Graziano Giovanni, Delre Pietro, Carofiglio Francesca, Brea Josè, Ligresti Alessia, Kostrzewa Magdalena, Riganti Chiara, Gioè-Gallo Claudia, Majellaro Maria, Nicolotti Orazio, Colabufo Nicola Antonio, Abate Carmen, Loza Maria Isabel, Sotelo Eddy, Mangiatordi Giuseppe Felice, Contino Marialessandra, Stefanachi Angela, Leonetti Francesco
Department of Pharmacy-Pharmaceutical Sciences, University of the Studies of Bari "Aldo Moro", Via E.Orabona 4, 70125, Bari, Italy.
CNR - Institute of Crystallography, Via Giovanni Amendola, 122/O, 70126, Bari, Italy.
Eur J Med Chem. 2023 Feb 15;248:115109. doi: 10.1016/j.ejmech.2023.115109. Epub 2023 Jan 13.
Cannabinoid type 2 receptor (CB2R) is a G-protein-coupled receptor that, together with Cannabinoid type 1 receptor (CB1R), endogenous cannabinoids and enzymes responsible for their synthesis and degradation, forms the EndoCannabinoid System (ECS). In the last decade, several studies have shown that CB2R is overexpressed in activated central nervous system (CNS) microglia cells, in disorders based on an inflammatory state, such as neurodegenerative diseases, neuropathic pain, and cancer. For this reason, the anti-inflammatory and immune-modulatory potentials of CB2R ligands are emerging as a novel therapeutic approach. The design of selective ligands is however hampered by the high sequence homology of transmembrane domains of CB1R and CB2R. Based on a recent three-arm pharmacophore hypothesis and latest CB2R crystal structures, we designed, synthesized, and evaluated a series of new N-adamantyl-anthranil amide derivatives as CB2R selective ligands. Interestingly, this new class of compounds displayed a high affinity for human CB2R along with an excellent selectivity respect to CB1R. In this respect, compounds exhibiting the best pharmacodynamic profile in terms of CB2R affinity were also evaluated for the functional behavior and molecular docking simulations provided a sound rationale by highlighting the relevance of the arm 1 substitution to prompt CB2R action. Moreover, the modulation of the pro- and anti-inflammatory cytokines production was also investigated to exert the ability of the best compounds to modulate the inflammatory cascade.
大麻素2型受体（CB2R）是一种G蛋白偶联受体，它与大麻素1型受体（CB1R）、内源性大麻素以及负责其合成和降解的酶一起，构成了内源性大麻素系统（ECS）。在过去十年中，多项研究表明，在基于炎症状态的疾病中，如神经退行性疾病、神经性疼痛和癌症，CB2R在活化的中枢神经系统（CNS）小胶质细胞中过度表达。因此，CB2R配体的抗炎和免疫调节潜力正成为一种新的治疗方法。然而，选择性配体的设计受到CB1R和CB2R跨膜结构域高度序列同源性的阻碍。基于最近的三臂药效团假说和最新的CB2R晶体结构，我们设计、合成并评估了一系列新型N-金刚烷基-邻氨基苯甲酰胺衍生物作为CB2R选择性配体。有趣的是，这类新化合物对人CB2R显示出高亲和力，并且对CB1R具有优异的选择性。在这方面，还评估了就CB2R亲和力而言表现出最佳药效学特征的化合物的功能行为，分子对接模拟通过突出臂1取代对促进CB2R作用的相关性提供了合理的依据。此外，还研究了促炎和抗炎细胞因子产生的调节，以发挥最佳化合物调节炎症级联反应的能力。
