Mingle David, Ospanov Meirambek, Radwan Mohamed O, Ashpole Nicole, Otsuka Masami, Ross Samir A, Walker Larry, Shilabin Abbas G, Ibrahim Mohamed A
Department of Chemistry, East Tennessee State University, Johnson City, TN 37614, USA.
National Center for Natural Products Research, University of Mississippi, University, MS 38677.
Med Chem Res. 2021 Jan;30(1):98-108. doi: 10.1007/s00044-020-02640-2. Epub 2020 Oct 4.
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 (,)-11-[2-(arylmethylene)hydrazono]-PBD analogs, have revealed the presence of potential selectivity in binding attraction towards 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 towards the cannabinoid receptors tested. Intriguingly, initial cannabinoid binding assay showed a selective binding affinity of and showed of 0.49 and 4.7 μM towards 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]苯并二氮杂卓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在小胶质细胞源性神经炎症中起关键作用，它调节细胞增殖、迁移以及分化为M1或M2表型。从基于计算机的对接研究开始，考虑到最近发现的CB2的X射线晶体结构，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，几种选定的（，）-11-[2-（芳基亚甲基）腙]-PBD类似物的计算研究和理论结合亲和力揭示了对CB1和CB2的结合吸引力存在潜在选择性。本文报道了该系列中首个对CB2具有选择性结合的代表物的发现。初步数据表明，这类分子对所测试的大麻素受体显示出潜在的结合效力。有趣的是，初始大麻素结合试验显示其对CB2受体的选择性结合亲和力为，对CB2受体的亲和力分别为0.49和4.7μM，而对CB1未观察到结合。所设计的先导化合物在生理pH下显示出显著的稳定性模式，放大了它们的治疗价值。我们推测，PBD三环结构为分子提供了合适的三维构象，使其能够紧密地契合在CB2受体的活性位点内，从而使其优于已报道的CB2激动剂/反向激动剂。我们的研究结果表明，通过二氮杂卓腙与S-或N-杂环醛的缩合连接杂环可增强CB2对CB1的选择性。
