"Molecular switches" on mGluR allosteric ligands that modulate modes of pharmacology.
"Molecular switches" on mGluR allosteric ligands that modulate modes of pharmacology.
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DOI：
10.1021/bi200129s
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发表时间：
2011-04-05
期刊：
影响因子：
2.9
通讯作者：
Lindsley CW
中科院分区：
文献类型：
--
作者：
Wood MR;Hopkins CR;Brogan JT;Conn PJ;Lindsley CW
G蛋白偶联受体（GPCR）是最大的一类药物靶点，占上市药物的40%以上;然而，许多GPCR的发现工作未能提供可行的候选药物。从历史上看，药物发现工作集中在开发作用于内源性激动剂的正构位点的配体。最近，努力集中于功能测定范例和发现在变构位点起作用以正、负或中性方式调节受体功能的配体。变构调节剂具有优于正构配体的许多优点，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;以及减少的副作用。尽管有这些优点，但代谢型谷氨酸受体（mGluRs）的变构调节剂现在已经出现了具有挑战性的问题：浅SAR，配体定向贩运，以及识别调节药理学模式的微妙“分子开关”。在这里，我们将讨论适度的结构变化的影响，多个mGluR变构配体支架，出乎意料地调节药理学和代谢产物的药理学引起关注。
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.
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DOI：
10.1038/nrd2760
发表时间：
2009-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
影响因子：
5
作者：
Hammond, Alexis S.;Rodriguez, Alice L.;Townsend, Steven D.;Niswender, Colleen M.;Gregory, Karen J.;Lindsley, Craig W.;Conn, P. Jeffrey
通讯作者：
Conn, P. Jeffrey
影响因子：
13.8
作者：
Conn PJ;Lindsley CW;Jones CK
通讯作者：
Jones CK
影响因子：
4.7
作者：
Gasparini, F;Lingenhöhl, K;Kuhn, R
通讯作者：
Kuhn, R
影响因子：
3
作者：
Chavez-Noriega, Laura E.;Schaffhauser, Herve;Campbell, Una C.
通讯作者：
Campbell, Una C.