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

甲基谷氨酸受体的潜在代理商，如L-CCG-I、DCG-IV、顺式MCG-I和反式MCG-我在目前的研究中找到了。它们都是由2-（羧环丙基）甘氨酸（CCG）衍生而来的，其中提供了关于谷氨酸受体之间的关系和拮抗剂的构成的有用信息。它们的构象是一种扩展的形式，它们减少了孤立的新生大鼠脊柱脊柱中的单同步激发，并通过抑制神经终端的发射机释放。这四种用于代谢谷氨酸受体的抑制剂抑制了抗胆碱素刺激的环AMP含量，并在大鼠中演示潜在的中枢神经系统抑制剂行为。在他们中间，DCG-IV是最有潜力的。我们最近开发的代谢谷氨酸受体的药理学行动已被明确为Kainate Excitotoxicity的特别参考。Intraventricular DCG-I·V导致选择性神经元损伤在Cingulate Cortex和Hippancampal subiculum中相对较高的剂量，但其他代理人并没有导致神经元损伤在Rat. DCG-IV确信地允许了Kainate-induced的肢体序列。在相对较低剂量的情况下， DCG-IV保护河马CA 3中的一些神经元和阿米达拉对肾脏神经毒性的治疗，当内向性地受到大鼠的影响。These new agonists would provide useful probe for elucidating the Mechanism underlying neuron damage induced by excitatory amino acids。

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.