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

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.