PHARMACOLOGICAL STRATEGIES FOR GLUTAMATE SIGNALING

在哺乳动物中枢神经系统中，由谷氨酸（Glu）携带的细胞外信号通过位于细胞膜上的谷氨酸受体转导为细胞内信号。根据其独特的细胞内信号转导系统，目前将谷氨酸受体分为代谢型受体和离子型受体两大类。在这项国际研究合作中，我们的目标是通过对Glu受体亚类的生化和药理学评估，发现和开发一种用于治疗和治疗各种神经精神疾病的药物。对嗜离子亚类的受体结合研究表明，5,7-二氯喹啉-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区域结合的有效配体替代物。然而，DCQX并没有显著影响NMDA通道上其他识别结构域的各种放射性配体的结合，也没有显著影响非NMDA受体的放射性配体的结合。这些结果表明DCQX是一种特异性拮抗剂，对NMDA受体上的甘氨酸识别结构域具有高亲和力。另一方面，谷氨酸对新生大鼠突触体中磷脂酰肌醇的水解有刺激作用，而对成年大鼠无刺激作用。镉离子的加入对谷氨酸的水解有明显的抑制作用，而镉离子的加入对苯酚的水解没有影响。因此，镉离子可能对谷氨酸受体的代谢亚类具有选择性抑制作用。我们的最终目标是制定药理学策略，通过评估这两个亚类的生化和药理学特性，发现具有巨大临床效益的药物。

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.