Synthesis and in vitro evaluation of novel amino-phenylmethylene-imidazolone 5-HT2A receptor antagonists†

Many drugs target the serotonin 2A (5-HT_2A) receptor, including psychedelics, antidepressants, and antipsychotics. This study investigates the 5-HT_2A receptor-binding properties of a series of novel compounds with an amino-phenylmethylene-imidazolone (APMI) core structure. Two compounds (2a and 2c) demonstrated significant 5-HT_2A receptor-binding affinity without agonistic activity, instead displaying antagonistic effects. Structurally, these compounds differ from previously reported phenethylamine-based antagonists. This work introduces APMIs as a novel pharmacophore for 5-HT_2A receptor interaction and provides a foundation for developing new 5-HT_2A receptor-targeting therapeutic agents.