Recent Advances on Type-2 Cannabinoid (CB₂) Receptor Agonists and their Therapeutic Potential

In the last decade, selective modulators of type-2 cannabinoid receptor (CB₂) have become a major focus to target endocannabinoid signaling in humans. Indeed, heterogeneously expressed within our body, CB₂ actively regulates several physio-pathological processes, thus representing a promising target for developing specific and safe therapeutic drugs. If CB₂ modulation has been extensively studied since the very beginning for the treatment of pain and inflammation, the more recent involvement of this receptor in other pathological conditions has further strengthened the pursuit of novel CB₂ agonists in the last five years. Against this background, here we discuss the most recent evidence of the protective effects of CB₂ against pathological conditions, emphasizing central nervous system disorders, bone and synovial diseases, and cancer. We also summarize the most recent advances in the development of CB₂ agonists, focusing on the correlation between different chemical classes and diverse therapeutic applications. Data mining includes a review of the CB₂ ligands disclosed in patents also released in the last five years. Finally, we discuss how the recent elucidation of CB₂ tertiary structure has provided new details for the rational design of novel and more selective CB₂ agonists, thus supporting innovative strategies to develop effective therapeutics. Our overview of the current knowledge on CB₂ agonists provides pivotal information on the structure and function of different classes of molecules and opens possible avenues for future research.