RECEPTOR SPECIFIC EXCITATORY AMINO ACID ANALOGS

作为哺乳动物中枢神经系统的主要兴奋性神经递质，L- 谷氨酸信号是通过至少五种信号的组合来调节的。 受体的类别。这些受体的特性是一个主题 处于神经科学的前沿，因为它们不仅在 标准的快速兴奋性突触传递，但它们参与了 更复杂的神经过程，如发育、学习和记忆。 然而，谷氨酸系统似乎有能力 参与这些方面的中枢神经系统功能是由其额外的 对神经病理学有贡献的能力。因此，许多相同的属性 使这些受体对细胞内信号转导做出贡献， 当调控不当时，会导致神经元损伤，最终导致 神经元死亡。这种兴奋性毒性被认为是 与各种神经侮辱相关的神经元损伤 疾病，包括缺血、缺氧、中风、低血糖、癫痫、 亨廷顿氏病、肌萎缩侧索硬化症、甲状腺机能亢进和 阿尔茨海默氏症。 本项目的目标是更好地了解 谷氨酸与其各种受体之间的相互作用。有一种 大量构象受限的谷氨酸类似物 选择性地结合到特定的谷氨酸受体亚群，但 尽管有这些经验上的选择性，但人们并没有明确的理解 在分子水平上的这些相互作用。事实是这样的 选择性的存在意味着谷氨酸本身与每种类型的 一种独特构象的受体，每一种受体都由一种或一种 更多的类比。为了确定构象首选项， 每种受体类型，即官能团的最佳位置和 中间碳氢链负责结合激动剂或 拮抗剂，合理设计一套广泛的构象 正在进行定义明确的类比。具体目标为(一) 不同构型但构象不同的一系列系统 定义明确的、对映体纯的欧米伽-羧基-α-氨基酸将 为模拟兴奋性酸性分子的特定构象而准备 氨基酸如L-谷氨酸。重点将放在化合物上，在 影响，限制围绕谷氨酸的两个中心C-C键的旋转， 二)将进行结构/活动研究，以确定 构象定义的系列化合物的选择性和效价 类似物与EAA受体和运输系统结合，以及iii) 分子模拟将比较谷氨酸的已知构象， 每种类似物可获得的构象，以及 结构/活性研究，以确定EEA的选择性 变送器组件并导致进一步的结构改进 设计和综合。最终目标是完全理解 激动剂和拮抗剂在每种受体类型上的作用，这可能 最终导致中枢神经系统药物设计的改进。

As the primary excitatory neurotransmitter in the mammalian CNS, L- glutamate signalling is mediated through a combination of at least five classes of receptors. The characterization of these receptors is a topic at the forefront of neuroscience because of their role not only in standard fast excitatory synaptic transmission, but their involvement in more complex neuronal processes, such as development, learning and memory. It appears, however, that the ability of the glutamate system to participate in these aspects of CNS function is balanced by its additional ability to contribute to neuropathology. Thus, many of the same properties that allow these receptors to contribute to intracellular signalling can, when not properly regulated, lead to neuronal injury and the eventual death of the neuron. Such excitotoxicity is thought to underlie the neuronal damage associated with a wide variety of neurological insults and diseases, including, ischemia, anoxia, stroke, hypoglycemia, epilepsy, Huntington's disease, amyotrophic lateral sclerosis, lathyrisms, and Alzheimer's disease. The goal of this project is to provide a better understanding of the interactions between glutamate and its various receptors. There are a large number of conformationally restricted glutamate analogs that exhibit selective binding to specific subpopulations of glutamate receptors, but despite these empirical selectivities, there is not a clear understanding of these interactions at the molecular level. The fact that such selectivities exist implies that glutamate itself binds to each type of receptor in a unique conformation, each of which is mimicked by one or more of the analogs. In order to determine conformational preferences for each receptor type, i.e., optimal positioning of the functional groups and intervening hydrocarbon chain responsible for binding of agonists or antagonists, the rational design of an extensive set of conformationally well-defined analogues is being undertaken. The specific objectives are i) A systematic series of configurationally varied, but conformationally well-defined, enantiomerically pure omega-carboxy-alpha-amino acids will be prepared in order to mimic defined conformations of excitatory acidic amino acids such as L-glutamate. Emphasis will be on compounds that, in effect, restrict rotation about the two central C-C bonds of glutamate, ii) structure/activity studies will be performed to identify the selectivity and potency with which the series of conformationally defined analogues bind to the EAA receptors and transport systems, and iii) molecular modelling will compare known conformations of glutamate, conformations attainable by each analogue, and the results of the structure/activity studies to define the selectivities of the EEA transmitter components and lead to further structural refinements in design and synthesis. The ultimate goal is a complete understanding of agonist and antagonist action at each receptor type, which could ultimately lead to the improved design of CNS drugs.