Newly designed pyrrolo[2,1-c][1,4]benzodiazepines tricyclic skeleton has shown potential clusters of cannabinoid receptors CB1/CB2 selective ligands. CB2 plays a critical role in microglial-derived neuroinflammation, where it modulates cell proliferation, migration, and differentiation into M1 or M2 phenotypes. Beginning with computer-based docking studies accounting the recently discovered X-ray crystal structure of CB2, we designed a series of PBD analogs as potential ligands of CB2 and tested their binding affinities. Interestingly, computational studies and theoretical binding affinities of several selected (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs, have revealed the presence of potential selectivity in binding attraction toward CB1 and CB2. Reported here is the discovery of the first representatives of this series of selective binding to CB2. Preliminary data showed that this class of molecules display potential binding efficacy toward the cannabinoid receptors tested. Intriguingly, initial cannabinoid binding assay showed a selective binding affinity of 4g and 4h showed K_i of 0.49 and 4.7 μM toward CB2 receptors while no binding was observed to CB1. The designed leads have shown remarkable stability pattern at the physiological pH magnifying their therapeutic values. We hypothesize that the PBD tricyclic structure offers the molecule an appropriate three-dimensional conformation to fit snugly within the active site of CB2 receptors, giving them superiority over the reported CB2 agonists/inverse agonists. Our findings suggested that the attachment of heterocyclic ring through the condensation of diazepine hydrazone and S- or N-heterocyclic aldehydes enhances the selectivity of CB2 over CB1.

新设计的吡咯并[2,1-c][1,4]苯并二氮杂三环骨架已显示出潜在的大麻素受体CB1/CB2选择性配体簇。CB2 在小胶质细胞衍生的神经炎症中起着关键作用，它调节细胞增殖、迁移和分化为 M1 或 M2 表型。从最近发现的 CB2 的 X 射线晶体结构的基于计算机的对接研究开始，我们设计了一系列 PBD 类似物作为 CB2 的潜在配体并测试了它们的结合亲和力。有趣的是，几个选定的（S，E)-11-[2-(芳基亚甲基)腙]-PBD 类似物已经揭示了在对 CB1 和 CB2 的结合吸引力方面存在潜在的选择性。这里报道的是该系列选择性结合 CB2 的第一个代表的发现。初步数据表明，这类分子对测试的大麻素受体显示出潜在的结合功效。有趣的是，最初的大麻素结合试验显示选择性结合亲和力为4g，4h显示K _i0.49 和 4.7 μM 对 CB2 受体的影响，而未观察到与 CB1 的结合。设计的导线在生理 pH 值下显示出显着的稳定性模式，从而放大了它们的治疗价值。我们假设 PBD 三环结构为分子提供了合适的三维构象，以紧密配合 CB2 受体的活性位点，使其优于报道的 CB2 激动剂/反向激动剂。我们的研究结果表明，通过二氮腙和 S-或 N-杂环醛的缩合连接杂环增强了 CB2 对 CB1 的选择性。