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

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.

属于内源性大麻素系统的2型大麻素受体（CB2R）在炎症相关病理状态中呈过表达，其激活可对抗炎症反应。脂肪酸酰胺水解酶（FAAH）是负责降解主要内源性大麻素——花生四烯酸乙醇胺（anandamide）的酶；因此，同时激活CB2R并抑制FAAH，或可成为协同抗炎的有效策略。得益于主成分分析（PCA）所揭示的CB2R与FAAH配体共享广阔化学空间的结果，我们设计了金刚烷基苯甲酰胺小分子库，作为兼具CB2R激动剂与FAAH抑制剂活性的双靶点调节剂。我们对新型化合物的CB2R亲和力/选择性以及CB2R和FAAH活性进行了测试。衍生物13、26和27作为CB2R完全激动剂与FAAH抑制剂，展现出最优的药效学特征，可下调促炎细胞因子的产生并上调抗炎细胞因子的产生。分子对接模拟通过阐释活性背后的分子作用机制，进一步补充了实验结果。此类多靶点配体是极具潜力的抗炎候选药物。