Structure-based discovery of nonhallucinogenic psychedelic analogs

作者：Dongmei Cao, Jing Yu, Huan Wang, Zhipu Luo, Xinyu Liu, Licong He, Jianzhong Qi, Luyu Fan, Lingjie Tang, Zhangcheng Chen, Jinsong Li, Jianjun Cheng, Sheng Wang · 发表于：Science · 年份：2022 · DOI：10.1126/science.abl8615 · 被引用次数：309 · 研究领域：Psychedelics and Drug Studies、Chemical synthesis and alkaloids、Neurotransmitter Receptor Influence on Behavior

Drugs that target the human serotonin 2A receptor (5-HT 2A R) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use. Here, we present structures of 5-HT 2A R complexed with the psychedelic drugs psilocin (the active metabolite of psilocybin) and d -lysergic acid diethylamide (LSD), as well as the endogenous neurotransmitter serotonin and the nonhallucinogenic psychedelic analog lisuride. Serotonin and psilocin display a second binding mode in addition to the canonical mode, which enabled the design of the psychedelic IHCH-7113 (a substructure of antipsychotic lumateperone) and several 5-HT 2A R β-arrestin–biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects. The 5-HT 2A R complex structures presented herein and the resulting insights provide a solid foundation for the structure-based design of safe and effective nonhallucinogenic psychedelic analogs with therapeutic effects.