Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants
Chemical Reviews November 30, 2023 Wenwen Duan, Dongmei Cao, Sheng Wang et al. 62 citations
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.