Referenced in: none

Automatically associated channels: Kv11.1

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

Authors: Jianjun Cheng, Patrick M Giguere, Claire M Schmerberg, Vladimir M Pogorelov, Ramona M Rodriguiz, Xi-Ping Huang, Hu Zhu, John D McCorvy, William C Wetsel, Bryan L Roth, Alan P Kozikowski

Journal, date & volume: J. Med. Chem., 2016 Jan 28 , 59, 578-91

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/26704965

Abstract
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.