SAR INVESTIGATION OF THE NMDA-PCP-GLYCINE PHARMACOPHORE

兴奋性氨基酸，尤其是谷氨酸，会导致过量 伴随神经元变性和神经元变性的神经元兴奋 死亡。这种兴奋性毒性可能是导致许多 神经退行性疾病，如亨廷顿舞蹈症、阿尔茨海默氏症 疾病、缺血性脑损伤、癫痫、脑性瘫痪以及 增强能力，以及其他。因此，兴奋性毒性的拮抗或调制 神经递质是潜在控制这些疾病的有效方法。 病理学。谷氨酸受体的一个主要亚型是超分子。 由NMDA受体、PCP受体和甘氨酸位点组成的复合体 (NMDA-PCP-甘氨酸)。这项建议旨在调查这一命题。 谷氨酸的神经毒性作用是通过 NMDA-PCP-甘氨酸受体可通过甘氨酸识别位点进行调节 与这种受体有关。因为我们已经确定了 1-氨基环丙烷羧酸(ACPC)作为一种特异、高亲和力的化合物 发现了这个士的宁不敏感的[~3H]甘氨酸结合部位的配体 它能有效地阻断NMDA诱导的惊厥，我们建议 研究ACPC的结构类似物以确定其构效关系 此站点的要求。我们调查的目标是获得一个 对甘氨酸在这方面的作用和作用机制的理解 超分子复合体。这将导致治疗方法的发展 和/或谷氨酸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.