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

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.