Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
Biochemistry. 2011 Apr 5;50(13):2403-10. doi: 10.1021/bi200129s. Epub 2011 Mar 4.
G-protein-coupled receptors (GPCRs) represent the largest class of drug targets, accounting for more than 40% of marketed drugs; however, discovery efforts for many GPCRs have failed to provide viable drug candidates. Historically, drug discovery efforts have focused on developing ligands that act at the orthosteric site of the endogenous agonist. Recently, efforts have focused on functional assay paradigms and the discovery of ligands that act at allosteric sites to modulate receptor function in either a positive, negative, or neutral manner. Allosteric modulators have numerous advantages over orthosteric ligands, including high subtype selectivity; the ability to mimic physiological conditions; the lack of densensitization, downregulation, and internalization; and reduced side effects. Despite these virtues, challenging issues have now arisen for allosteric modulators of metabotropic glutamate receptors (mGluRs): shallow SAR, ligand-directed trafficking, and the identification of subtle "molecular switches" that modulate the modes of pharmacology. Here, we will discuss the impact of modest structural changes to multiple mGluR allosteric ligands scaffolds that unexpectedly modulate pharmacology and raise concerns over metabolism and the pharmacology of metabolites.
G 蛋白偶联受体 (GPCRs) 是最大的药物靶点类别之一，占已上市药物的 40%以上；然而，许多 GPCR 的发现工作都未能提供可行的药物候选物。从历史上看，药物发现工作一直集中在开发作用于内源性激动剂的正构部位的配体上。最近，人们的注意力集中在功能测定范例和发现作用于变构部位的配体上，这些配体以正、负或中性方式调节受体功能。变构调节剂与正构配体相比具有许多优势，包括高亚型选择性；模拟生理条件的能力；缺乏脱敏、下调和内化；以及减少副作用。尽管有这些优点，但代谢型谷氨酸受体 (mGluR) 的变构调节剂现在出现了一些挑战问题：SAR 浅，配体导向的转运，以及鉴定微妙的“分子开关”，调节药理学模式。在这里，我们将讨论对多个 mGluR 变构配体支架进行适度结构改变的影响，这些改变出人意料地调节了药理学，并引起了对代谢和代谢物药理学的关注。
