机构：[1]Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China四川大学华西医院[2]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, Sichuan, China[3]Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China四川大学华西医院
Cannabis sativa is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, Δ9-tetrahydrocannabinol (THC), and other agonists engage the orthosteric site of CB1, activating both Gi and β-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.
基金：
National Natural Science
Foundation of China (T2221004 to S.Y. and Z.S., 32371288 and 32100988 to
W.Y., 31972916 to Z.S., 22277085 to X.Y., and 823B2101 to C.W.), Frontiers Medical Center, Tianfu Jincheng Laboratory Foundation (TFJC2023010010 to Z.S., TFJC2023010009 to S.Y.), 1.3.5 Project for Disciplines of Excellence,West China Hospital, Sichuan University (ZYYC23022 to Z.S., ZYXY21001 and ZYGD23006 to S.Y.), the China Postdoctoral Science Foundation (2023M732474 and GZB20230480 to S.S.), Science and Technology Department of Sichuan Province (2022ZYD0085 to Z.S. and 2021ZYD0080 to W.Y.), and Ministry of Technology Department of China grant (2019YFA0508800 to Z.S.)
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2025]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
最新[2025]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
第一作者：
第一作者机构：[1]Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China[2]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, Sichuan, China
共同第一作者：
通讯作者：
通讯机构：[1]Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China[2]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, Sichuan, China
推荐引用方式(GB/T 7714)：
Shen Siyuan,Wu Chao,Lin Guifeng,et al.Structure-based identification of a G protein-biased allosteric modulator of cannabinoid receptor CB1[J].Proceedings Of The National Academy Of Sciences Of The United States Of America.2024,121(24):e2321532121.doi:10.1073/pnas.2321532121.
APA：
Shen Siyuan,Wu Chao,Lin Guifeng,Yang Xin,Zhou Yangli...&Shao Zhenhua.(2024).Structure-based identification of a G protein-biased allosteric modulator of cannabinoid receptor CB1.Proceedings Of The National Academy Of Sciences Of The United States Of America,121,(24)
MLA：
Shen Siyuan,et al."Structure-based identification of a G protein-biased allosteric modulator of cannabinoid receptor CB1".Proceedings Of The National Academy Of Sciences Of The United States Of America 121..24(2024):e2321532121
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