Structure-based discovery of nonhallucinogenic psychedelic analogs

• Published in: Science (American Association for the Advancement of Science) 2022-01, Vol.375 (6579), p.403-411
• Main Authors: Cao, Dongmei, Yu, Jing, Wang, Huan, Luo, Zhipu, Liu, Xinyu, He, Licong, Qi, Jianzhong, Fan, Luyu, Tang, Lingjie, Chen, Zhangcheng, Li, Jinsong, Cheng, Jianjun, Wang, Sheng
• Format: Article
• Language: English
• Subjects: Analogs; Animals; Antidepressants; Antidepressive Agents - chemistry; Antidepressive Agents - metabolism; Antidepressive Agents - pharmacology; Arrestin; Arrestin - metabolism; Binding Sites; Crystallography, X-Ray; Drug Design; Hallucinations; Hallucinations - chemically induced; Hallucinogens - chemistry; Hallucinogens - metabolism; Hallucinogens - pharmacology; Heterocyclic Compounds, 4 or More Rings - chemistry; Humans; Ligands; Lisuride - chemistry; Lisuride - metabolism; LSD; Lysergic acid diethylamide; Lysergic Acid Diethylamide - chemistry; Lysergic Acid Diethylamide - metabolism; Lysergide; Mice; Protein Conformation; Psilocybin; Psilocybin - analogs & derivatives; Psilocybin - chemistry; Psilocybin - metabolism; Psychedelic drugs; Receptor, Serotonin, 5-HT2A - chemistry; Receptor, Serotonin, 5-HT2A - metabolism; Receptors; Recruitment; Serotonin; Serotonin - chemistry; Serotonin - metabolism; Serotonin S2 receptors; Signal Transduction; Structure-Activity Relationship
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.abl8615

Drugs that target the human serotonin 2A receptor (5-HT R) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use. Here, we present structures of 5-HT 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 R β-arrestin-biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects. The 5-HT 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.