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

Abstract

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.

Endocannabinoid Hydrolase Inhibitors: Potential Novel Anxiolytic Drugs

“… 193 Compounds designed to target FAAH inhibition/activation of CB2R also have potent neuroinflammatory inhibitory effects. 194 …”

“…193 Compounds designed to target FAAH inhibition/activation of CB2R also have potent neuroinflammatory inhibitory effects. 194 Furthermore, FAAH inhibitors also have central and peripheral inhibition selectivity. For example, ASP3652, which entered clinical trials, is a well-tolerated peripheral reversible FAAH inhibitor that reduces lower urinary tract symptoms but no efficacy in the improvement of patients' pain symptoms, possibly related to its lack of central inhibition.…”

Endocannabinoid Degradation Enzyme Inhibitors as Potential Antipsychotics: A Medicinal Chemistry Perspective

“…A disruption of the physiological activity of this system (i.e., modifications in the expression of receptors or the functions of enzymes) is associated with various pathologies. This situation, therefore, is the basis for therapeutic pharmacological opportunities founded on drugs able to interact naturally with ECS [26][27][28][29][30]. The inhibition of enzymes responsible for the degradation of the ECS endogenous ligands might overcome the above obstacles to the systemic use of exogenous substances acting on ECS.…”

“…A disruption of the physiological activity of this system (i.e., modifications in the expression of receptors or the functions of enzymes) is associated with various pathologies. This situation, therefore, is the basis for therapeutic pharmacological opportunities founded on drugs able to interact naturally with ECS [26][27][28][29][30].…”