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