Department of Pharmaceutical Sciences Pietro Pratesi, University of Milan, via Mangiagalli 25, 20133 Milano, Italy.
Med Res Rev. 2010 May;30(3):463-549. doi: 10.1002/med.20166.
Allosteric receptor ligands bind to a recognition site that is distinct from the binding site of the endogenous messenger molecule. As a consequence, allosteric agents may attach to receptors that are already transmitter-bound. Ternary complex formation opens an avenue to qualitatively new drug actions at G protein-coupled receptors (GPCRs), in particular receptor subtype selective potentiation of endogenous transmitter action. Consequently, suitable exploitation of allosteric recognition sites as alternative molecular targets could pave the way to a drug discovery paradigm different from those aimed at mimicking or blocking the effects of endogenous (orthosteric) receptor activators. The number of allosteric ligands reported to modulate GPCR function is steadily increasing and some have already reached routine clinical use. This review aims at introducing into this fascinating field of drug discovery and at providing an overview about the achievements that have already been made. Various case examples will be discussed in the framework of GPCR classification (family A, B, and C receptors). In addition, the behavior at muscarinic receptors of hybrid derivatives incorporating both an allosteric and an orthosteric fragment in a common molecular skeleton will be illustrated.
变构受体配体与内源性信使分子的结合位点不同,结合在识别位点上。因此,变构调节剂可能与已经结合递质的受体结合。三元复合物的形成为 G 蛋白偶联受体 (GPCR) 开辟了一条新的药物作用途径,特别是内源性递质作用的受体亚型选择性增强。因此,适当地利用变构识别位点作为替代的分子靶点,可以为药物发现范式开辟不同于模仿或阻断内源性(变构)受体激动剂作用的途径。据报道,调节 GPCR 功能的变构配体数量正在稳步增加,其中一些已经常规用于临床。本综述旨在介绍这一引人入胜的药物发现领域,并概述已经取得的成就。将在 GPCR 分类(A、B 和 C 受体家族)的框架内讨论各种案例示例。此外,还将说明在共同分子骨架中包含变构和变构片段的混合衍生物在毒蕈碱受体上的行为。