Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants

Psychedelics such as psilocybin activate the serotonin 2A receptor (5-HT2AR) to produce hallucinogenic effects, and clinical trials show they can act as rapid-acting, long-lasting antidepressants. However, there is a need for rationally designed 5-HT2AR agonists with optimal pharmacological profiles to unlock therapeutic potential and identify safer, nonhallucinogenic drug candidates. This Perspective reviews structure-activity relationships of existing 5-HT2AR agonists by chemical classification and discusses recent structural-level advances in molecular pharmacology. Encouraging clinical outcomes have spurred drug discovery efforts to develop novel agonists with improved subtype selectivity and signaling bias, potentially yielding safer antidepressants. Structure-based methods and functional selectivity-directed screening could accelerate these efforts.

Study at a glance

Abstract

Psychedelics make up a group of psychoactive compounds that induce hallucinogenic effects by activating the serotonin 2A receptor (5-HT2AR). Clinical trials have demonstrated the traditional psychedelic substances like psilocybin as a class of rapid-acting and long-lasting antidepressants. However, there is a pressing need for rationally designed 5-HT2AR agonists that possess optimal pharmacological profiles in order to fully reveal the therapeutic potential of these agonists and identify safer drug candidates devoid of hallucinogenic effects. This Perspective provides an overview of the structure-activity relationships of existing 5-HT2AR agonists based on their chemical classifications and discusses recent advancements in understanding their molecular pharmacology at a structural level. The encouraging clinical outcomes of psychedelics in depression treatment have sparked drug discovery endeavors aimed at developing novel 5-HT2AR agonists with improved subtype selectivity and signaling bias properties, which could serve as safer and potentially nonhallucinogenic antidepressants. These efforts can be significantly expedited through the utilization of structure-based methods and functional selectivity-directed screening.