A pharmacological review of competitive inhibitors and substrates of high-affinity, sodium-dependent glutamate transport in the central nervous system.
A pharmacological review of competitive inhibitors and substrates of high-affinity, sodium-dependent glutamate transport in the central nervous system.
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DOI：
10.1002/chin.199929281
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发表时间：
1999-05
影响因子：
3.1
通讯作者：
R. Bridges;M. Kavanaugh;A. Chamberlin
中科院分区：
文献类型：
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作者：
R. Bridges;M. Kavanaugh;A. Chamberlin
酸性氨基酸L-谷氨酸在哺乳动物中枢神经系统内既作为主要的兴奋性神经递质又作为潜在的神经毒素。这些神经生理和病理作用之间的功能并列是一组分类的整合膜转运蛋白，快速有效地螯合谷氨酸进入细胞和亚细胞区室。虽然存在能够介导L-谷氨酸摄取的多种系统，但高亲和力钠依赖性转运蛋白已成为CNS中最突出的参与者，其终止兴奋性信号，回收递质，并将谷氨酸的细胞外水平调节至低于可诱导兴奋性毒性病理的水平。本综述的重点是这些钠依赖性转运蛋白的药理学特异性，更具体地说，竞争性抑制剂已被用来描绘的化学要求的结合和易位。由于在谷氨酸或天冬氨酸的碳骨架上添加取代基而在构象上受到限制的谷氨酸类似物（例如，β-羟基天冬氨酸或谷氨酸甲酯衍生物）或引入环系统（例如，（羧基环丙基）甘氨酸、氨基环丁烷二羧酸酯或吡咯烷二羧酸酯）在这些努力中特别有价值。在这篇评论中，一个特别强调的是放置在最近克隆的转运蛋白亚型之间表现出优先活性的类似物的识别和非转运抑制剂的底物的分化。
The acidic amino acid L-glutamate acts as both a primary excitatory neurotransmitter and a potential neurotoxin within the mammalian central nervous system. Functionally juxtaposed between these neurophysiological and pathological actions are an assorted group of integral membrane transporter proteins that rapidly and efficiently sequester glutamate into cellular and subcellular compartments. While multiple systems exist that are capable of mediating the uptake of L-glutamate, the high-affinity, sodium-dependent transporters have emerged as the most prominent players in the CNS with respect to terminating the excitatory signal, recycling the transmitter, and regulating extracellular levels of glutamate below those which could induce excitotoxic pathology. The focus of the present review is on the pharmacological specificity of these sodium-dependent transporters and, more specifically, on the competitive inhibitors that have been used to delineate the chemical requirements for binding and translocation. Analogues of glutamate that are conformationally constrained as a consequence of either the addition of substituents to the carbon backbone of glutamate or aspartate (e.g., beta-hydroxyaspartate or methylglutamate derivatives) or the incorporation of ring systems (e.g., (carboxycyclopropyl)glycines, aminocyclobutane dicarboxylates, or pyrrolidine dicarboxylates), have been especially valuable in these efforts. In this review, a particular emphasis is placed on the identification of analogues that exhibit preferential activity among the recently cloned transporter subtypes and on the differentiation of substrates from non-transportable inhibitors.