PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Department of Chemistry, Faculty of Science, Sultan Qaboos University, P.O. Box 36, 123 Muscat, Oman.
J Med Chem. 2020 Jun 11;63(11):6164-6178. doi: 10.1021/acs.jmedchem.0c00435. Epub 2020 May 27.
Antagonists for the ATP-gated ion channel receptor P2X1 have potential as antithrombotics and for treating hyperactive bladder and inflammation. In this study, salicylanilide derivatives were synthesized based on a screening hit. P2X1 antagonistic potency was assessed in 1321N1 astrocytoma cells stably transfected with the human P2X1 receptor by measuring inhibition of the ATP-induced calcium influx. Structure-activity relationships were analyzed, and selectivity versus other P2X receptor subtypes was assessed. The most potent compounds, -[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (, IC 0.0192 μM) and -[3,5-bis(trifluoromethyl)phenyl]-4-chloro-2-hydroxybenzamide (, IC 0.0231 μM), displayed >500-fold selectivity versus P2X2 and P2X3, and 10-fold selectivity versus P2X4 and P2X7 receptors, and inhibited collagen-induced platelet aggregation. They behaved as negative allosteric modulators, and molecular modeling studies suggested an extracellular binding site. Besides selective P2X1 antagonists, compounds with ancillary P2X4 and/or P2X7 receptor inhibition were discovered. These compounds represent the first potent, non-acidic, allosteric P2X1 receptor antagonists reported to date.
针对 ATP 门控离子通道受体 P2X1 的拮抗剂有望成为抗血栓药物，用于治疗膀胱过度活动症和炎症。在这项研究中，基于筛选命中的结果，合成了水杨酰苯胺衍生物。通过测量对 ATP 诱导的钙内流的抑制作用，在稳定转染人 P2X1 受体的 1321N1 星形细胞瘤细胞中评估了 P2X1 拮抗作用。分析了结构-活性关系，并评估了对其他 P2X 受体亚型的选择性。最有效的化合物为-[3,5-双（三氟甲基）苯基]-5-氯-2-羟基苯甲酰胺（，IC 0.0192 μM）和-[3,5-双（三氟甲基）苯基]-4-氯-2-羟基苯甲酰胺（，IC 0.0231 μM），对 P2X2 和 P2X3 的选择性>500 倍，对 P2X4 和 P2X7 受体的选择性为 10 倍，并抑制胶原诱导的血小板聚集。它们表现为负变构调节剂，分子建模研究表明存在细胞外结合位点。除了选择性 P2X1 拮抗剂外，还发现了具有辅助 P2X4 和/或 P2X7 受体抑制作用的化合物。这些化合物代表了迄今为止报道的第一个有效的、非酸性的、变构的 P2X1 受体拮抗剂。
