Optimization of 2-phenylcyclopropylmethylamines as selective serotonin 2C receptor agonists and their evaluation as potential antipsychotic agents.

Journal Article (Journal Article)

The discovery of a new series of compounds that are potent, selective 5-HT2C receptor agonists is described herein as we continue our efforts to optimize the 2-phenylcyclopropylmethylamine scaffold. Modifications focused on the alkoxyl substituent present on the aromatic ring led to the identification of improved ligands with better potency at the 5-HT2C receptor and excellent selectivity against the 5-HT2A and 5-HT2B receptors. ADMET studies coupled with a behavioral test using the amphetamine-induced hyperactivity model identified four compounds possessing drug-like profiles and having antipsychotic properties. Compound (+)-16b, which displayed an EC50 of 4.2 nM at 5-HT2C, no activity at 5-HT2B, and an 89-fold selectivity against 5-HT2A, is one of the most potent and selective 5-HT2C agonists reported to date. The likely binding mode of this series of compounds to the 5-HT2C receptor was also investigated in a modeling study, using optimized models incorporating the structures of β2-adrenergic receptor and 5-HT2B receptor.

Full Text

Duke Authors

Cited Authors

  • Cheng, J; Giguère, PM; Onajole, OK; Lv, W; Gaisin, A; Gunosewoyo, H; Schmerberg, CM; Pogorelov, VM; Rodriguiz, RM; Vistoli, G; Wetsel, WC; Roth, BL; Kozikowski, AP

Published Date

  • February 26, 2015

Published In

Volume / Issue

  • 58 / 4

Start / End Page

  • 1992 - 2002

PubMed ID

  • 25633969

Pubmed Central ID

  • PMC4834193

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

Digital Object Identifier (DOI)

  • 10.1021/jm5019274


  • eng

Conference Location

  • United States