Department of Chemistry and Biochemistry, University of Berne, P/A Weissensteinweg 3, CH-3303 Jegenstorf, Berne, Switzerland.
Pharmacol Rev. 2011 Mar;63(1):59-126. doi: 10.1124/pr.109.002501. Epub 2011 Jan 12.
Allosteric receptor modulation is an attractive concept in drug targeting because it offers important potential advantages over conventional orthosteric agonism or antagonism. Allosteric ligands modulate receptor function by binding to a site distinct from the recognition site for the endogenous agonist. They often have no effect on their own and therefore act only in conjunction with physiological receptor activation. This article reviews the current status of allosteric modulation at family C G-protein coupled receptors in the light of their specific structural features on the one hand and current concepts in receptor theory on the other hand. Family C G-protein-coupled receptors are characterized by a large extracellular domain containing the orthosteric agonist binding site known as the "venus flytrap module" because of its bilobal structure and the dynamics of its activation mechanism. Mutational analysis and chimeric constructs have revealed that allosteric modulators of the calcium-sensing, metabotropic glutamate and GABA(B) receptors bind to the seven transmembrane domain, through which they modify signal transduction after receptor activation. This is in contrast to taste-enhancing molecules, which bind to different parts of sweet and umami receptors. The complexity of interactions between orthosteric and allosteric ligands is revealed by a number of adequate biochemical and electrophysiological assay systems. Many allosteric family C GPCR modulators show in vivo efficacy in behavioral models for a variety of clinical indications. The positive allosteric calcium sensing receptor modulator cinacalcet is the first drug of this type to enter the market and therefore provides proof of principle in humans.
变构受体调节是药物靶向的一个有吸引力的概念，因为它提供了比传统的同型激动剂或拮抗剂重要的潜在优势。变构配体通过与内源性激动剂的识别位点不同的结合位点来调节受体功能。它们本身通常没有作用，因此仅在与生理受体激活结合时起作用。本文综述了 C 族 G 蛋白偶联受体的变构调节现状，一方面考虑了其特定的结构特征，另一方面考虑了受体理论的当前概念。C 族 G 蛋白偶联受体的特征是含有变构激动剂结合位点的大型细胞外结构域，称为“捕蝇草模块”，因为其具有双叶结构和激活机制的动力学。突变分析和嵌合构建体表明，钙敏感受体、代谢型谷氨酸和 GABA(B)受体的变构调节剂结合到跨膜七域，通过该结构域在受体激活后修饰信号转导。这与甜味增强分子形成对比，后者结合到甜味和鲜味受体的不同部位。许多变构 C 族 GPCR 调节剂在各种临床适应症的行为模型中表现出体内疗效。阳性变构钙敏感受体调节剂西那卡塞是第一种进入市场的此类药物，因此为人类提供了原理证明。
