Abstract：
Chemokine receptors are relevant targets for a multitude of immunological diseases, but drug attrition for these receptors is remarkably high. While many drug discovery programs have been pursued, most prospective drugs failed in the follow-up studies due to clinical inefficacy, and hence there is a clear need for alternative approaches. Allosteric modulators of receptor function represent an excellent opportunity for novel drugs, as they modulate receptor activation in a controlled manner and display increased selectivity, and their pharmacological profile can be insurmountable. Here, we discuss allosteric ligands and their pharmacological characterization for modulation of chemokine receptors. Ligands are included if (1) they show clear signs of allosteric modulation in vitro and (2) display evidence of binding in a topologically distinct manner compared to endogenous chemokines. We discuss how allosteric ligands affect binding of orthosteric (endogenous) ligands in terms of affinity as well as binding kinetics in radioligand binding assays. Moreover, their effects on signaling events in functional assays and how their binding site can be elucidated are specified. We substantiate this with examples of published allosteric ligands targeting chemokine receptors and hypothetical graphs of pharmacological behavior. This review should serve as an effective starting point for setting up assays for characterizing allosteric ligands to develop safer and more efficacious drugs for chemokine receptors and, ultimately, other G protein-coupled receptors.
摘要：
趋化因子受体是多种免疫性疾病的相关靶点,但是这些受体的药物消耗非常高。虽然已经进行了许多药物发现计划，由于临床无效，大多数前瞻性药物在后续研究中失败，因此，显然需要替代方法。受体功能的变构调节剂代表了新药的绝佳机会，因为它们以受控的方式调节受体激活并显示出增加的选择性，它们的药理学特征是不可逾越的。这里,我们讨论了变构配体及其调节趋化因子受体的药理学表征。如果(1)配体在体外显示出明显的变构调节迹象和(2)与内源性趋化因子相比以拓扑上不同的方式显示出结合的证据,则包括配体。我们讨论了变构配体如何在亲和力以及放射性配体结合测定中的结合动力学方面影响正构（内源性）配体的结合。此外，具体说明了它们在功能测定中对信号事件的影响以及如何阐明它们的结合位点。我们通过已发表的靶向趋化因子受体的变构配体的例子和药理学行为的假设图来证实这一点。这篇综述应作为建立表征变构配体的测定方法的有效起点，以开发更安全，更有效的趋化因子受体药物，最终,其他G蛋白偶联受体。
