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

哺乳动物中枢神经系统(CNS)中许多突触上的谷氨酸受体和转运体参与记忆和早期学习的构建，以及神经元损伤引起各种神经性疾病的发病机制。近年来，我们通过合成构象受限的谷氨酸类似物，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特定的谷氨酸构象，而且类似物也被用作神经药理学研究的工具。我们完成了(1)合成构象受碳环或谷氨酸的α-取代严格或特定限制的新的氨基酸配基，(2)合成了β-苄氧天冬氨酸(TBOA)及其光亲和标记的衍生物作为谷氨酸转运系统的抑制剂，(3)合成了一种新型的具有方酸结构的谷氨酸类似物，这是一种有效的酸性氨基酸，以及(4)合成了谷氨酸受体和转运体的谷氨酸类似物的药理性质。谷氨酸受体的新型和亚型选择性激动剂已经被开发出来。光学活性的L-TBOA是一种高效的转运抑制剂，被广泛用作研究谷氨酸转运系统的生化和生物学功能的工具。

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.