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DESIGN AND SYNTHESIS OF NEUROEXCITATORY AMINO ACIDS

神经兴奋氨基酸的设计与合成

基本信息

批准号：
02453029
负责人：
OHFUNE Yasufumi
金额：
$ 3.52万
依托单位：
SUNTORY INSTITUTE FOR BIOORGANIC RESEARCH
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1990
资助国家：
日本
起止时间：
1990 至 1992
项目状态：
已结题

项目摘要

Glutamate receptors mediate synaptic excitation in the mammalian central nervous system. The receptors have been classified into two major classes, ionotropic glutamate receptors and metabotropic glutamate receptors. Our recent work concerning the syntheses and the pharmacology of L-2-(carboxycyclopropyl)-glycines (L-CCG-I-IV) have demonstrated that an extended conformer of L-glutamate is one of the most effective factor for activating metabotropic glutamate receptors, and a folded one for NMDA receptors. In this study, conformational requirements of glutamate receptors regarding rotamers around alpha-amino acid moiety have been examined by the spectroscopic studies of CCGs and by the synthesis of the 3'-substituted analogues of CCGs, L-2-(2-carboxy-3-methoxymethylcyclopropyl)glycines (cis- and trans-MCGs), which freeze CCG's possible rotamers at C2-C1'.NMR studies of CCGs under variable pHs and variable temperatures indicated that the C2-C1' bond of CCGs can not freely rotate but relatively fixes either CC or NC conformer in aqueous solution. This was well supported by the facts that the conformationally frozen analogues of CCGs [cis-MCG-I (NC conformer) and IV (CC conformer)], synthesized from D-serinal derivative in a stereocontrolled manner, showed similar activities as that of L-CCG-I and IV, respectively. Thus, we propose that the conformational requirement of metabotropic glutamate receptors is an anti-(NC) conformer of L-glutamate and that of NMDA receptors is a gauche-(CC). In addition, trans-MCG-IV and CPG-IV exhibited kainate-type responses at the dorsal root C-fibre of the immature rat. These results suggest that a folded form of L-glutamate, gauche-(CC), is also responsible for activating kainate receptors.

谷氨酸受体介导哺乳动物中枢神经系统中的突触兴奋。受体已被分为两大类，离子型谷氨酸受体和代谢型谷氨酸受体。本课题组近年来对L-2-（羧基环丙基）-甘氨酸（L-CCG-I-IV）的合成和药理学研究表明，L-谷氨酸的延伸构象是激活代谢型谷氨酸受体的最有效因子之一，而对NMDA受体则是折叠构象。在这项研究中，谷氨酸受体对α-氨基酸部分周围旋转异构体的构象要求已经通过CCG的光谱研究和CCG的3 '-取代类似物L-2-的合成进行了研究。（2-羧基-3-甲氧基甲基环丙基）甘氨酸（顺式和反式MCG），其将CCG的可能的旋转异构体冻结在C2-C1 '。在可变pH和可变温度下对CCG的NMR研究表明，C2-C1'的C2-C1 '的C2-CCG的C1'键在水溶液中不能自由旋转，只能相对固定CC或NC构象异构体。这是很好地支持的事实，构象冷冻类似物的CCG [顺MCG-I（NC构象异构体）和IV（CC构象异构体）]，合成D-丝氨酸衍生物在立体控制的方式，显示类似的活动，L-CCG-I和IV，分别。因此，我们认为代谢型谷氨酸受体的构象要求是L-谷氨酸的反（NC）构象，而NMDA受体的构象要求是左（CC）构象。此外，trans-MCG-IV和CPG-IV在未成熟大鼠的背根C-纤维处表现出红藻氨酸盐型反应。这些结果表明，L-谷氨酸的折叠形式，gauche-（CC），也是负责激活红藻氨酸受体。