四川大学邵振华团队在研究中取得进展。他们发现了致幻剂通过5-HT_2A受体介导的G_i信号传导引起其作用。2026年1月28日，国际知名学术期刊《自然》发表了这一成果。

在这里，课题组人员比较了致幻剂及其非致幻类似物（nHAs）在体外和体内的主题，发现5-HT_2AR介导的非规范G_i信号对于致幻作用至关重要。研究团队进一步展示了5-HT_2AR-G_i /G_q与致幻剂或nHAs配合物的5-HT_2AR-G_i /G_q的低温电镜结构。结构分析和药理学研究表明，nHAs与5-HT_2AR之间的特殊接触介导了信号偏倚。在此基础上，研究组确定了2,5-二甲氧基-4-碘安非他明衍生物DOI-NBOMe，它具有强效和选择性Gq偏倚活性，并在无致幻作用的小鼠模型中显示出有希望的治疗效果。他们的发现揭示了5-HT_2AR介导的G_i信号传导的功能机制，并为设计以致幻剂为基础的药物提供了有价值的见解，使致幻剂效应的风险降到最低。

据介绍，致幻剂作为精神疾病的潜在疗法正在经历复兴，在几个国家进行了200多项临床试验。然而，这些药物带来益处和潜在临床风险的确切机制尚不完全清楚。据报道，5-羟色胺2A受体（5-HT_2AR）是一种Gq偶联受体，是迷幻药的主要内感受靶点。

附：英文原文

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

Author: 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

Issue&Volume: 2026-01-28

Abstract: 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.

DOI: 10.1038/s41586-025-10061-7

Source: https://www.nature.com/articles/s41586-025-10061-7