Leff P, Scaramellini C, Law C, McKechnie K
Astra Charnwood, Loughborough, UK.
Trends Pharmacol Sci. 1997 Oct;18(10):355-62. doi: 10.1016/s0165-6147(97)01105-x.
The concept that receptors can exist in multiple conformational states is becoming a physical reality. A fundamental question is how many active states need to be proposed in order to account for pharmacological observations, in particular, the finding that the same receptor type can exhibit a different agonist pharmacology when coupled to different effector pathways. In this article, Paul Leff, Clare Scaramellini, Clare Law and Ken McKechnie propose and develop a three-state receptor model in which two active conformations are assumed to exist. They show that this relatively simple theoretical model provides a basis for predicting variable agonist and inverse agonist behaviour in different systems containing the same receptor, and that it is able to account for emerging data obtained on promiscuously coupled receptors. It is argued that, while these new theoretical considerations challenge the fundamental assumptions and concepts of traditional receptor theory, the general principles of pharmacological receptor classification are largely preserved.
受体可存在多种构象状态这一概念正成为一种物理现实。一个基本问题是，为了解释药理学观察结果，特别是发现同一受体类型与不同效应器途径偶联时可表现出不同的激动剂药理学特性，需要提出多少种活性状态。在本文中，保罗·莱夫、克莱尔·斯卡拉梅利尼、克莱尔·劳和肯·麦基尔尼提出并发展了一种三态受体模型，其中假定存在两种活性构象。他们表明，这个相对简单的理论模型为预测包含相同受体的不同系统中可变的激动剂和反向激动剂行为提供了基础，并且能够解释在杂乱偶联受体上获得的新数据。有人认为，虽然这些新的理论思考挑战了传统受体理论的基本假设和概念，但药理学受体分类的一般原则在很大程度上得以保留。
