Structure-Guided Design of Novel 5-HT<sub>2A</sub> Partial Agonists as Psychedelic Analogues with Antidepressant Effects.
Abstract
Depression is primarily treated with selective serotonin reuptake inhibitors (SSRIs), which are limited by delayed onset of effects and low rates of remission. Recent studies showed that serotonergic psychedelics such as psilocybin can reduce depressive symptoms both rapidly and enduringly. Such effects have been associated with the activation of the serotonin 2A (5-HT<sub>2A</sub>) receptor in the central nervous system, which has prompted medicinal chemistry studies of novel 5-HT<sub>2A</sub> agonists. In this study, we designed and synthesized novel 5-HT<sub>2A</sub> partial agonists based on the structures of the antipsychotic drug aripiprazole and our previously reported lead compound IHCH-7086. Two series of new compounds were synthesized, a number of which exhibited potent 5-HT<sub>2A</sub> partial agonist activity in G protein coupling and β-arrestin2 recruitment assays. Compound <b>28c</b> exhibited antidepressant effects in the mouse tail-suspension test without inducing head-twitch responses, supplementing the growing reservoir of nonhallucinogenic 5-HT<sub>2A</sub> agonists.
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