Functional selectivity and classical concepts of quantitative pharmacology
Functional selectivity and classical concepts of quantitative pharmacology
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DOI：
10.1124/jpet.106.104463
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发表时间：
2007-01-01
影响因子：
3.5
通讯作者：
Mailman, Richard B.
中科院分区：
文献类型：
--
作者：
Urban, Jonathan D.;Clarke, William P.;Mailman, Richard B.
内在功效的概念在药理学中已经存在了半个世纪，但最近的数据显示，许多配体可以不同地激活通过单个G蛋白偶联受体介导的信号通路，这种方式挑战了内在功效的传统定义。这种现象的一些术语包括功能选择性、激动剂定向贩运和偏向激动作用。在极端情况下，功能选择性配体可能是由同一受体介导的不同功能的激动剂和拮抗剂。说明这一现象的数据来自血清素、阿片类药物、多巴胺、抗利尿激素和肾上腺素受体系统。多种机制可能影响这一明显普遍存在的现象。它可能是由配体诱导的中间构象状态的差异引起的，如β(2)-肾上腺素能受体所示。随后可能发挥作用的机制包括G蛋白的多样性、支架和信号伙伴以及受体低聚物。显然，需要扩大研究来阐明近端机制（例如，功能选择性配体如何引起启动差异信号传导的构象变化）、中间机制（将构象变化转化为差异信号传导的机制）和远端机制（对目标组织或生物体的差异影响）。除了启发式的功能选择性之外，它对药物发现也有明显的影响，因为这种机制提高了选择或设计新的配体的可能性，这些配体只激活单个受体的一部分功能，从而优化治疗作用。修订定量药理学中的经典概念和相关药理学惯例以纳入这些新概念也可能是及时的。
The concept of intrinsic efficacy has been enshrined in pharmacology for half of a century, yet recent data have revealed that many ligands can differentially activate signaling pathways mediated via a single G protein-coupled receptor in a manner that challenges the traditional definition of intrinsic efficacy. Some terms for this phenomenon include functional selectivity, agonist-directed trafficking, and biased agonism. At the extreme, functionally selective ligands may be both agonists and antagonists at different functions mediated by the same receptor. Data illustrating this phenomenon are presented from serotonin, opioid, dopamine, vasopressin, and adrenergic receptor systems. A variety of mechanisms may influence this apparently ubiquitous phenomenon. It may be initiated by differences in ligand-induced intermediate conformational states, as shown for the beta(2)-adrenergic receptor. Subsequent mechanisms that may play a role include diversity of G proteins, scaffolding and signaling partners, and receptor oligomers. Clearly, expanded research is needed to elucidate the proximal ( e. g., how functionally selective ligands cause conformational changes that initiate differential signaling), intermediate ( mechanisms that translate conformation changes into differential signaling), and distal mechanisms ( differential effects on target tissue or organism). Besides the heuristically interesting nature of functional selectivity, there is a clear impact on drug discovery, because this mechanism raises the possibility of selecting or designing novel ligands that differentially activate only a subset of functions of a single receptor, thereby optimizing therapeutic action. It also may be timely to revise classic concepts in quantitative pharmacology and relevant pharmacological conventions to incorporate these new concepts.