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- 谷氨酸信号传导是通过至少五种 受体的种类。这些受体的特性是一个主题 在神经科学的前沿，因为他们的作用不仅在 标准的快速兴奋性突触传递，但它们参与 更复杂的神经过程，如发育，学习和记忆。 然而，似乎谷氨酸系统的能力， 参与CNS功能的这些方面是通过其额外的 有助于神经病理学的能力。因此，许多相同的属性 允许这些受体参与细胞内信号传导的分子， 如果没有适当的调节，会导致神经元损伤， 神经元的死亡这种兴奋性毒性被认为是 与各种神经损伤相关的神经元损伤， 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、懒洋洋症和 老年痴呆症 该项目的目标是提供一个更好的了解 谷氨酸和它的各种受体之间的相互作用。有 大量构象受限的谷氨酸类似物， 选择性结合谷氨酸受体的特定亚群，但 尽管有这些经验上的选择性， 在分子水平上的相互作用。这类 选择性的存在意味着谷氨酸本身与每种类型的 受体在一个独特的构象，其中每一个是模仿一个或 更多的类比。为了确定构象偏好， 每种受体类型，即，功能组的最佳定位， 负责结合激动剂的中间烃链，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似物。具体目标是：（一） 一系列有系统的构型变化，但构象 定义明确的、对映体纯的ω-羧基-α-氨基酸将 制备以模拟兴奋性酸性物质的限定构象 氨基酸如L-谷氨酸。重点将放在化合物上， 作用，限制谷氨酸的两个中心C-C键的旋转， ii）将进行结构/活性研究，以确定 选择性和效力， 类似物与EAA受体和转运系统结合，和iii） 分子建模将比较谷氨酸盐的已知构象， 每个类似物可达到的构象，以及 结构/活性研究，以确定EEA的选择性 发射机组件，并导致进一步的结构改进， 设计与合成最终目标是全面了解 激动剂和拮抗剂作用于每种受体类型，这可能 最终导致中枢神经系统药物的改进设计。

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.