Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
Prog Mol Biol Transl Sci. 2013;118:469-97. doi: 10.1016/B978-0-12-394440-5.00018-8.
Our growing appreciation of the pluridimensionality of G protein-coupled receptor (GPCR) efficacy, coupled with the phenomenon of orthosteric ligand "bias," offers the prospect of drugs that selectively modulate different aspects of GPCR function for therapeutic benefit. As the best-studied non-G protein effectors, arrestins have been shown to mediate a wide range of GPCR signals, and arrestin pathway-selective ligands have been identified for several receptors. When viewed from the perspective of short term in vitro assays, such "biased" agonists appear to activate a subset of the response profile produced by a conventional agonist. Yet, when examined in vivo, the limited data available suggest that biased ligand effects can diverge from their conventional counterparts in ways that cannot be predicted from their in vitro efficacy profile. While some widely conserved arrestin-regulated biological processes are becoming apparent, what is lacking at present is a rational framework for relating the in vitro efficacy of a "biased" agonist to its in vivo actions that will aid drug discovery programs in identifying "biased" ligands with the desired biological effects.
我们越来越意识到 G 蛋白偶联受体 (GPCR) 效能的多维性，再加上变构配体“偏向性”的现象，为开发选择性调节 GPCR 功能不同方面的药物以带来治疗益处提供了前景。作为研究得最多的非 G 蛋白效应物，arrestin 已被证明可以介导广泛的 GPCR 信号，并且已经为几种受体鉴定了 arrestin 途径选择性配体。从短期体外测定的角度来看，这种“偏向性”激动剂似乎激活了传统激动剂产生的反应谱的子集。然而，在体内进行检查时，现有的有限数据表明，偏向性配体的作用与其体外效能谱预测的方式不同，不能从其体外效能谱预测。虽然一些广泛保守的 arrestin 调节的生物过程正在变得明显，但目前缺乏将“偏向性”激动剂的体外效能与其体内作用联系起来的合理框架，这将有助于药物发现计划识别具有所需生物学效应的“偏向性”配体。
