State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
2 papers in the library · 368 citations · publishing 2022-2023
Drugs targeting the human serotonin 2A receptor (5-HT2AR) are used for neuropsychiatric diseases, but many have hallucinogenic effects. Structures of 5-HT2AR complexed with psilocin, LSD, serotonin, and lisuride reveal that serotonin and psilocin show a second binding mode. This insight enabled design of the psychedelic IHCH-7113 and several 5-HT2AR β-arrestin–biased agonists that displayed antidepressant-like activity in mice without hallucinogenic effects. These structures provide a foundation for designing safe, nonhallucinogenic psychedelic analogs with therapeutic potential.
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.