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

Development of a new synthetic 5HT2A receptor compound to reduce side effects

Researchers developed a novel psychedelic compound (VCU-1012) that selectively activates the therapeutic 5-HT2A receptor while avoiding activation of the 5-HT3 receptor, which is linked to nausea and other gastrointestinal side effects.

In preclinical mouse studies, VCU-1012 promoted neuroplasticity and produced antidepressant- and anxiolytic-like effects without the gastrointestinal adverse effects seen with quipazine. The findings suggest a promising strategy for developing psychedelics with improved tolerability, although human clinical trials are still needed.

Abstract

Psychedelics that target serotonin 2A receptors (5-HT2ARs) hold therapeutic promise for neuropsychiatric disorders but are often hindered by off-target actions. The 5-HT2AR agonist quipazine also activates 5-HT3R, which contributes to undesirable side effects. Here, we developed VCU-1012, a quipazine-based, structurally distinct 5-HT2AR 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-HT2AR 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-HT2AR 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-HT2AR.

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.

Jason Younkin et al. Design of a new psychedelic quipazine analog with therapeutic efficacy and potentially fewer side effects.Sci. Signal.19,eadw6055(2026). DOI:10.1126/scisignal.adw6055, Read Paper

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