Discovery of a CB and 5-HT receptor dual agonist for the treatment of depression and anxiety.

Cannabinoid CBR agonists have gained considerable attention as potential novel therapies for psychiatric disorders due to their non-psychoactive nature, in contrast to CBR agonists. In this study, we employed molecular docking to design and synthesize 23 derivatives of cannabidiol (CBD) with the aim of discovering potent CBR agonists rather than CBR antagonists or inverse agonists. Structure-activity relationship (SAR) investigations highlighted the critical importance of the amide group at the C-3' site and the cycloalkyl group at the C-4' site for CBR activation. Interestingly, three CBD derivatives, namely 2o, 6g, and 6h, exhibited substantial partial agonistic activity towards the CB receptor, in contrast to the inverse agonistic property of CBD. Among these, 2o acted as a CBR and 5-HTR dual agonist, albeit with some undesired antagonist activity for CBR. It demonstrated significant CBR partial agonism while maintaining a level of 5-HTR agonistic and CBR antagonistic activity similar to CBD. Pharmacokinetic experiments confirmed that 2o possesses favorable pharmacokinetic properties. Behavioral studies further revealed that 2o elicits significant antidepressant-like and anxiolytic-like effects while maintaining a good safety profile.