Reverse intrinsic activity of antagonists on G protein-coupled receptors.
Reverse intrinsic activity of antagonists on G protein-coupled receptors.
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DOI：
10.1016/0165-6147(92)90116-n
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发表时间：
1992
影响因子：
13.8
通讯作者：
W. Schütz;M. Freissmuth
中科院分区：
文献类型：
--
作者：
W. Schütz;M. Freissmuth
用拮抗剂观察到的生物效应通常被解释为其阻断内源性激动剂产生的受体激活的能力的结果。在这篇原理文章中，Wolfgang Schiitz和Michael Freissmuth展示了目前积累的大量证据，证明G蛋白偶联受体拮抗剂不仅能与受体结合，还能诱导一种有利于受体与G蛋白解偶联的对抗变化。无配体受体（即未被任何配体占据的受体）的自发活性是具有纯化组分的重组系统中公认的现象。然而，在拮抗剂的生物学效应主要归因于负性内在活性之前，其生理相关性需要在更生理的环境中得到验证。根据药物受体相互作用的经典模型，竞争性拮抗剂和激动剂都具有与受体分子上的共同位点结合的能力。它们与激动剂的不同之处在于，它们不能触发导致生物反应的刺激，即它们缺乏内在活性。一个具有挑战性的概念是，拮抗剂可能会
Biological effects observed with an antagonist are usually interpreted as the result of its ability to block receptor activation produced by an endogenous agonist. In this Principles article, Wolfgang Schiitz and Michael Freissmuth show how considerable evidence has now been accumulated for G proteincoupled receptors that antagonists not only bind to the receptor, but also induce a confonnational change that favours uncoupling of the receptor from its G protein. The spontaneous activity of the unliganded receptor (ie the receptor not occupied by any ligand) is a well-established phenomenon in reconstituted systems with purified components. However, its physioiogical relevance needs to be verified in a more physiological environment before biological effect of antagonists can be primarily ascribed to negative intrinsic activity.According to classical models for drug-receptor interactions, competitive antagonists share with agonists their ability to bind to a common site on the receptor molecule. They differ from agonists in that they cannot trigger the stimulus that leads to biological responses, ie they lack intrinsic activity. A challenging concept would be that an antagonist may