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

哺乳动物中枢神经系统（CNS）中许多突触的谷氨酸受体和转运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，不仅受体和转运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。我们已经完成了(1)合成新的EAA配体，其构象严格或特别受谷氨酸碳环或α-取代的限制，(2)合成β-苯氧天冬氨酸（TBOA）及其光亲和标记的衍生物，作为谷氨酸运输系统的抑制剂，(3)合成具有方酸片段的新型谷氨酸类似物，这是一种强酸性氨基酸。(4)合成谷氨酸类似物对谷氨酸受体和转运体的药理特性。因此，谷氨酸受体的新型和亚类型选择性激动剂已经被开发出来。旋光性L-TBOA是一种高效的转运抑制剂，被广泛用于研究谷氨酸转运系统的生化和生物学功能。

Glutamate receptors and transporters 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 and transporters required a specific conformation of glutamate, but also the analogs are used as tools for the neruopharmacological research.We have performed (1) the synthesis of new EAA ligands whose conformations are strictly or partically restricted by a carbocycle or an α-substitition of glutamate, (2) the synthesis of β-benzyloxyaspartate (TBOA) and its photoaffinity-labelled derivative as an inhibitor of glutamate transport systems, (3) synthesis of a novel glutamate analog posessing squaric acid moiety which is potent acidic amino acid, and (4) pharmacological characterization of the synthetic glutamate analogs to glutamate receptors and transporters.Thus, new and sub-type selective agonists for the glutamate receptors have been developed. Optically active L-TBOA was found to be highly effective transport inhibitor and is widely used as a tool to investigate biochemical and biological functions of glutamate transport systems.