Design of a new psychedelic quipazine analog with therapeutic efficacy and potentially fewer side effects

Psychedelics that target serotonin 2A receptors (5-HT_2ARs) hold therapeutic promise for neuropsychiatric disorders but are often hindered by off-target actions. The 5-HT_2AR agonist quipazine also activates 5-HT₃R, which contributes to undesirable side effects. Here, we developed VCU-1012, a quipazine-based, structurally distinct 5-HT_2AR agonist devoid of 5-HT₃R activity. VCU-1012 was developed by applying a strategic chemical design that combined deconstruction to pinpoint the nitrogen atom critical for 5-HT_2AR activation with structure-activity relationship studies to minimize 5-HT₃R agonism. We showed that VCU-1012 modulated dendritic spine structural plasticity in the frontal cortex and produced antidepressant-like effects in mice through 5-HT_2AR without activating 5-HT₃R, thereby avoiding the gastrointestinal side effects of quipazine. In addition, our molecular modeling and mutant analysis suggested that VCU-1012 interacted in the canonical orthosteric binding pocket of 5-HT_2AR. Together, these findings establish VCU-1012 as a potential therapeutic agent with reduced gastrointestinal impact, emphasize how differences in ligand-receptor interactions influence ligand positioning in the receptor binding pocket, and provide guidance for designing psychedelics with targeted therapeutic benefits.