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Drug Design and Development of Glutamate Blockers which protect against Neuronal Death.

防止神经元死亡的谷氨酸阻断剂的药物设计和开发。

基本信息

批准号：
02557104
负责人：
SHINOZAKI Haruhiko
金额：
$ 7.68万
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：
1990
资助国家：
日本
起止时间：
1990 至 1991
项目状态：
已结题

项目摘要

L-CCG-I, a potent metabotropic glutamate receptor agonist, potentiated markedly the presynaptic inhibition in the isolated newborn rat spinal cord preparation, preferentially depressing monosynaptic reflexes induced by electrical stimulation of the dorsal root fibres. The depression of monosynaptic reflexes by L-CCG-I was caused in concentrations wen below those which did not cause postsynaptic depolarization. This inhibitory action of L-CCG-I is somewhat different from that of trans-ACPD, another metabotropic glutamate receptor agonist. The inhibitory action of L-CCG-I is not depressed by any known pharmacological agents. When this drug was asministered into the ventricule, generalized muscle relaxtant actions were observed in the rat. When L-CCG-L and trans-ACPD were injected into the lateral ventricule, cortex, and hippocampus, they did not induce neuronal damage in these areas. In the mongolian gerbil, ischemic neuronal damage was considerably blocked by pretreatmefnt with intraventricular L-CCG I. These experimental data suggest that the metabotropic glutamate receptor agonist may be useful for the prevention of neuronal damage.An interesting compound has been succeeded in, synthesis by a group of the Tohoku University. This compound has been knwon as an endogenous one, but the pharmacological and physiological actions have been unknown. This compound demonstrated to be a considerably potent NMDA antagonist, and its activity was about 20 times lower than that of CPP. However, NMDA receptors have been believed to be related to neuronal death induced by excitatory amino acids, therefore, it is of great interest to examine the physiological function of this compound in the body.

L-CCG-I是一种有效的代谢型谷氨酸受体激动剂，在离体新生大鼠脊髓标本中，明显增强突触前抑制，优先抑制电刺激背根纤维引起的单突触反射。L-CCG-I抑制单突触反射的浓度低于不引起突触后去极化的浓度。L-CCG-I的这种抑制作用与另一种代谢型谷氨酸受体激动剂trans-ACPD的抑制作用有些不同。L-CCG-I的抑制作用不被任何已知的药理学试剂抑制。将本品缓慢注入大鼠心室，可观察到全身性肌松作用。当L-CCG-L和trans-ACPD被注射到侧脑室、皮质和海马中时，它们在这些区域中不诱导神经元损伤。脑室内注射L-CCG Ⅰ可明显阻断沙土鼠缺血性神经元损伤。这些实验数据表明，代谢型谷氨酸受体激动剂可能有助于预防神经元损伤。东北大学的一个小组成功合成了一种有趣的化合物。已知该化合物为内源性化合物，但其药理和生理作用尚不清楚。该化合物是一种相当有效的NMDA拮抗剂，其活性比CPP低约20倍。然而，NMDA受体被认为与兴奋性氨基酸诱导的神经元死亡有关，因此，研究该化合物在体内的生理功能具有重要意义。