グルタミン酸類縁体の合成と神経活性

概要

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To elucidate the conformational role of L-glutamic acid in activating its different types of excitatory receptors in the mammalian central nervous systems, we designed eight diastereomers of 2-(carboxycyclopropyl) glycine (L-CCG-IIV and D-CCG-IIV) which are the conformationally constrained analogues of glutamate as either the extended form or the folded form. The syntheses of CCGs were carried out using efficient methods (mainly based on palladium catalyzed inter- or intramolecular cyclopropanation) starting from chiral amino acids. Electrophysiological assay of all distereomers using the new born rat spinal cord demonstrated a large variety of depolarizing activities : D-CCG-II and L-CCG-IV were potent NMDA agonists and L-CCG- III markedly potentiated the response to L-glutamate. Moreover, L-CCG-I activated selectively the metabotropic receptor. The conformation-activity relationship of CCG isomers strongly suggested that NMDA receptor is activated by the folded form of glutamate and that the extended form of glutamate is crucial for the activation of metabotropic glutamate receptor.