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-HT_2C agonists. Compound (+)-<b>22a</b> was identified as a potent 5-HT_2C receptor agonist, with good selectivity against the 5-HT_2B and the 5-HT_2A receptors. ADMET assays showed that compound (+)-<b>22a</b> possessed desirable properties in terms of its microsomal stability, and CYP and hERG inhibition, along with an excellent brain penetration profile. Evaluation of (+)-<b>22a</b> in animal models of schizophrenia-related behaviors revealed that it had a desirable activity profile, as it reduced <i>d</i>-amphetamine-stimulated hyperlocomotion in the open field test, it restored <i>d</i>-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 (+)-<b>22a</b> as a drug candidate for the treatment of schizophrenia

Optimization of 2‑Phenylcyclopropylmethylamines as Selective Serotonin 2C Receptor Agonists and Their Evaluation as Potential Antipsychotic Agents

The discovery of a new series of compounds that are potent, selective 5-HT_2C 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-HT_2C receptor and excellent selectivity against the 5-HT_2A and 5-HT_2B 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 (+)-<b>16b</b>, which displayed an EC₅₀ of 4.2 nM at 5-HT_2C, no activity at 5-HT_2B, and an 89-fold selectivity against 5-HT_2A, is one of the most potent and selective 5-HT_2C agonists reported to date. The likely binding mode of this series of compounds to the 5-HT_2C receptor was also investigated in a modeling study, using optimized models incorporating the structures of β₂-adrenergic receptor and 5-HT_2B receptor