Identification of Cannabigerol-Derived Dual CB 2 Receptor Agonists and TRPM8 Antagonists with Anti-Inflammatory and Analgesic Activities

作者：Wenjiao Yang, Haiguo Sun, Jing Ji, Hailan Chen, Jiaxin Cheng, Zhengtao Hu, Xudong Gong, Qi Liu, Peng Su, Jin Suo, Tianwen Hu, Guanghui Tian, Jingshan Shen, Qiongqiong Hou, He Yang, Haji Akber Aisa · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.4c03220 · 被引用次数：3 · 研究领域：Cannabis and Cannabinoid Research、Ion Channels and Receptors、Pharmacological Receptor Mechanisms and Effects

Emerging evidence suggests that compounds possessing both CB 2 receptor (CB 2 R) 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 CB 2 R 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 CB 2 R agonistic and TRPM8 antagonistic activities. CBG amides 2a and 6b exhibited dual activity as CB 2 R 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.