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Design and development of excitatory amino acid related compounds for protection against senile neuronal death

设计和开发用于预防老年神经元死亡的兴奋性氨基酸相关化合物

基本信息

批准号：
05557113
负责人：
SHINOZAKI Haruhiko
金额：
$ 7.17万
依托单位：
The Tokyo Metropolitan Institute of Medical Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research (B)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

项目摘要

Potent agonist for metabotropic glutamate receptors, such as L-CCG-I,DCG-IV,cis-MCG-I and trans-MCG-I were found in the present study. All of them are derivatives of 2- (carboxycyclopropyl) glycine (CCG), which provided useful information about relationship between activation of glutamate receptors and conformation of agonists. Their conformation of glutamate skeleton is an extended form, and they reduced monosynaptic excitation in the isolated newborn rat spinal cord, by inhibiting transmitter release from nerve terminal. These four agonists for metabotropic glutamate receptors inhibited forskolin-stimulated cyclic AMP content in a dose dependent manner, and they demonstrated potent CNS depressant actions in the rat. Among them DCG-IV was the most potent. Pharmacological actions of our newly developed agonists for metabotropic glutamate receptors were clarified with special reference to kainate excitotoxicity. Intraventricular DCG-I・V caused selective neuron damage at relatively high doses in the cingulate cortex and the hippocampal subiculum in the rat, but other agonists did not cause neuron damage in the rat.DCG-IV considerably alleviated the kainate-induced limbic seizures. At relatively low doses, DCG-IV protected some kinds of neurons in the hippocampal CA3 and the amygdala against kainate neurotoxicity, when intraventricularly injected to the rat. These new agonists would provide useful probe for elucidating the mechanism underlying neuron damage induced by excitatory amino acids.

本研究发现了L-CCG-I、DCG-IV、cis-MCG-I和trans-MCG-I等代谢型谷氨酸受体的有效激动剂。这些化合物均为2-羧基环丙基甘氨酸（CCG）的衍生物，为研究谷氨酸受体的激活与激动剂构象的关系提供了有用的信息。它们的谷氨酸骨架是一种延伸形式，通过抑制神经末梢递质的释放，降低离体新生大鼠脊髓单突触兴奋。这四种代谢型谷氨酸受体激动剂以剂量依赖性方式抑制毛喉素刺激的环AMP含量，并且它们在大鼠中表现出强有力的CNS抑制作用。其中DCG-IV是最有效的。我们新开发的代谢型谷氨酸受体激动剂的药理作用，特别是红藻氨酸兴奋毒性澄清。脑室注射DCG-I·V可引起大鼠扣带皮层和海马下托神经元选择性损伤，而其他激动剂对大鼠无神经元损伤作用。DCG-IV可明显减轻红藻氨酸诱发的边缘系统癫痫发作。在相对较低的剂量下，DCG-IV保护海马CA 3和杏仁核中的某些神经元免受红藻氨酸神经毒性，当脑室注射给大鼠时。这些新的激动剂将为阐明兴奋性氨基酸引起神经元损伤的机制提供有用的探针。