Structure-based discovery of nonhallucinogenic psychedelic analogs
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
Science January 27, 2022 DOI: 10.1126/science.abl8615 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Structural biology study Peer reviewed |
|---|---|
| Topics | LSD Psilocybin Serotonin |
| Keywords | Hallucinogen Pharmacology 5-HT Receptor Metabolite |
| Citations | 306 |
| Key points | Structures of 5-HT2AR complexed with psychedelic drugs reveal a second binding mode for serotonin and psilocin, enabling design of nonhallucinogenic agonists with antidepressant-like activity in mice. |
Abstract
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.