Structure- based identification of a G protein-biased allosteric modulator of cannabinoid receptor CB1

• 成果类型: Article
• 署名作者: Shen, Siyuan; Wu, Chao; Lin, Guifeng; Yang, Xin; Zhou, Yangli; Zhao, Chang; Miao, Zhuang; Tian, Xiaowen; Wang, Kexin; Yang, Zhiqian; Liu, Zhiyu; Guo, Nihong; Li, Yueshan; Xia, Anjie; Zhou, Pei; Liu, Jingming; Yan, Wei; Ke, Bowen; Yang, Shengyong; Shao, Zhenhua
• 署名单位: Sichuan University; Sichuan University; Sichuan University; Tianfu Jincheng Laboratory; Sichuan University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13260
• DOI: 10.1073/pnas.2321532121
• 发表日期: 2024-06-11
• 关键词: morphine; delta(9)-tetrahydrocannabinol; agonists; SYSTEM; pain; antinociception; RECOGNITION; activation; mechanisms; DISCOVERY

摘要

Cannabis sativa is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, A 9 - tetrahydrocannabinol (THC), and other agonists engage the orthosteric site of CB1, activating both Gi and (3- arrestin signaling pathways. The activation of diverse pathways could result in on - target side effects and cannabis addiction, which may hinder therapeutic potential. A significant challenge in pharmacology is the design of a ligand that can modulate specific signaling of CB1. By leveraging insights from the structure-function selectivity relationship (SFSR), we have identified Gi signaling- biased agonist - allosteric modulators (ago - BAMs). Further, two cryoelectron microscopy (cryo - EM) structures reveal the binding mode of ago - BAM at the extrahelical allosteric site of CB1. Combining mutagenesis and pharmacological studies, we elucidated the detailed mechanism of ago - BAM - mediated biased signaling. Notably, ago - BAM CB - 05 demonstrated analgesic efficacy with fewer side effects, minimal drug toxicity and no cannabis addiction in mouse pain models. In summary, our finding not only suggests that ago - BAMs of CB1 provide a potential nonopioid strategy for pain management but also sheds light on BAM identification for GPCRs.