中国科学院分子细胞科学卓越创新中心（生物化学与细胞生物学研究所）汪胜与上海科技大学iHuman研究所程建军研究组合作取得进展。他们研发了基于结构的非致幻性致幻剂类似物。该项研究成果发表在2022年1月28日出版的《科学》杂志上。

在本研究中，研究人员解析人类血清素2A受体 (5-HT2AR)与迷幻药物psilocin（裸盖菇素的活性代谢物）和D-麦角酸二乙胺 (LSD)以及内源性神经递质5-羟色胺和非致幻性迷幻类似物甘草苷复合的结构。除了经典模式外，5-羟色胺和psilocin还显示出第二种结合模式，这使得迷幻性IHCH-7113（抗精神病药lumateperone的亚结构）和几种5-HT2AR β-arrestin 特异性激动剂的设计成为可能，这些激动剂在小鼠中具有抗抑郁作用但没有致幻作用。该研究揭示的5-HT2AR复杂结构和基于此的见解为基于结构设计安全有效的非致幻性致幻类似物提供了坚实的基础。

据悉，靶向5-HT2AR的药物常用于治疗神经精神疾病；然而，许多具有致幻作用因而阻碍了它们的使用。

附：英文原文

Title: Structure-based discovery of nonhallucinogenic psychedelic analogs

Author: 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

Issue&Volume: 2022-01-28

Abstract: Drugs that target the human serotonin 2A receptor (5-HT2AR) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use. Here, we present structures of 5-HT2AR 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-HT2AR β-arrestin–biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects. The 5-HT2AR 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.

DOI: abl8615

Source: https://www.science.org/doi/10.1126/science.abl8615