Structure-Guided Design of Novel 5-HT 2A Partial Agonists as Psychedelic Analogues with Antidepressant Effects
Journal of Medicinal Chemistry October 14, 2025 Rongyan Li, Hong Yan, Yujin Chen et al. 1 citation
New compounds designed to activate the serotonin 2A receptor without causing hallucinations show antidepressant effects in mice. Building on the structures of the antipsychotic aripiprazole and a previously reported lead compound, two series of novel 5-HT2A partial agonists were synthesized and tested. Several compounds demonstrated potent activity in G protein coupling and β-arrestin2 recruitment assays. One compound, 28c, reduced depressive-like behavior in the mouse tail-suspension test without producing head-twitch responses, a rodent correlate of hallucinogenic effects. These results add to the growing collection of nonhallucinogenic 5-HT2A agonists that could potentially provide rapid and enduring antidepressant effects.