Faculty Collaboration Database

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

Date

06/29/2017

Pubmed ID

28657744

Pubmed Central ID

PMC7374938

DOI

10.1021/acs.jmedchem.7b00584

Scopus ID

2-s2.0-85026350812 (requires institutional sign-in at Scopus site)   18 Citations

Abstract

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.

Author List

Zhang G, Cheng J, McCorvy JD, Lorello PJ, Caldarone BJ, Roth BL, Kozikowski AP

Author

John McCorvy PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antipsychotic Agents
Benzylamines
Cyclopropanes
HEK293 Cells
Humans
Hyperkinesis
Male
Methylamines
Mice, Inbred C57BL
Receptor, Serotonin, 5-HT2B
Receptor, Serotonin, 5-HT2C
Serotonin 5-HT2 Receptor Agonists
Stereoisomerism
Structure-Activity Relationship
beta-Arrestins