The function of G protein‐coupled receptors (GPCRs) can be modulated by compounds that bind to other sites than the endogenous orthosteric binding site, so‐called allosteric sites. Structure elucidation of a number of GPCRs has revealed the presence of a sodium ion bound in a conserved allosteric site. The small molecule amiloride and analogs thereof have been proposed to bind in this same sodium ion site. Hence, this review seeks to summarize and reflect on the current knowledge of allosteric effects by amiloride and its analogs on GPCRs. Amiloride is known to modulate adenosine, adrenergic, dopamine, chemokine, muscarinic, serotonin, gonadotropin‐releasing hormone, GABA_B, and taste receptors. Amiloride analogs with lipophilic substituents tend to be more potent modulators than amiloride itself. Adenosine, α‐adrenergic and dopamine receptors are most strongly modulated by amiloride analogs. In addition, for a few GPCRs, more than one binding site for amiloride has been postulated. Interestingly, the nature of the allosteric effect of amiloride and derivatives varies considerably between GPCRs, with both negative and positive allosteric modulation occurring. Since the sodium ion binding site is strongly conserved among class A GPCRs it is to be expected that amiloride also binds to class A GPCRs not evaluated yet. Investigating this typical amiloride‐GPCR interaction further may yield general insight in the allosteric mechanisms of GPCR ligand binding and function, and possibly provide new opportunities for drug discovery.

中文翻译：

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阿米洛利及其衍生物对G蛋白偶联受体的变构调节。药物发现的前景？

G蛋白偶联受体（GPCR）的功能可以通过与内源性正构结合位点以外的其他位点（所谓的变构位点）结合的化合物来调节。许多GPCR的结构阐明已经揭示了在保守的变构位点结合的钠离子的存在。已经提出小分子阿米洛利及其类似物在该相同的钠离子位点结合。因此，本综述旨在总结和反思阿米洛利及其类似物对GPCR的变构作用的最新知识。已知阿米洛利可调节腺苷，肾上腺素，多巴胺，趋化因子，毒蕈碱，5-羟色胺，促性腺激素释放激素，GABA _B和味觉感受器。具有亲脂性取代基的阿米洛利类似物往往比阿米洛利本身更有效。腺苷，α-肾上腺素和多巴胺受体受阿米洛利类似物的调节最强。另外，对于一些GPCR，已假定阿米洛利有一个以上的结合位点。有趣的是，阿米洛利及其衍生物的变构作用的性质在GPCR之间存在很大差异，同时发生了负和正变构调节。由于钠离子结合位点在A类GPCR中高度保守，因此可以预期阿米洛利也与尚未评估的A类GPCR结合。研究这种典型的阿米洛利与GPCR的相互作用可能会进一步了解GPCR配体结合和功能的变构机制，