21 新規グルタミン酸レセプターアンタゴニストkaitocephalinに関する研究(口頭発表の部)

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During cerebral ischemia and subsequent reperfusion injury, neuronal degeneration is caused by the excitatory amino acid, L-glutamic acid, which acts as a neurotransmitter in the major part of brain. The ionotropic L-glutamate receptors, which are considered to play an important role in neuronal cell death, are mainly classified into two types; NMDA (N-methyl-D-aspartic acid) and AMPA/KA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/kainate) receptors. Since the AMPA/KA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) was reported to protect neuronal cells from ischemia injury even administered after an ischemic attack, AMPA/KA receptor antagonists are expected to treat ischemia-reperfusion injury such as stroke. In the course of our screening for substances that protect chick primary telencephalic neurons from kainate toxicity, we have isolated a potent kainate-toxicity suppressor designated as kaitocephalin from Eupenicillium sheariiPF1191. The structure of kaitocephalin (C_<18>H_<21>N_3O_9Cl_2) was elucidated on the basis of spectral analyses including 2D NMR (HMQC, DQF-COSY, ^1H-^<13>C HMBC and ^1H-^<15>N HMBC) to consist of a pyrrolidine moiety with tricarboxylic acids and a dichlorohydroxybenzoate substructure as shown in Fig. 1. The absolute structure of kaitocephalin was also determined by NMR studies after series of chemical modifications to be 2S3S4R7R9S. Kaitocephalin protected rat hippocampal neurons from kainate and AMPA toxicity with similar potency to those of known AMPA/KA antagonists without showing cytotoxic effect. Although, kaitocephalin protected rat hippocampal neurons from kainate and AMPA toxicity, it failed to block the Ca^<2+> influx elicited by kainate (Kaitocephalin effectively blocked Ca^<2+> influx induced by AMPA). This result is incompatible with the hypothesis of Ca^<2+> induced neurotoxicity. Thus, kaitocephalin is expected to be a useful tool to reveal the role and cytotoxic action mechanism of kainate receptor.
天然有機化合物討論会の論文
2001-09-01

21 新規グルタミン酸レセプターアンタゴニストkaitocephalinに関する研究(口頭発表の部)

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