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

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.