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PHARMACOLOGICAL STRATEGIES FOR GLUTAMATE SIGNALING

谷氨酸信号传导的药理学策略

基本信息

批准号：
08044326
负责人：
YONEDA Yukio
金额：
$ 4.86万
依托单位：
SETSUNAN UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for international Scientific Research
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

In the mammalian central nervous system, extracellular signals carried by glutamate (Glu) are transduced into intracellular signals through Glu receptors located on cellular mambranes. These receptors for Glu are nowadays classified into two major categories such as metabotropic and ionotropic receptors according to their unique intracellular signal transduction systems. In this international research collaboration, we have aimed at discovery and development of a drug useful for the treatment and therapy of a variety of neuropsychiatric disorders through biochemical and mpharmacological evaluations of both subclasses of Glu receptors. Receptor binding studies on the ionotropic subclass revealed that 5,7-dichloroquinoxaline-2.3-dione 8DCQX) is a potent displacer of ligand binding to a glycine recognition domain on the ion channel associated with the N-methyl-D-aspartate (NMDA)-sensitive subtype. However, DCQX did not significantly affect binding of either a variety of radioligands for other recognition domains on the NMDA channel, or radioligands for the non-NMDA receptors. These results suggest that DCQX is a specific antagonist with high affinity fot the glycine recognition domain on the NMDA receptor. On the other hand, Glu was effective in stimulating hydrolysis of phosphatidylinositol in synaptoneurosomes of brains from newborn but not adult rats. The hydrolysis by Glu was markedly inhibited by the addition of cadmiun ions which did not affect the hydrolysis by carbachol at all. Therefore, cadmiun ions may have selective inhibitory actions on the metabotropic subclass of Glu receptors. Our final goal is to develop pharmacological strategies for the discovery of medicines of great clinical benefits through evaluation of biochemical andmpharmacological properties of both subclasses.

在哺乳动物中枢神经系统中，谷氨酸（Glu）携带的细胞外信号通过位于细胞膜上的Glu受体转化为细胞内信号。根据其独特的细胞内信号转导系统，这些谷氨酸受体目前被分为两大类，例如代谢型和离子型受体。在这项国际研究合作中，我们的目标是通过对Glu受体的两个亚类进行生物化学和药理学评价，发现和开发一种可用于治疗和治疗各种神经精神疾病的药物。对离子型亚型的受体结合研究表明，5，7-二氯喹喔啉-2，3-二酮（8DCQX）是与N-甲基-D-天冬氨酸（NMDA）敏感亚型相关的离子通道上的甘氨酸识别结构域结合的配体的有效置换剂。然而，DCQX没有显着影响结合的各种放射性配体的其他识别结构域的NMDA通道，或放射性配体的非NMDA受体。这些结果表明DCQX是一种对NMDA受体上甘氨酸识别结构域具有高亲和力的特异性拮抗剂。另一方面，谷氨酸能有效地刺激新生大鼠脑突触神经元中磷脂酰肌醇的水解，但对成年大鼠无效。镉离子的加入对氨甲酰胆碱的水解没有影响，但对谷氨酸的水解有明显的抑制作用。因此，镉离子对Glu受体的代谢型亚类可能具有选择性抑制作用。我们的最终目标是通过评价这两个亚类的生化和药理学特性，为发现具有巨大临床益处的药物开发药理学策略。