RECEPTOR-SPECIFIC EXCITATORY AMINO ACID ANALOGUES

L-谷氨酸已被确定为体内主要的兴奋性递质 哺乳动物中枢神经系统。最近的研究还表明，除了正常 神经传递，兴奋性氨基酸系统也与 神经元病理学的基本机制，称为 兴奋性毒性。L-谷氨酸的兴奋作用是通过 几种不同类别的受体，并由高亲和力终止 运输。目前的药理和生化证据表明 至少有三个不同的受体类别和两个不同的 运输系统，所有这些都可以结合L-谷氨酸。 这项提案的总体目标是提供一个理解，在 L-谷氨酸与蛋白质相互作用的分子水平 兴奋性神经的组成部分(例如，受体和运输系统) 神经递质系统。尽管一些谷氨酸类似物具有 被鉴定为表现出选择性结合(即，红藻氨酸， 喹乙醇和N-甲基-D-天冬氨酸)目前还没有明确的认识 这种选择性的化学基础。事实是这样的 选择性的存在意味着L-谷氨酸可能与每种类型的 一种独特的构象的受体，每一种受体都由一种 以某种化学定义不明确的方式进行类似物。为了确定 每种受体类型和运输系统的构象偏好(即， 负责结合的官能团的最佳位置 激动剂或拮抗剂)广泛的一组构象上定义良好的 将制备谷氨酸类似物，并对其进行生化表征。 结构/活动数据的结果与 L-谷氨酸类似物的构象分析将提供 了解结合选择性的结构基础。此数据 将在识别和设计选择性探针方面具有巨大的价值 最终将允许它们各自的贡献的受体 对兴奋性传输进行单独检查。此外，由于 已知兴奋性传递的不平衡会产生神经元 退化，对拮抗剂的鉴定应该是实质性的 治疗价值。

L-Glutamate has been identified as the major excitatory transmitter in the mammalian CNS. Recent studies also suggest that in addition to normal neurotransmission, the excitatory amino acid system is also closely tied to an underlying mechanism of neuronal pathology, referred to as excitotoxicity. The excitatory action of L-glutamate is mediated through several different classes of receptors and is terminated by high-affinity transport. Current pharmacological and biochemical evidence suggests that there are at least three distinct receptor classes and two distinct transport systems, all of which can bind L-glutamate. The overall goal of this proposal is to provide an understanding, at the molecular level, of the interactions between L-glutamate and the proteins components (e.g., receptors and transport systems) of the excitatory neurotransmitter system. Although a number of glutamate analogues have been identified that exhibit selectively binding (i.e., kainate, quisqualate, and N-methyl-D-aspartate) there is not a clear understanding of the chemical basis of this selectivity. The fact that such selectivities exist implies the L-glutamate may be binding to each type of receptor in a unique conformation, each of which is mimicked by one of the analogues in some chemically ill-defined way. In order to determine conformation preferences for each receptor type and transport system (i.e., optimal positioning of the functional groups responsible for the binding of agonists or antagonists) an extensive set of conformationally well-defined glutamate analogues will be prepared and biochemically characterized. The results of the structure/activity data, in conjunction with the conformational analysis of the L-glutamate analogues, will provide an understanding of the structural basis of binding selectivity. This data will be of tremendous value in identifying and designing selective probes of the receptors that will eventually allow their respective contributions to excitatory transmission to be individually examined. Furthermore, as imbalances in excitatory transmission are known to produce neuronal degeneration, the identification of antagonists should be of substantial therapeutic value.