Psychedelics elicit their effects by 5-HT2A receptor-mediated Gi signalling

• 成果类型: Article
• 署名作者: Xu, Zheng; Wang, Hongshuang; Yu, Jingjing; Deng, Yue; Tian, Xiaowen; Ni, Rongjun; Xia, Fan; Yang, Lingyi; Xu, Chanjuan; Zhang, Liting; Luo, Renxuan; Chen, Peipei; Zhang, Xiaoyu; Liu, Yuxuan; Hou, Jingyu; Zhang, Miyuan; Chen, Shasha; Su, Lantian; Sun, Hui; He, Yixiao; Chen, Dandan; Chen, Xiaoting; Miao, Zhuang; Xie, Jie; Liu, Xinlei; Zhao, Jie; Ke, Bowen; Tian, Xiaohe; Zeng, Linan; Zhang, Lingli; Tang, Xiangdong; Yang, Shengyong; Liu, Jianfeng; Wang, Xiaohui; Yan, Wei; Shao, Zhenhua
• 署名单位: Sichuan University; Sichuan University; Tianfu Jincheng Laboratory; Sichuan University; Chinese Academy of Sciences; Changchun Institute of Applied Chemistry, CAS; Sichuan University; Sichuan University; Sichuan University; Huazhong University of Science & Technology; Bioland Lab; Chinese Academy of Sciences; University of Science & Technology of China, CAS; Sichuan University; Sichuan University; Sichuan University; Sichuan Normal University; Sichuan University; Sichuan University; Zhejiang University
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-10061-7
• 发表日期: 2026-03-19
• 页码: 410462
• 关键词: activation; agonism; cells

摘要

Psychedelics are undergoing a renaissance as potential therapy for psychiatric disorders, with more than 200 clinical trials being studied across several countries1, 2-3. However, the precise mechanisms by which these drugs bring about benefits and the potential clinical risks are not yet fully understood. The serotonin 2A receptor (5-HT2AR) was reported to be a Gq-coupled receptor and the primary interoceptive target of psychedelics4,5. Here we compared psychedelics and their non-hallucinogenic analogues (nHAs) using in vitro and in vivo approaches, finding that 5-HT2AR-mediated non-canonical Gi signalling is essential for hallucinogenic effect. We further presented five cryo-electron microscopy structures of 5-HT2AR-Gi/Gq in complex with psychedelics or nHAs. Structural analysis and pharmacological investigation revealed that a special contact between nHAs with 5-HT2AR mediated the signalling bias. Building on this insight, we identified a 2,5-dimethoxy-4-iodoamphetamine derivative, DOI-NBOMe, which exhibits potent and selective Gq-biased activity, and demonstrates promising therapeutic effects in mouse models without hallucinogenic effect. Our finding uncovers the functional mechanisms underlying the Gi signalling mediated by 5-HT2AR and provides valuable insights for designing psychedelic-based drugs with minimized risk from hallucinogenic effects.