Rational design of Gi-biased CB1 agonist with reduced side effects

  • Cell. 2026 May 28;189(11):3432-3443.e16. doi: 10.1016/j.cell.2026.03.020.
Yu-Ying Liao  1 ,  Jinxin Che  2 ,  Yun-Tao Gao  1 ,  Jianheng Xue  3 ,  Linjie Li  2 ,  Lin-Lin Wu  1 ,  Jia-Xue Hu  1 ,  Meng-Ting Hu  1 ,  Linghua Xie  1 ,  Huibing Zhang  3 ,  Dan-Dan Shen  3 ,  Yingjun Dong  3 ,  Shaokun Zang  3 ,  Na Zhang  1 ,  Hao Wang  4 ,  Yan Zhang  5 ,  Xiaowu Dong  6 ,  Xiao-Ming Li  7
Affiliations
  • 1. Department of Neurology and Department of Psychiatry of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Nanhu Brain-Computer Interface Institute, Hangzhou 311100, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Center of Brain Science and Brain-Machine Integration, School of Brain Science and Brain Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou 310058, China.
  • 2. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 3. Department of Pathology of Sir Run Run Shaw Hospital, Department of Pharmacology and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 4. Department of Neurology and Department of Psychiatry of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Affiliated Mental Health Center and Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Zhejiang 310013, China.
  • 5. NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Center of Brain Science and Brain-Machine Integration, School of Brain Science and Brain Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou 310058, China; Department of Pathology of Sir Run Run Shaw Hospital, Department of Pharmacology and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: [email protected].
  • 6. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].
  • 7. Department of Neurology and Department of Psychiatry of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Nanhu Brain-Computer Interface Institute, Hangzhou 311100, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Center of Brain Science and Brain-Machine Integration, School of Brain Science and Brain Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].
PMID: 41980782 DOI: 10.1016/j.cell.2026.03.020
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.

Keywords
CB1; analgesic; cannabinoid; non-opioid; rational design; signaling bias.
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