Discipline of Pharmacology, School of Medical Sciences, University of Sydney, Sydney, NSW, Australia.
Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany.
Trends Pharmacol Sci. 2020 Dec;41(12):947-959. doi: 10.1016/j.tips.2020.09.009. Epub 2020 Oct 20.
G protein-biased agonists of the μ-opioid receptor (MOPr) have been proposed as an improved class of opioid analgesics. Recent studies have been unable to reproduce the original experiments in the β-arrestin2-knockout mouse that led to this proposal, and alternative genetic models do not support the G protein-biased MOPr agonist hypothesis. Furthermore, assessment of putatively biased ligands has been confounded by several factors, including assay amplification. As such, the extent to which current lead compounds represent mechanistically novel, extremely G protein-biased agonists is in question, as is the underlying assumption that β-arrestin2 mediates deleterious opioid effects. Addressing these current challenges represents a pressing issue to successfully advance drug development at this receptor and improve upon current opioid analgesics.
μ 阿片受体（MOPr）的 G 蛋白偏向激动剂被提议为一种改进的阿片类镇痛药。最近的研究未能重现导致这一建议的β-arrestin2 敲除小鼠的原始实验，并且替代遗传模型不支持 G 蛋白偏向 MOPr 激动剂假说。此外，对假定的偏向配体的评估受到几个因素的混淆，包括测定放大。因此，目前的先导化合物在多大程度上代表机制新颖的、极度偏向 G 蛋白的激动剂，以及β-arrestin2 介导有害阿片类效应的基本假设，都存在疑问。解决这些当前的挑战是成功推进该受体的药物开发并改进当前阿片类镇痛药的紧迫问题。
