DESIGN AND SYNTHESIS OF HIGH AFFINITY LIGANDS FOR EXCITATORY AMINO ACID RECEPTORS

哺乳动物中枢神经系统（CNS）许多突触上的谷氨酸受体与记忆和早期学习的构建以及神经元损伤引起各种神经元疾病的发病机制有关。近年来，我们通过合成谷氨酸的构象限制性类似物，即L-2-（羧基环丙基）甘氨酸（CCGs）及其3'取代类似物（MCGs和DCG-IV），研究了谷氨酸与受体结合时的构象作用。这些工作表明，不仅受体需要谷氨酸的特定构象，而且这些类似物也可以作为神经药理学研究的工具。在本项目中，我们进行了(1)改进了各种类型的mcg和DCG-IV的合成方法，包括基于手性rh催化的重氮乙酰胺分子内环加成的光亲和标记类似物，(2)合成了具有4和6元环类似物的新型谷氨酸类似物，以及(3)使用几种生物制剂对合成的谷氨酸类似物进行了药理学表征。因此，已经开发出谷氨酸受体的亚型选择性激动剂，并以更精确的方式清楚地解释了几种谷氨酸受体的构象要求。引入限制其α位置旋转的谷氨酸α取代类似物的工作正在进行中。

Glutamate receptors at many synapses in mammalian central nervous systems (CNS) are implicated in the construction of memory and early learnings as well as in the pathogenesis of neuron damage to cause various neuronal diseases. In the recent years, we have studied the conformational role of glutamate when it binds to the receptors through the synthesis of conformationally restricted analogs of glutamate, i.e., L-2-(carboxycyclopropyl) glycines (CCGs) and their 3'-substituted analogs (MCGs and DCG-IV). These works have demonstrated that not only the receptors required a specific conformation of glutamate, but also these analogs are used as tools for the neruopharmacological research. In this project, we have performed (1) improved procedure for the syntheses of various types of MCGs and DCG-IV including photoaffinity labelled analogs based on chiral Rh-catalyzed intramolecular cycloaddition of diazoacetamides, (2) the syntheses of new glutamate analogs with 4 and 6 membered ring analogs, and (3) pharmacological characterization of the synthetic glutamate analogs using several biological preparations. Thus, sub-type selective agonists for the glutamate receptors has been developed and conformational requirements of several types of glutamate receptors in a more presice manner were clearly explained. Works for an introduction of alpha-substituted analogs of glutamate which restricts the rotation of its alpha-position are in progress.