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

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

  • J Med Chem. 2017 Jul 27;60(14):6273-6288. doi: 10.1021/acs.jmedchem.7b00584.
Guiping Zhang 1,  Jianjun Cheng 1,  John D McCorvy 2,  Paul J Lorello 3,  Barbara J Caldarone 3,  Bryan L Roth 2,  Alan P Kozikowski 1
Affiliations

Affiliations

  • 1 Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.
  • 2 National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School , Chapel Hill, North Carolina 27599, United States.
  • 3 Department of Neurology, Brigham and Women's Hospital, and Harvard NeuroDiscovery Center, Harvard Medical School , Boston, Massachusetts 02115, United States.
PMID: 28657744 DOI: 10.1021/acs.jmedchem.7b00584
Abstract

A series of N-substituted (2-phenylcyclopropyl)methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT2C)-selective agonists with a preference for Gq signaling. A number of these compounds exhibit 5-HT2C selectivity with a preference for Gq-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-HT2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC50 of 24 nM at the 5-HT2C receptor, is fully selective over the 5-HT2B 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-HT2C receptor with respect to antipsychotic activity.

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