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Vol. 298, Issue 1, 249-256, July 2001
Laboratory of Medicinal Pharmacology (T.M., Ya.K.) and Laboratory
of Neuropharmacology (N.A., Yo.K., M.S., A.B.), Graduate School of
Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan;
Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences,
Kobe Gakuin University, Ikawadani-cho, Nishi-ku, Kobe, Japan (Ka.T.);
and Medicinal Research Laboratories, Taisho Pharmaceutical Co., LTD.,
Omiya, Saitama, Japan (Ke.T., T.T., T.S., T.O., A.H.-T., M.O., Y.T.,
K.K.)
The effect of the newly synthesized compound
2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline
(SEA0400) on the Na+-Ca2+ exchanger (NCX) was
investigated and compared against that of 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea
(KB-R7943). In addition, the effects of SEA0400 on reperfusion injury
in vitro and in vivo were examined. SEA0400 was extremely more potent
than KB-R7943 in inhibiting Na+-dependent Ca2+
uptake in cultured neurons, astrocytes, and microglia:
IC50s of SEA0400 and KB-R7943 were 5 to 33 nM and 2 to 4 µM, respectively. SEA0400 at the concentration range that inhibited
NCX exhibited negligible affinities for the Ca2+ channels,
Na+ channels, K+ channels, norepinephrine
transporter, and 14 receptors, and did not affect the activities of the
Na+/H+ exchanger,
Na+,K+-ATPase, Ca2+-ATPase, and
five enzymes. SEA0400, unlike KB-R7943, did not inhibit the
store-operated Ca2+ entry in cultured astrocytes. SEA0400
attenuated dose- dependently paradoxical Ca2+
challenge-induced production of reactive oxygen species, DNA ladder
formation, and nuclear condensation in cultured astrocytes, whereas it
did not affect thapsigargin-induced cell injury. Furthermore, administration of SEA0400 reduced infarct volumes after a transient middle cerebral artery occlusion in rat cerebral cortex and striatum. These results indicate that SEA0400 is the most potent and selective inhibitor of NCX, and suggest that the compound may exert protective effects on postischemic brain damage.
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