Leach Katie, Sexton Patrick M, Christopoulos Arthur
Drug Discovery Biology Laboratory, Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia.
Trends Pharmacol Sci. 2007 Aug;28(8):382-9. doi: 10.1016/j.tips.2007.06.004. Epub 2007 Jul 13.
The past decade has witnessed a dramatic increase in the identification of allosteric modulators of G-protein-coupled receptor (GPCR) activity. Concomitantly, several new perspectives and hypotheses regarding the way ligands regulate GPCR signalling have also emerged. Here, we briefly discuss how the concepts of collateral efficacy and permissive agonism-antagonism intersect the field of allosteric GPCR modulation. Despite the challenges associated with detecting and quantifying the myriad of possible allosteric effects on GPCR activity, it is proposed that allosteric ligands offer the exciting prospect of engendering stimulus-bias in orthosteric ligand signalling, thus paving the way for not only receptor-selective but also signalling-pathway-selective therapies.
在过去十年中，G蛋白偶联受体（GPCR）活性变构调节剂的鉴定数量急剧增加。与此同时，关于配体调节GPCR信号传导方式的一些新观点和假设也应运而生。在此，我们简要讨论旁效和允许性激动-拮抗概念如何与变构GPCR调节领域相互交叉。尽管检测和量化对GPCR活性的无数可能变构效应存在挑战，但有人提出变构配体为在正构配体信号传导中产生刺激偏向提供了令人兴奋的前景，从而不仅为受体选择性疗法，也为信号通路选择性疗法铺平了道路。
