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，通过谷氨酸（GLU）携带的细胞外信号通过位于细胞乳腺癌上的GLU受体转导为细胞内信号。如今，这些用于GLU的受体根据其独特的细胞内信号转导系统分为两个主要类别，例如代谢性受体和离子受体。在这项国际研究合作中，我们旨在发现和开发一种可通过对GLU受体的两个亚类的生化和型药学评估来治疗和治疗各种神经精神疾病的药物。对离子型亚类的受体结合研究表明，5,7-二氯喹又2.3-dione 8dcqx）是配体与甘氨酸识别结构域与与N-甲基 - d-甲酸盐（NMDA）相关的离子通道上与甘氨酸识别域结合的有效置换剂。敏感的亚型。但是，DCQX并未显着影响NMDA通道上其他识别域或非NMDA受体的放射性识别域的各种放射线的结合。这些结果表明，DCQX是一种特定的拮抗剂，具有高亲和力FOT的NMDA受体上的甘氨酸识别结构域。另一方面，GLU可有效刺激新生儿但不是成年大鼠的大脑突触中磷脂酰肌醇的水解。通过添加Cadmiun离子，GLU的水解被明显抑制，而Cadmiun离子根本不影响卡尔巴霍尔的水解。因此，Cadmiun离子可能对GLU受体的代谢子类具有选择性抑制作用。我们的最终目标是通过评估这两个子类的生化和明药理学特性，制定药理学策略，以发现具有巨大临床益处的药物。