减少副作用的Gi偏置CB1激动剂的合理设计，这一成果由浙江大学医学院李晓明小组经过不懈努力而取得。这一研究成果发表在2026年4月13日出版的国际学术期刊《细胞》上。
通过对偏倚信号的构效关系分析，该研究组合理设计了两种Gi偏倚CB1激动剂LZD503和LZD505。他们的设计策略采用激动剂支架的结构空间调整来破坏特定的分子相互作用，并最大限度地减少与配体结合口袋内关键尖端残基的空间冲突，从而促进优先的Gi通路信号传导。与这些设计的激动剂结合的CB1-G蛋白复合物的低温电子显微镜结构证实了它们预期的构象姿势有利于Gi偏向信号。两种设计的化合物在减轻小鼠疼痛和减轻不必要的反应方面都显示出有希望的结果。阐明的CB1复合物结构和由此产生的见解为结构导向的创新CB1靶向镇痛药的开发建立了一个全面的框架，减少了不良反应。
据悉，大麻素受体1 （CB1）已成为下一代非阿片类药物治疗的有希望的候选者。然而，针对CB1的治疗方法的发展一直受到严重副作用的阻碍。
附：英文原文
Title: Rational design of Gi-biased CB1 agonist with reduced side effects
Author: Yu-Ying Liao, Jinxin Che, Yun-Tao Gao, Jianheng Xue, Linjie Li, Lin-Lin Wu, Jia-Xue Hu, Meng-Ting Hu, Linghua Xie, Huibing Zhang, Dan-Dan Shen, Yingjun Dong, Shaokun Zang, Na Zhang, Hao Wang, Yan Zhang, Xiaowu Dong, Xiao-Ming Li
Issue&Volume: 2026-04-13
Abstract: The cannabinoid receptor 1 (CB1) has emerged as a promising candidate for next-generation non-opioid therapies. However, the development of therapeutics targeting CB1 has been consistently hindered by significant adverse effects. Here, through structure-activity relationship analyses focused on biased signaling, we rationally design two Gi-biased CB1 agonists, LZD503 and LZD505. Our design strategy employed structural spatial tuning of the agonist scaffold to disrupt specific molecular interactions and minimize steric conflicts with critical tip residues within the ligand-binding pocket, thereby promoting preferential Gi-pathway signaling. Cryo-electron microscopy structures of the CB1-G-protein complexes bound to these designed agonists confirmed that their anticipated conformational poses favored Gi-biased signaling. Both designed compounds demonstrated promising results by alleviating pain and mitigating unwanted responses in mice. The elucidated CB1 complex structures and the resulting insights establish a comprehensive framework for the structure-guided development of innovative CB1-targeted analgesics with reduced adverse effect profiles.
DOI: 10.1016/j.cell.2026.03.020
Source: https://www.cell.com/cell/abstract/S0092-8674(26)00287-4