Download MendeleyStructure-based discovery of nonhallucinogenic psychedelic analogs.
Cao, D., Yu, J., Wang, H., Luo, Z., Liu, X., He, L., Qi, J., Fan, L., Tang, L., Chen, Z., Li, J., Cheng, J., Wang, S.(2022) Science 375: 403-411
- PubMed: 35084960
- DOI: https://doi.org/10.1126/science.abl8615
- Primary Citation of Related Structures:
7WC4, 7WC5, 7WC6, 7WC7, 7WC8, 7WC9 - PubMed 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.
Organizational Affiliation:
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.
