Functional Selectivity and Biased Receptor Signaling
Functional Selectivity and Biased Receptor Signaling
复制标题
DOI：
10.1124/jpet.110.173948
复制
发表时间：
2011-02-01
影响因子：
3.5
通讯作者：
Kenakin, Terry
中科院分区：
文献类型：
--
作者：
Kenakin, Terry
随着描述功能选择性以及有偏向的激动剂和拮抗剂的信息的出现，人们对“一刀切”的激动检测检测缺乏信心。七次跨膜受体对于它们在细胞中偶联的信号蛋白而言是多效性的，并且可以形成受体的许多构象；这导致配体可以稳定独特构象的系统，从而选择性地激活信号通路。因此，这种“偏向”配体可以产生细胞特异性激动，可能需要靶向测定来检测和定量。它还预测配体对于受体可以表现出的许多行为可以具有许多不同的功效（称为“多维功效”），从而导致激动剂和拮抗剂的常见分类的崩溃。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药理特性的关联提出了独特的挑战。
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.