SAR INVESTIGATION OF THE NMDA-PCP-GLYCINE PHARMACOPHORE

兴奋性氨基酸，特别是谷氨酸，可以导致过量的 神经元兴奋，随之发生神经元变性和神经元 死亡这种兴奋性毒性可能是导致许多 神经退行性疾病如亨廷顿氏舞蹈病、阿尔茨海默氏病 疾病，缺血性脑损伤，癫痫，脑瘫以及损失 增强，以及其他。因此，兴奋性毒性的拮抗或调节 神经递质是一种有效的方法来潜在的控制这些 病理学谷氨酸受体的主要亚型是超分子谷氨酸受体。 由NMDA受体、PCP受体和甘氨酸位点组成的复合物 （NMDA-PCP-甘氨酸）。这一建议旨在调查 谷氨酸的神经毒性作用表现在 NMDA-PCP-甘氨酸受体可通过甘氨酸识别位点进行调节 与这个受体有关。既然我们已经确定 1-氨基环丙烷羧酸（ACPC）作为一种特异性，高亲和力 这种士的宁不敏感的[3 H]甘氨酸结合位点的配体，并发现 它能有效阻断NMDA诱导的惊厥，我们建议 研究ACPC的结构类似物以确定结构-活性 这个网站的要求。我们调查的目的是 了解甘氨酸在这方面的作用和作用机制 超分子复合物这将导致治疗的发展 和/或谷氨酸的神经毒性作用的保护剂。

Excitatory amino acids, in particular glutamic acid, can lead to excessive neuronal excitation with consequential neuronal degeneration and neuronal death. This excitotoxicity may be the cause of a number of neurodegenerative disorders such as Huntington's chorea, Alzheimer's disease, ischemic brain damage, epilepsy, cerebral palsy as well as loss of potentiation, and others. Thus, antagonism or modulation of excitotoxic neurotransmitters is a valid approach to the potential control of these pathologies. A major subtype of glutamate receptors is the supramolecular complex consisting of an NMDA receptor, a PCP receptor and a glycine site (NMDA-PCP-glycine). This proposal is aimed at investigating the proposition that the neurotoxic action of glutamate manifested through the NMDA-PCP-glycine receptor can be modulated via the glycine recognition site associated with this receptor. Since we have identified 1-aminocyclopropanecarboxylic acid (ACPC) as a specific, high affinity ligand of this strychnine-insensitive [3H] glycine binding site and found that it is effective in blocking NMDA-induced convulsions, we propose to investigate structural analogs of ACPC to determine the structure-activity requirement of this site. The goal of our investigations is to gain an understanding of the role and mechanism of action of glycine in this supramolecular complex. This will result in the development of therapeutic and/or protective agents for the neurotoxic actions of glutamate.