Further Advances in Optimizing (2-Phenylcyclopropyl)methylamines as Novel Serotonin 2C Agonists: Effects on Hyperlocomotion, Prepulse Inhibition, and Cognition Models.

Journal Article (Journal Article)

A series of novel compounds with two halogen substituents have been designed and synthesized to further optimize the 2-phenylcyclopropylmethylamine scaffold in the quest for drug-like 5-HT2C agonists. Compound (+)-22a was identified as a potent 5-HT2C receptor agonist, with good selectivity against the 5-HT2B and the 5-HT2A receptors. ADMET assays showed that compound (+)-22a possessed desirable properties in terms of its microsomal stability, and CYP and hERG inhibition, along with an excellent brain penetration profile. Evaluation of (+)-22a in animal models of schizophrenia-related behaviors revealed that it had a desirable activity profile, as it reduced d-amphetamine-stimulated hyperlocomotion in the open field test, it restored d-amphetamine-disrupted prepulse inhibition, it induced cognitive improvements in the novel object recognition memory test in NR1-KD animals, and it produced very little catalepsy relative to haloperidol. These data support the further development of (+)-22a as a drug candidate for the treatment of schizophrenia.

Full Text

Duke Authors

Cited Authors

  • Cheng, J; Giguere, PM; Schmerberg, CM; Pogorelov, VM; Rodriguiz, RM; Huang, X-P; Zhu, H; McCorvy, JD; Wetsel, WC; Roth, BL; Kozikowski, AP

Published Date

  • January 28, 2016

Published In

Volume / Issue

  • 59 / 2

Start / End Page

  • 578 - 591

PubMed ID

  • 26704965

Pubmed Central ID

  • PMC8317212

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

Digital Object Identifier (DOI)

  • 10.1021/acs.jmedchem.5b01153


  • eng

Conference Location

  • United States