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Research ArticleArticle

Characterization of Novel L-threo-β-Benzyloxyaspartate Derivatives, Potent Blockers of the Glutamate Transporters

Keiko Shimamoto, Ryuichi Sakai, Kiyo Takaoka, Noboru Yumoto, Terumi Nakajima, Susan G. Amara and Yasushi Shigeri
Molecular Pharmacology April 2004, 65 (4) 1008-1015; DOI: https://doi.org/10.1124/mol.65.4.1008
Keiko Shimamoto
Suntory Institute for Bioorganic Research, Osaka,Japan (K.S., K.T., T.N.); Kitasato University School of Fisheries Sciences, Iwate, Japan (R.S.); National Institute of Advanced Industrial Science and Technology, Ikeda, Japan (N.Y., Y.S.); and Department of Neurobiology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (S.G.A.)
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Ryuichi Sakai
Suntory Institute for Bioorganic Research, Osaka,Japan (K.S., K.T., T.N.); Kitasato University School of Fisheries Sciences, Iwate, Japan (R.S.); National Institute of Advanced Industrial Science and Technology, Ikeda, Japan (N.Y., Y.S.); and Department of Neurobiology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (S.G.A.)
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Kiyo Takaoka
Suntory Institute for Bioorganic Research, Osaka,Japan (K.S., K.T., T.N.); Kitasato University School of Fisheries Sciences, Iwate, Japan (R.S.); National Institute of Advanced Industrial Science and Technology, Ikeda, Japan (N.Y., Y.S.); and Department of Neurobiology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (S.G.A.)
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Noboru Yumoto
Suntory Institute for Bioorganic Research, Osaka,Japan (K.S., K.T., T.N.); Kitasato University School of Fisheries Sciences, Iwate, Japan (R.S.); National Institute of Advanced Industrial Science and Technology, Ikeda, Japan (N.Y., Y.S.); and Department of Neurobiology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (S.G.A.)
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Terumi Nakajima
Suntory Institute for Bioorganic Research, Osaka,Japan (K.S., K.T., T.N.); Kitasato University School of Fisheries Sciences, Iwate, Japan (R.S.); National Institute of Advanced Industrial Science and Technology, Ikeda, Japan (N.Y., Y.S.); and Department of Neurobiology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (S.G.A.)
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Susan G. Amara
Suntory Institute for Bioorganic Research, Osaka,Japan (K.S., K.T., T.N.); Kitasato University School of Fisheries Sciences, Iwate, Japan (R.S.); National Institute of Advanced Industrial Science and Technology, Ikeda, Japan (N.Y., Y.S.); and Department of Neurobiology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (S.G.A.)
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Yasushi Shigeri
Suntory Institute for Bioorganic Research, Osaka,Japan (K.S., K.T., T.N.); Kitasato University School of Fisheries Sciences, Iwate, Japan (R.S.); National Institute of Advanced Industrial Science and Technology, Ikeda, Japan (N.Y., Y.S.); and Department of Neurobiology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (S.G.A.)
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Abstract

Nontransportable blockers of the glutamate transporters are important tools for investigating mechanisms of synaptic transmission. DL-threo-β-Benzyloxyaspartate (DL-TBOA) is a potent blocker of all subtypes of the excitatory amino acid transporters (EAATs). We characterized novel L-TBOA analogs possessing a substituent on their respective benzene rings. The analogs significantly inhibited labeled glutamate uptake, the most potent of which was (2S,3S)-3-{3-[4-(trifluoromethyl)benzoylamino]benzyloxy}aspartate (TFB-TBOA). In an uptake assay using cells transiently expressing EAATs, the IC50 values of TFB-TBOA for EAAT1, EAAT2, and EAAT3 were 22, 17, and 300 nM, respectively. TFB-TBOA was significantly more potent at inhibiting EAAT1 and EAAT2 compared with L-TBOA (IC50 values for EAAT1-3 were 33, 6.2, and 15 μM, respectively). Electrophysiological analyses revealed that TBOA analogs block the transport-associated currents in all five EAAT subtypes and also block leak currents in EAAT5. The rank order of the analogs for potencies at inhibiting substrate-induced currents was identical to that observed in the uptake assay. However, the kinetics of TFBTBOA differed from the kinetics of L-TBOA, probably because of the strong binding affinity. Notably, TFB-TBOA did not affect other representative neurotransmitter transporters or receptors, including ionotropic and metabotropic glutamate receptors, indicating that it is highly selective for EAATs. Moreover, intracerebroventricular administration of the TBOA analogs induced severe convulsive behaviors in mice, probably because of the accumulation of glutamate. Taken together, these findings indicate that novel TBOA analogs, especially TFB-TBOA, should serve as useful tools for elucidating the physiological roles of the glutamate transporters.

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Molecular Pharmacology: 65 (4)
Molecular Pharmacology
Vol. 65, Issue 4
1 Apr 2004
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Research ArticleArticle

Characterization of Novel L-threo-β-Benzyloxyaspartate Derivatives, Potent Blockers of the Glutamate Transporters

Keiko Shimamoto, Ryuichi Sakai, Kiyo Takaoka, Noboru Yumoto, Terumi Nakajima, Susan G. Amara and Yasushi Shigeri
Molecular Pharmacology April 1, 2004, 65 (4) 1008-1015; DOI: https://doi.org/10.1124/mol.65.4.1008

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Research ArticleArticle

Characterization of Novel L-threo-β-Benzyloxyaspartate Derivatives, Potent Blockers of the Glutamate Transporters

Keiko Shimamoto, Ryuichi Sakai, Kiyo Takaoka, Noboru Yumoto, Terumi Nakajima, Susan G. Amara and Yasushi Shigeri
Molecular Pharmacology April 1, 2004, 65 (4) 1008-1015; DOI: https://doi.org/10.1124/mol.65.4.1008
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