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

Jianjun Cheng, Patrick M. Giguère, Oluseye K. Onajole, Wei Lv, Arsen Gaisin, Hendra Gunosewoyo, Claire M. Schmerberg, Vladimir M. Pogorelov, Ramona M. Rodriguiz, Giulio Vistoli, William C. Wetsel, Bryan L. Roth, Alan P. Kozikowski

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1992-2002
Number of pages11
JournalJournal of medicinal chemistry
Volume58
Issue number4
DOIs
StatePublished - Feb 26 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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