23 α-カルボキシシクロプロピルグリシン類の合成と神経生理活性 : 神経伝達物質L-グルタミン酸類縁体(口頭発表の部)

抄録

L-Glutamic acid (Glu) has received much current attention because it is an excitatory neurotransmitter in the mammalian central nervous system and because it is a potent excitotoxin which causes various acute and chronic brain diseases. It is suggested that Glu receptors are classified into three subtypes; N-methyl-D-aspartic acid (NMDA), kainic acid (KA), and quisqualic acid (QA) receptor subtypes. It is reasonable to assume that Glu has different conformations (extended or folded) which fit to the different types of glutamate receptors. We approached this problem by designing four diastereoisomers of L-α-(carboxycyclopropyl)-glycines (L-CCG-I-IV) in which the cyclopropyl group constrains the Glu carbon chain to the extended form or to the folded form. The syntheses of L-CCGs were carried out using efficient methods starting from chiral amino acids: (1) cyclopropanation of (2S)-2-amino-3-butenol derivatives for the syntheses of all L-isomers; (2) intramolecular cyclopropanation of 4 for L-III; and (3) cyclopropanation of an α,β-unsaturated-γ-lactam 10 for L-III and δ-lactone 13 for L-IV. In addition, D-CCG-I-IV were synthesized using the method (1). Neurophysiological actions of all isomers of CCG were electrophysiologically examined in the isolated spinal cord of the new born rat. Eight diastereomers of CCG demonstrated a large variety of depolarizing activities. The D-CCG-II and L-CCG-IV showed potent depolarizing activity which were effectively depressed by the NMDA antagonists. The depolarization of L-CCG-I was not depressed in the presence of D-APV, CPP, and CNOX. This suggests that L-CCG-I might activate a new type of L-Glu receptors. L-CCG-III, in spite of its weak depolarizing activity, potentiated the L-Glu response. The potentiation might be due to inhibition of the L-Glu uptake process. Conformation and activity relationships between the L-isomers revealed that the NMDA receptor is activated by the folded form of Glu.