Bond Richard A, Ijzerman Ad P
Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 4800 Calhoun, Houston, TX 77204-5037, USA.
Trends Pharmacol Sci. 2006 Feb;27(2):92-6. doi: 10.1016/j.tips.2005.12.007. Epub 2006 Jan 6.
The concept of constitutively active G-protein-coupled receptors is now firmly rooted in receptor pharmacology. Many independent research groups have contributed to its acceptance since its introduction by Costa and Herz in 1989. This concept necessitated a revised ligand classification, and a new category of inverse agonists was introduced alongside existing agonist and antagonist ligands. Initially, it was hoped that new therapeutic modalities would become available. However, the drug industry has not adopted inverse agonism as a design criterion and instead accepted that some compounds emerge as (neutral) antagonists in compound screening, whereas other compounds possess inverse agonistic activity. In this article, we summarize aspects of the impact of constitutive activity on the drug-discovery process: for example, its use in orphan receptor assays, its link with pharmacogenetics and genomics, and its relevance for currently marketed drugs.
组成型激活的G蛋白偶联受体的概念如今已在受体药理学中深深扎根。自1989年科斯塔和赫茨引入该概念以来，许多独立的研究小组都为其被接受做出了贡献。这一概念需要对配体进行修订分类，除了现有的激动剂和拮抗剂配体外，还引入了一类新的反向激动剂。最初，人们希望能有新的治疗方式出现。然而，制药行业并未将反向激动作用作为一种设计标准，而是接受了在化合物筛选中一些化合物表现为（中性）拮抗剂，而其他化合物则具有反向激动活性这一事实。在本文中，我们总结了组成型活性对药物发现过程的影响的一些方面：例如，它在孤儿受体检测中的应用、它与药物遗传学和基因组学的联系以及它与当前上市药物的相关性。
