SAR INVESTIGATION OF THE NMDA-PCP-GLYCINE PHARMACOPHORE

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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.