RECEPTOR-SPECIFIC EXCITATORY AMINO ACID ANALOGUES

L-谷氨酸已被确定为主要的兴奋性递质， 哺乳动物中枢神经系统 最近的研究还表明，除了正常的 神经传递，兴奋性氨基酸系统也密切相关， 神经元病理学的潜在机制，称为 兴奋性毒性 L-谷氨酸的兴奋作用是通过 几种不同类型的受体，并通过高亲和力终止 运输 目前的药理学和生物化学证据表明， 至少有三种不同的受体类型和两种不同的受体类型， 运输系统，所有这些都可以结合L-谷氨酸。 本提案的总体目标是提供一种理解， 分子水平上，L-谷氨酸和蛋白质之间的相互作用 组件（例如，受体和运输系统）的兴奋性 神经递质系统 尽管许多谷氨酸类似物具有 已经鉴定出表现出选择性结合（即，红藻氨酸盐， quisqualate，和N-甲基-D-天冬氨酸），没有一个明确的认识 这种选择性的化学基础。 这类 选择性的存在意味着L-谷氨酸可能与每种类型的 受体在一个独特的构象，其中每一个是模仿的一个 类似物在某种化学上不明确的方式。 为了确定 每种受体类型和转运系统的构象偏好（即， 负责结合的官能团的最佳定位 激动剂或拮抗剂）构象上明确定义的一组广泛的 将制备谷氨酸类似物并进行生物化学表征。 结构/活性数据的结果，连同 L-谷氨酸类似物的构象分析，将提供一个 理解结合选择性的结构基础。 该数据 将在识别和设计选择性探针方面具有巨大价值 这些受体最终将允许它们各自的贡献 兴奋性传递进行单独检查。 此外如 已知兴奋性传递的不平衡会产生神经元 退化，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.