Platform Technology Sciences, GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709, USA.
J Pharmacol Exp Ther. 2011 Feb;336(2):296-302. doi: 10.1124/jpet.110.173948. Epub 2010 Oct 28.
With the emergence of information describing functional selectivity and biased agonists and antagonists has come a lack of confidence in "one size fits all" assays for detection of agonism. Seven-transmembrane receptors are pleiotropic with respect to the signaling protein to which they couple in a cell, and many conformations of the receptor can be formed; this leads to systems where ligands can stabilize unique conformations that go on to selectively activate signaling pathways. Thus, such "biased" ligands can produce cell-specific agonism that may require targeted assays to detect and quantify. It also predicts that ligands can have many different efficacies for the many behaviors that the receptor can exhibit (referred to as "pluridimensional efficacy"), leading to a breakdown in the common classifications of agonist and antagonist. This all poses unique challenges to the pharmacologic nomenclature of drugs, the detection and optimization of new drugs, and the association of phenotypic clinical profiles with pharmacological properties of drugs.
随着描述功能选择性和偏向激动剂和拮抗剂的信息的出现，人们对用于检测激动作用的“一刀切”检测方法的信心不足。七跨膜受体在与其在细胞中偶联的信号蛋白方面是多效的，并且可以形成许多受体构象；这导致系统中的配体可以稳定独特的构象，从而选择性地激活信号通路。因此，这种“偏向性”配体可以产生细胞特异性激动作用，可能需要靶向检测来检测和量化。它还预测配体可以对受体可以表现出的许多不同行为（称为“多维功效”）具有许多不同的功效，从而导致激动剂和拮抗剂的常见分类失效。这一切都对药物的药理学命名、新药的检测和优化以及表型临床特征与药物的药理学特性之间的关联带来了独特的挑战。
