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

强效代谢型谷氨酸受体激动剂L-CCG-I可明显增强电刺激背根纤维引起的单突触反射，明显增强新生大鼠脊髓标本的突触前抑制作用。L-CCG-I对单突触反射的抑制是在低于未引起突触后去极化的浓度时引起的。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反式-乙酰胆碱受体激动剂有所不同。L-CCG-I的抑制作用不被任何已知的药理药物所抑制。当这种药物进入脑室时，在大鼠体内观察到全身肌肉松弛作用。将L-CCG-L和反式-ACPD注射到侧脑室、皮质和海马区，均未引起这些区域的神经元损伤。在蒙古沙土鼠，脑室内注射L-CCG I可显著阻断缺血神经元的损伤。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已成功合成了一种有趣的化合物。该化合物被认为是内源性化合物，但其药理和生理作用尚不清楚。该化合物是一种很强的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，研究这种化合物在体内的生理功能是非常有意义的。

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.