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Vol. 53, Issue 2, 195-201, February 1998
-Benzyloxyaspartate, A
Potent Blocker of Excitatory Amino Acid Transporters
Suntory Institute for Bioorganic Research, Wakayamadai,
Shimamoto-cho, Mishima-gun, Osaka 618, Japan (K.S., B.L., Y.Y-K., M.S.,
T.N), and
Osaka National Research Institute (Agency of Industrial
Science and Technology, Ministry of International Trade and Industry),
Midorigaoka, Ikeda, Osaka 563, Japan (Y.S., N.Y.)
DL-threo-
-Benzyloxyaspartate
(DL-TBOA), a novel derivative of
DL-threo--hydroxyaspartate, was
synthesized and examined as an inhibitor of sodium-dependent
glutamate/aspartate (excitatory amino acid) transporters.
DL-TBOA inhibited the uptake of
[14C]glutamate in COS-1 cells expressing the human
excitatory amino acid transporter-1 (EAAT1)
(Ki = 42 µM)
with almost the same potency as
DL-threo--hydroxyaspartate
(Ki = 58 µM).
With regard to the human excitatory amino acid transporter-2 (EAAT2),
the inhibitory effect of DL-TBOA
(Ki = 5.7 µM) was much more potent than that of dihydrokainate
(Ki = 79 µM),
which is well known as a selective blocker of this subtype. Electrophysiologically, DL-TBOA induced no detectable
inward currents in Xenopus laevis oocytes expressing
human EAAT1 or EAAT2. However, it significantly reduced the
glutamate-induced currents, indicating the prevention of transport. The
dose-response curve of glutamate was shifted by adding
DL-TBOA without a significant change in the maximum
current. The Kb values for human
EAAT1 and EAAT2 expressed in X. laevis oocytes were 9.0 µM and 116 nM, respectively. These
results demonstrated that DL-TBOA is, so far, the most
potent competitive blocker of glutamate transporters.
DL-TBOA did not show any significant effects on either
the ionotropic or metabotropic glutamate receptors. Moreover,
DL-TBOA is chemically much more stable than its
benzoyl analog, a previously reported blocker of excitatory amino acid
transporters; therefore, DL-TBOA should be a useful
tool for investigating the physiological roles of transporters.
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