PDF(Pubmed)
Abstract：
G protein-coupled receptors (GPCRs) represent the target for approximately a third of FDA-approved small molecule drugs. The adenosine A1 receptor (A1R), one of four adenosine GPCR subtypes, has important (patho)physiological roles in humans. A1R has well-established roles in the regulation of the cardiovascular and nervous systems, where it has been identified as a potential therapeutic target for a number of conditions, including cardiac ischemia-reperfusion injury, cognition, epilepsy, and neuropathic pain. A1R small molecule drugs, typically orthosteric ligands, have undergone clinical trials. To date, none have progressed into the clinic, predominantly due to dose-limiting unwanted effects. The development of A1R allosteric modulators that target a topographically distinct binding site represent a promising approach to overcome current limitations. Pharmacological parameters of allosteric ligands, including affinity, efficacy and cooperativity, can be optimized to regulate A1R activity with high subtype, spatial and temporal selectivity. This review aims to offer insights into the A1R as a potential therapeutic target and highlight recent advances in the structural understanding of A1R allosteric modulation.
摘要：
G蛋白偶联受体（GPCRs）代表了大约三分之一的FDA批准的小分子药物的靶标。腺苷A1受体（A1R），四种腺苷GPCR亚型之一，在人类中具有重要的（病理）生理作用。A1R在心血管和神经系统的调节中具有公认的作用，它已被确定为许多疾病的潜在治疗靶标，包括心脏缺血再灌注损伤,认知，癫痫,和神经性疼痛。A1R小分子药物，通常是正构配体，经过临床试验。迄今为止,没有人进入诊所，主要是由于剂量限制的不必要的影响。靶向拓扑上不同的结合位点的A1R变构调节剂的开发代表了克服当前限制的有希望的方法。变构配体的药理学参数，包括亲和力，功效和协同性，可以优化以调节高亚型的A1R活性，空间和时间的选择性。这篇综述旨在提供对A1R作为潜在治疗靶标的见解，并强调对A1R变构调制的结构理解的最新进展。
