Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Department of Pathology, University of Pisa, 56126 Pisa, Italy.
Int J Mol Sci. 2023 Jan 21;24(3):2135. doi: 10.3390/ijms24032135.
Very recently, we have developed a new generation of ligands targeting the cannabinoid receptor type 2 (CB2R), namely compounds, which combine the pharmacophoric portion of the CB2R positive allosteric modulator (PAM), , with that of the CB2R selective orthosteric agonist , both synthesized in our laboratories. The functional examination enabled us to identify , , and as the most promising compounds of the series. In the current study, we focused on the assessment of the bitopic (dualsteric) nature of these three compounds. Experiments in cAMP assays highlighted that only behaves as a CB2R bitopic (dualsteric) ligand. In parallel, computational studies helped us to clarify the binding mode of these three compounds at CB2R, confirming the bitopic (dualsteric) nature of . Finally, the potential of to prevent neuroinflammation was investigated on a human microglial cell inflammatory model.
最近，我们开发了新一代靶向大麻素受体 2（CB2R）的配体，即化合物，它们结合了我们实验室合成的 CB2R 正变构调节剂（PAM）和 CB2R 选择性正构激动剂的药效部分。功能检测使我们能够确定、和为该系列中最有前途的化合物。在当前的研究中，我们专注于评估这三种化合物的双位（双体）性质。cAMP 测定实验强调，只有作为 CB2R 的双位（双体）配体。同时，计算研究帮助我们阐明了这三种化合物在 CB2R 上的结合模式，证实了的双位（双体）性质。最后，研究了在人类小胶质细胞炎症模型上预防神经炎症的潜力。
