DESIGN AND SYNTHESIS OF HIGH AFFINITY LIGANDS FOR EXCITATORY AMINO ACID RECEPTORS

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Glutamate receptors at many synapses in mammalian central nervous systems (CNS) are implicated in the construction of memory and early learnings as well as in the pathogenesis of neuron damage to cause various neuronal diseases. In the recent years, we have studied the conformational role of glutamate when it binds to the receptors through the synthesis of conformationally restricted analogs of glutamate, i.e., L-2-(carboxycyclopropyl) glycines (CCGs) and their 3'-substituted analogs (MCGs and DCG-IV). These works have demonstrated that not only the receptors required a specific conformation of glutamate, but also these analogs are used as tools for the neruopharmacological research. In this project, we have performed (1) improved procedure for the syntheses of various types of MCGs and DCG-IV including photoaffinity labelled analogs based on chiral Rh-catalyzed intramolecular cycloaddition of diazoacetamides, (2) the syntheses of new glutamate analogs with 4 and 6 membered ring analogs, and (3) pharmacological characterization of the synthetic glutamate analogs using several biological preparations. Thus, sub-type selective agonists for the glutamate receptors has been developed and conformational requirements of several types of glutamate receptors in a more presice manner were clearly explained. Works for an introduction of alpha-substituted analogs of glutamate which restricts the rotation of its alpha-position are in progress.