Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity.
Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity.
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DOI：
10.1093/ijnp/pyy071
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发表时间：
2018-10-01
期刊：
影响因子：
--
通讯作者：
Clarke WP
中科院分区：
文献类型：
--
作者：
Berg KA;Clarke WP
组成型受体活性/反向激动作用和功能选择性/偏性激动作用是当代药理学中的两个概念，对药物在医学和研究中的使用以及新药开发过程具有重要意义。传统的受体理论假设，除非被配体激活，否则群体中的受体是静止的。在该框架内，配体可以作为具有不同程度的内在功效的激动剂，或作为具有零内在功效的拮抗剂。我们现在知道，受体可以在没有激活配体的情况下具有活性，因此显示出“组成型”活性。结果，发现了一类新的配体，其可以降低受体的组成性活性。这些配体产生与激动剂相反的作用，称为反向激动剂。第二个讨论的主题是功能选择性，通常也被称为偏向激动。传统的受体理论还认为，内在功效是一种独立于药物作用系统的单一药物性质。然而，我们现在知道，作用于单一受体亚型的药物可以具有多种内在功效，这些功效取决于测量与受体偶联的多种反应中的哪一种。因此，药物可以同时是作用于相同受体的激动剂、拮抗剂和反向激动剂。这意味着药物具有超出传统受体选择性的额外水平的选择性（信号传导选择性或“功能选择性”）。当药物被用作药物或作为研究工具时，需要考虑反向激动作用和功能选择性。
Constitutive receptor activity/inverse agonism and functional selectivity/biased agonism are 2 concepts in contemporary pharmacology that have major implications for the use of drugs in medicine and research as well as for the processes of new drug development. Traditional receptor theory postulated that receptors in a population are quiescent unless activated by a ligand. Within this framework ligands could act as agonists with various degrees of intrinsic efficacy, or as antagonists with zero intrinsic efficacy. We now know that receptors can be active without an activating ligand and thus display “constitutive” activity. As a result, a new class of ligand was discovered that can reduce the constitutive activity of a receptor. These ligands produce the opposite effect of an agonist and are called inverse agonists. The second topic discussed is functional selectivity, also commonly referred to as biased agonism. Traditional receptor theory also posited that intrinsic efficacy is a single drug property independent of the system in which the drug acts. However, we now know that a drug, acting at a single receptor subtype, can have multiple intrinsic efficacies that differ depending on which of the multiple responses coupled to a receptor is measured. Thus, a drug can be simultaneously an agonist, an antagonist, and an inverse agonist acting at the same receptor. This means that drugs have an additional level of selectivity (signaling selectivity or “functional selectivity”) beyond the traditional receptor selectivity. Both inverse agonism and functional selectivity need to be considered when drugs are used as medicines or as research tools.
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1124/jpet.110.177493
发表时间：
2011-07-01
影响因子：
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作者：
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通讯作者：
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