Design and Development of New Dual Target Agents, Cannabinoid Subtype 2 Receptor (CB2R) Agonists, and Fatty Acid Amide Hydrolase (FAAH) Inhibitors against Neurodegeneration.

As dual modulators of Cannabinoid subtype 2 receptor (CB2R) and fatty acid amide hydrolase (FAAH)an arising therapeutic strategy against diseases based on neuroinflammationwe developed a new series of N-adamantyl-benzamides bearing an anthranilic or salicylic scaffold. Derivatives 18, 22, and 25 emerged as an interesting compromise in terms of CB2R activity, CB2R/CB1R selectivity, and FAAH inhibition. All compounds were potent FAAH inhibitors; 18 and 25 acted as unbiased CB2R agonists with no CB1R affinity, whereas 22 was a CB2R antagonist in the cAMP pathway and partial agonist in β-arrestin-2 recruitment. The three compounds were tested in monocytes and macrophages in resting and activated states and in a human activated microglia model with a potent anti-inflammatory action. These results support the CB2R and FAAH engagement as a promising dual strategy against neuroinflammation providing valuable chemical tools for probing the structural determinants underlying CB2R binding, long residence time, and biased signaling.