-Phenylcyclopropyl)methylamines as Functionally Selective Serotonin 2C Receptor Agonists for Potential Use as Antipsychotic Medications

Paul J. Lorello, Guiping Zhang, Jianjun Cheng, Alan P. Kozikowski, Bryan L. Roth, John D. McCorvy, Barbara J. Caldarone

A series of N-substituted (2-phenylcyclopropyl)methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT_2C)-selective agonists with a preference for G_q signaling. A number of these compounds exhibit 5-HT_2C selectivity with a preference for G_q-mediated signaling compared with β-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC₅₀ of 23 nM in the calcium flux assay while showing no β-arrestin recruitment activity, is the most functionally selective 5-HT_2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC₅₀ of 24 nM at the 5-HT_2C receptor, is fully selective over the 5-HT_2B receptor. In an amphetamine-induced hyperactivity model, compound (+)-19 showed significant antipsychotic-drug-like activity. These novel compounds shed light on the role of functional selectivity at the 5-HT_2C receptor with respect to antipsychotic activity.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00584

DOI: 10.1021/acs.jmedchem.7b00584