Characterization of Novel L-threo-beta-benzyloxyaspartate Derivatives, High Affinity Blockers for the Glutamate Transporters

DL-threo-beta-benzyloxyaspartate (DL-TBOA) is a potent blocker of all EAATs. We characterized L-TBOA analogs possessing a substituent. The analogs significantly inhibited glutamate uptake with (2S, 3S)-3-{3-[4-(trifluoromethyl)-benzoylamino] benzyloxy}aspartate (TFB-TBOA) being the most potent. In t...

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Bibliographic Details
Published in:Journal of Pharmacological Sciences 2004, Vol.94 (suppl.2), p.163-163
Main Authors: Yasushi Shigeri, Ryuichi Sakai, Kiyo Takaoka, Noboru Yumoto, Terumi Nakajima, Susan Amara, Keiko Shimamoto
Format: Article
Language:Japanese
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Summary:DL-threo-beta-benzyloxyaspartate (DL-TBOA) is a potent blocker of all EAATs. We characterized L-TBOA analogs possessing a substituent. The analogs significantly inhibited glutamate uptake with (2S, 3S)-3-{3-[4-(trifluoromethyl)-benzoylamino] benzyloxy}aspartate (TFB-TBOA) being the most potent. In the uptake assay, TFB-TBOA was significantly more potent at EAAT1 and EAAT2 compared with L-TBOA. Electrophysiological analyses revealed TBOA analogs block the transport-associated currents in all EAATs subtypes and leak currents in EAAT5. The rank order of the potency for inhibiting currents was identical to that observed with the uptake assay. However, the kinetic character of TFB-TBOA was different from that of L-TBOA because of the strong binding affinity. TFB-TBOA did not affect other representative neurotransmitter transporters or receptors. Intracerebroventricular administration of the TBOA analogs induced severe convulsive behaviors in mice. Taken together, new TBOA analogs, TFB-TBOA should serve as useful tools for elucidating the physiological roles of EAATs.
ISSN:1347-8613