Drug Design & Discovery Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Allahabad, Uttar Pradesh, 211007, India.
Department of Medicine and Health Sciences, University Rovira i Virgili, Tarragona, 43007, Spain.
Neurosci Lett. 2020 Sep 14;735:135222. doi: 10.1016/j.neulet.2020.135222. Epub 2020 Jun 30.
Various studies showed adenosine AA receptors (AARs) antagonists have profound therapeutic efficacy in Parkinsons Disease (PD) by improving dopamine transmission, thus being active in reversing motor deficits and extrapyramidal symptoms related to the disease. Therefore, in the presents study, we have showed the development of novel 1,3,5-triazine-thiadiazole derivative as potent AARs antagonist. In the radioligand binding assay, these molecules showed excellent binding affinity with AAR compared to AR, with significant selectivity. Results suggest, compound 7e as most potent antagonist of AAR among the tested series. In docking analysis with AAR protein model, compound 7e found to be deeply buried into the cavity of receptor lined via making numerous interatomic contacts with His264, Tyr271, His278, Glu169, Ala63, Val84, Ile274, Met270, Phe169. Collectively, our study demonstrated 1,3,5-triazine-thiadiazole hybrid as a highly effective scaffold for the design of new AA antagonists.
各种研究表明，腺嘌呤 AA 受体（AARs）拮抗剂通过改善多巴胺传递，在帕金森病（PD）中具有深远的治疗效果，因此可有效逆转与疾病相关的运动缺陷和锥体外系症状。因此，在本研究中，我们开发了新型 1,3,5-三嗪-噻二唑衍生物作为有效的 AARs 拮抗剂。在放射性配体结合试验中，与 AR 相比，这些分子对 AAR 表现出优异的结合亲和力，具有显著的选择性。结果表明，在所测试的系列化合物中，化合物 7e 是 AAR 最强的拮抗剂。在与 AAR 蛋白模型的对接分析中，发现化合物 7e 通过与 His264、Tyr271、His278、Glu169、Ala63、Val84、Ile274、Met270、Phe169 等残基形成大量原子间相互作用，深深地埋藏在受体的空腔中。综上所述，我们的研究表明 1,3,5-三嗪-噻二唑杂合体是设计新型 AA 拮抗剂的高效骨架。
