Kenakin Terry
Department of Assay Development and Compound Profiling, GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709, USA.
Mol Pharmacol. 2004 Jan;65(1):2-11. doi: 10.1124/mol.65.1.2.
This article describes the expected phenotypic behavior of all types of ligands in constitutively active receptor systems and, in particular, the molecular mechanisms of inverse agonism. The possible physiological relevance of inverse agonism also is discussed. Competitive antagonists with the molecular property of negative efficacy demonstrate inverse agonism in constitutively active receptor systems. This is a phenotypic behavior that can only be observed in the appropriate assay; a lack of observed inverse agonism is evidence that the ligand does not possess negative efficacy only if it can be shown that constitutive receptor activity is present. In the absence of constitutive activity, inverse agonists behave as simple competitive antagonists. A survey of 105 articles on the activity of 380 antagonists on 73 biological G-protein-coupled receptor targets indicates that, in this sample dataset, 322 are inverse agonists and 58 (15%) are neutral antagonists. The predominance of inverse agonism agrees with theoretical predictions which indicate that neutral antagonists are the minority species in pharmacological space.
本文描述了组成型活性受体系统中各类配体预期的表型行为，特别是反向激动作用的分子机制。还讨论了反向激动作用可能的生理相关性。具有负效能分子特性的竞争性拮抗剂在组成型活性受体系统中表现出反向激动作用。这是一种只有在适当的检测中才能观察到的表型行为；只有在能够证明存在组成型受体活性时，未观察到反向激动作用才证明该配体不具有负效能。在没有组成型活性的情况下，反向激动剂表现为简单的竞争性拮抗剂。一项对105篇关于380种拮抗剂对73种生物G蛋白偶联受体靶点活性的文章的调查表明，在这个样本数据集中，322种是反向激动剂，58种（15%）是中性拮抗剂。反向激动作用的优势与理论预测一致，理论预测表明中性拮抗剂在药理学领域中是少数类型。
