2. Academic Validation
  3. Identification of Cannabigerol-Derived Dual CB2 Receptor Agonists and TRPM8 Antagonists with Anti-Inflammatory and Analgesic Activities

Identification of Cannabigerol-Derived Dual CB2 Receptor Agonists and TRPM8 Antagonists with Anti-Inflammatory and Analgesic Activities

  • J Med Chem. 2025 Jul 10;68(13):13335-13357. doi: 10.1021/acs.jmedchem.4c03220.
Wenjiao Yang 1 2,  Haiguo Sun 1,  Jing Ji 3 4,  Hai Chen 5,  Jiaxin Cheng 1 4,  Zhengtao Hu 5,  Xudong Gong 2,  Qi Liu 2,  Su Peng 6,  Jin Suo 1,  Tianwen Hu 2,  Guanghui Tian 2,  Jingshan Shen 1 3 4 5,  Qiongqiong Hou 2,  Yang He 1 4,  Haji Akber Aisa 3 4 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 Vigonvita Shanghai Co., Ltd, Shanghai 201210, China.
  • 3 State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 6 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 7 School of Pharmacy, Xinjiang Medical University, Urumqi 830054, China.
PMID: 40540228 DOI: 10.1021/acs.jmedchem.4c03220
Abstract

Emerging evidence suggests that compounds possessing both CB2 receptor (CB2R) agonist and TRPM8 antagonist activities may offer effective pain relief while minimizing the severe side effects commonly associated with current analgesics. In this study, we designed and synthesized a series of novel cannabigerol (CBG) derivatives with the goal of identifying potent dual ligands that act as both CB2R agonists and TRPM8 antagonists. Structure-activity relationship studies revealed that the introduction of an amide group at the C-2 position or alkylation at the C-3 position of CBG is essential for enhancing CB2R agonistic and TRPM8 antagonistic activities. CBG amides 2a and 6b exhibited dual activity as CB2R agonists and TRPM8 antagonists, displaying notable anti-inflammatory and analgesic efficacy alongside a favorable safety profile. Notably, compound 8b, a prodrug of 6b, demonstrated improved oral plasma exposure and enhanced analgesic effects in mice.

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