Milligan Graeme, Smith Nicola J
Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland, UK.
Trends Pharmacol Sci. 2007 Dec;28(12):615-20. doi: 10.1016/j.tips.2007.11.001. Epub 2007 Nov 19.
G-protein-coupled receptors (GPCRs) are, and will probably remain, the most tractable class of targets for the development of small-molecule therapeutic medicines. Currently, all approved GPCR-directed medicines are agonists or antagonists at orthosteric binding sites - except for the calcimimetic cinacalcet, which is a positive allosteric modulator of Ca(2+)-sensing receptors, and maraviroc, an allosteric inhibitor of CC-chemokine receptor (CCR) 5. It is now widely accepted that GPCRs exist and might function as dimers, and there is growing evidence for the physiological presence and relevance of GPCR heterodimers. Molecules that can regulate a GPCR within a heterodimer, through allosteric effects between the two protomers of the dimer or between a protomer or protomers and the associated G protein, offer the potential to function in a highly selective and tissue-specific way. Despite the conceptual attraction of such allosteric regulators of GPCR heterodimers as drugs, they cannot be identified by screening approaches that routinely use a 'one GPCR target at a time' strategy. In our opinion, this will require the development of new approaches for screening and a return to the use of physiologically relevant cell systems at an early stage in compound identification.
G蛋白偶联受体（GPCRs）过去是、而且可能仍将是小分子治疗药物开发中最易于处理的一类靶点。目前，所有已获批的针对GPCR的药物都是正构结合位点的激动剂或拮抗剂——除了拟钙剂西那卡塞，它是钙敏感受体的正变构调节剂，以及马拉维若，一种CC趋化因子受体（CCR）5的变构抑制剂。现在人们普遍认为GPCR以二聚体形式存在且可能发挥二聚体功能，并且越来越多的证据表明GPCR异二聚体在生理上的存在及其相关性。能够通过二聚体的两个亚基之间或一个亚基或多个亚基与相关G蛋白之间的变构效应来调节异二聚体内GPCR的分子，具有以高度选择性和组织特异性方式发挥作用的潜力。尽管GPCR异二聚体的这种变构调节剂作为药物具有概念上的吸引力，但它们无法通过常规采用“一次一个GPCR靶点”策略的筛选方法来识别。我们认为，这将需要开发新的筛选方法，并在化合物鉴定的早期阶段重新使用生理相关的细胞系统。
