Development of <i>N</i>‑(1-Adamantyl)benzamides as Novel Anti-Inflammatory Multitarget Agents Acting as Dual Modulators of the Cannabinoid CB2 Receptor and Fatty Acid Amide Hydrolase

Cannabinoid type 2 receptor (CB2R), belonging to the
endocannabinoid
system, is overexpressed in pathologies characterized by inflammation,
and its activation counteracts inflammatory states. Fatty acid amide
hydrolase (FAAH) is an enzyme responsible for the degradation of the
main endocannabinoid anandamide; thus, the simultaneous CB2R activation
and FAAH inhibition may be a synergistic anti-inflammatory strategy.
Encouraged by principal component analysis (PCA) data identifying
a wide chemical space shared by CB2R and FAAH ligands, we designed
a small library of adamantyl-benzamides, as potential dual agents,
CB2R agonists, and FAAH inhibitors. The new compounds were tested
for their CB2R affinity/selectivity and CB2R and FAAH activity. Derivatives 13, 26, and 27, displaying the best
pharmacodynamic profile as CB2R full agonists and FAAH inhibitors,
decreased pro-inflammatory and increased anti-inflammatory cytokines
production. Molecular docking simulations complemented the experimental
findings by providing a molecular rationale behind the observed activities.
These multitarget ligands constitute promising anti-inflammatory agents.