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

Therapeutic Approaches

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.

Authors

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

Keywords

  • Animals
  • Brain/ metabolism
  • Catalepsy/ chemically induced
  • Central Nervous System Stimulants
  • Cognition/ drug effects
  • Dextroamphetamine
  • Drug Design
  • Drug Evaluation, Preclinical
  • Ether-A-Go-Go Potassium Channels/ antagonists & inhibitors
  • Female
  • Humans
  • Hyperkinesis/ chemically induced
  • Hyperkinesis/ drug therapy
  • Hyperkinesis/ psychology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microsomes, Liver/ metabolism
  • Prepulse Inhibition/ drug effects
  • Receptor, Serotonin, 5-HT2C/ drug effects
  • Recognition (Psychology)/ drug effects
  • Schizophrenia/ drug therapy
  • Schizophrenic Psychology
  • Serotonin 5-HT2 Receptor Agonists/ chemical synthesis
  • Serotonin 5-HT2 Receptor Agonists/ pharmacology
  • Structure-Activity Relationship
  • Substrate Specificity

External Links