Eur J Pharmacol 1996 Aug 15;3093:299-306. doi: 10.1016/0014-2999(96)00321-4.

Characterization of YM90K, a selective and potent antagonist of AMPA receptors, in rat cortical mRNA-injected Xenopus oocytes.

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The inhibitory potencies of 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione hydrochloride (YM90K), 2-3,dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) and 1-(4-amino-phenyl)-4-methyl-7,8-methyl-endioxyl-5H-2,3-benzodiazep ine (GYKI 52466) at excitatory amino acid receptors were examined in rat cortical mRNA-injected Xenopus oocytes using a two-electrode voltage clamp. Schild analysis of YM90K and NBQX inhibition of kainate currents yielded pA2 values of 6.83 +/- 0.01 and 7.24 +/- 0.01, respectively. GYKI 52466 reduced the maximum kainate response and increased the kainate EC50 in a dose-dependent manner, suggesting that the antagonism of AMPA receptors by GYKI 52466 is mixed competitive and non-competitive for kainate. Schild analysis of YM90K and NBQX inhibition of kainate currents in the presence of 30 microM cyclothiazide yielded pA2 values of 6.62 +/- 0.03 (slope: 1.02 +/- 0.01) and 7.10 +/- 0.02 (slope: 1.00 +/- 0.02), respectively, consistent with competitive antagonism. Cyclothiazide potentiated the AMPA response as well as the kainate response and increased the apparent Hill coefficients in a concentration-dependent manner. The potency of YM90K to inhibit AMPA-induced current could be reduced by increasing the concentration of cyclothiazide. We showed that YM90K is a potent and competitive antagonist for AMPA receptors and the apparent affinity of competitive antagonists was reduced by cyclothiazide. Cyclothiazide can affect the interaction between receptors and both agonists and antagonists, suggesting that it might allosterically alter the affinity of agonists and competitive antagonists for their binding site on the AMPA receptor complex.

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