近期代谢型谷氨酸 4 受体配体鉴定的进展及其作为中枢神经系统治疗药物的潜在应用。
Recent progress on the identification of metabotropic glutamate 4 receptor ligands and their potential utility as CNS therapeutics.
机构信息
Chemical & Pharmacokinetic Sciences, Lundbeck Research USA, 215 College Road, Paramus, New Jersey 07652, USA.
出版信息
ACS Chem Neurosci. 2011 Aug 17;2(8):433-49. doi: 10.1021/cn200043e. Epub 2011 Jun 14.
Abstract
This Review describes recent activity in the advancement of ligands for the metabotropic glutamate 4 receptor subtype and their potential utility as central nervous system (CNS) therapeutics. Until recently, there was a paucity of compounds with suitable selectivity and druglike properties to elucidate the value of this target. The search for selective entities has led several groups to the investigation of allosteric modulators as a path to optimization of potential ligands. Recent efforts, discussed here, have afforded a variety of derivatives with improvements in potency, solubility, and pharmacokinetic properties that garner support for continued investigation and optimization.
摘要
本综述描述了最近在推进代谢型谷氨酸 4 受体亚型配体方面的进展，以及它们作为中枢神经系统 (CNS) 治疗药物的潜在用途。直到最近，具有适当选择性和类药性的化合物还很少，无法阐明该靶点的价值。对选择性实体的研究促使一些研究小组开始研究变构调节剂，以优化潜在配体。本文讨论了最近的研究进展，这些研究进展提供了各种具有更高活性、更好水溶性和更佳药代动力学性质的衍生物，为进一步研究和优化提供了支持。
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3
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