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Pharmacological modulation of P2X receptors by approved drugs and natural compounds

已批准药物和天然化合物对 P2X 受体的药理学调节

基本信息

批准号：
174288178
负责人：
Professor Dr. Michael Schaefer
金额：
--
依托单位：
Rudolf-Boehm-Institut für Pharmakologie und Toxikologie
依托单位国家：
德国
项目类别：
Research Units
财政年份：
2010
资助国家：
德国
起止时间：
2009-12-31 至 2013-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/174288178?language=en
关键词：
Pharmacological modulation P2X receptors approved

项目摘要

ATP-gated, non-selective cation channels of the P2X family are key regulators of glio-neuronal communication and pain perception in response to tissue damage or inflammation. Their activity is further tuned by numerous cell-biological mechanisms, including phosphorylation, glycosylation and allosteric modulation by extracellular ligands and lipids. Screening of a compound library that comprises 1040 approved drugs, 800 natural compounds with annotated biological activity and 160 toxins and pharmacological modulators revealed that both the number of active compounds and the potency of modulation is uniquely high for P2X7 compared to other channel entities. Therefore, this project will focus on the physiological and pathophysiological relevance of P2X receptor modulation by approved drugs and on structurally mapping allosteric binding sites on the P2X receptor ectodomains. By large-scale analysis of pharmacological modulation of P2X2, P2X4 and P2X7, the specificity of allosteric modulation will be assessed. For selected modulators, the mode of action, activity on endogenously expressed P2X receptors and cell-biological consequences will be worked out and pharmacological perspectives will be evaluated. Taking advantage of the recently solved structure of the P2X4 ectodomain, a map of allosteric modulation sites will be constructed applying various strategies. Experimental results of functional screens will be compared to docking analyses of the used compounds onto the known structure of zebrafish P2X4 and on homology models of human P2X4, P2X2 and P2X7. Targeted occlusion of single binding cavities by site-directed mutagenesis and biochemical approaches will be applied to firmly establish the mapping of allosteric modulatory sites. To gather information about potential endogenous modulators, phylogenetic conservation of binding pockets will be analyzed and the chemical structure of modulators that bind to conserved pockets will serve as template for the search of novel endogenous P2X receptor modulators.

ATP门控的、非选择性的P2X家族阳离子通道是神经胶质细胞通讯和组织损伤或炎症反应中痛觉的关键调节因子。它们的活性受到许多细胞生物学机制的进一步调节，包括细胞外配体和脂类的磷酸化、糖基化和变构调节。对包含1040种已批准药物、800种具有注释生物活性的天然化合物和160种毒素和药理调节剂的化合物文库的筛选表明，与其他通道实体相比，P2X7的活性化合物数量和调节效力都是独一无二的。因此，本项目将集中于已批准的药物对P2X受体调控的生理学和病理生理学相关性，并从结构上定位P2X受体胞外区上的变构结合部位。通过对P2X2、P2X4和P2X7的药理调控的大规模分析，将评估变构调控的特异性。对于选定的调节剂，将研究作用模式、对内源性表达的P2X受体的活性以及细胞生物学后果，并对药理学前景进行评估。利用最近解决的P2X4胞外结构域的结构，将应用各种策略构建变构调制位点图。功能筛选的实验结果将与所用化合物与斑马鱼P2X4的已知结构以及人类P2X4、P2X2和P2X7的同源模型的对接分析进行比较。通过定点突变和生化方法对单个结合腔进行靶向阻断将被用来牢固地建立变构调节位点的图谱。为了收集有关潜在内源性调节剂的信息，将分析结合口袋的系统发育保守，并将结合保守口袋的调节器的化学结构作为寻找新型内源性P2X受体调节剂的模板。