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Elucidation of glutamate transporter functions using selective inhibitors Keiko Shimamoto 1 1Suntory Institute for Bioorganic Research Keyword: 興奮性アミノ酸 , グルタミン酸トランスポーター , 選択的阻害剤 , ブロッカー pp.850-854
Published Date 2005/12/10
DOI https://doi.org/10.11477/mf.1431100103
  • Abstract
  • Look Inside

L-Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system(CNS). To terminate glutamate receptor activation and to protect neurons from excitotoxicity, extracellular glutamate concentrations are strictly controlled by sodium dependent glutamate transporters(excitatory amino acid transporters 1-5:EAATs1-5)located in nerve endings and surrounding glia cells. Selective and potent inhibitors have served as important experimental tools to identify the physiological roles of transporters in the regulation of synaptic transmission or in the pathogenesis of neurological diseases. A pharmacologically useful probe, threo-β-benzyloxyaspartate(DL-TBOA)which functions as a non-transportable blocker for all subtypes of EAATs, have emerged from modification of a known inhibitor threo-β-hydroxyaspartate(THA). Non-transportable blockers are indispensable because, unlike substrates, they do not cause heteroexchange. By comparing the effects of substrates and non-transportable blockers, physiological roles of EAATs have been revealed. EAATs not only remove transmitter from synaptic clefts but also actively modulate neurotransmission. Moreover, higher affinity ligands have been developed as novel pharmacological tools. TBOA analogs possessing a bulky substituent on their benzene ring significantly inhibited labeled glutamate uptake, the most potent of compound being(2S, 3S)-3-{3-[4-(trifluoromethyl)benzoyl-amino]benzyloxy}aspartate(TFB-TBOA). TFB-TBOA is genuinely non-transportable at effective dose and showed no effects on glutamate receptors. TFB-TBOA would be a suitable lead compound for designing functionalized ligands from the perspective of its markedly high affinity for EAAT proteins.


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電子版ISSN 1882-1243 印刷版ISSN 0001-8724 医学書院

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