NS-257, a novel competitive AMPA receptor antagonist, interacts with kainate and NMDA receptors

In this study, eve examined the effects of a novel, water-soluble, putative competitive AMPA receptor antagonist, 1,2,3,6,7,8-hexahydro-3- -(hydroxyim ino)-N,N,7-trimethyl-2-oxobenzo[2,1-b: 3,4-c']dipyrrole-5-sulfonamide (NS-2 57) on AMPA, kainate and NMDA receptors using the two-electrode voltage-cla mp technique in Xenopus oocytes. All glutamate receptor subtypes were inhib ited by NS-257 in a voltage-independent way. When kainate was applied to oo cytes injected with total mouse brain mRNA, mainly AMPA receptors were acti vated. The antagonistic effects of NS-257 on these kainate-induced currents were concentration-dependent and competitive. In the same way, NS-257 bloc ked kainate-induced currents recorded from oocytes expressing homomeric Glu R-1 receptors. In our experiments higher concentrations (> 1 phl) of NS-257 also produced inhibitory effects on kainate and to a lesser extent on NMDA receptor function as indicated by recordings from GluR-6 or NR-1b/2A cRNA injected oocytes. While NMDA receptor function was inhibited in a competiti ve fashion, kainate responses recorded from homomeric GluR-6 receptors were blocked in a mixed competitive-noncompetitive manner. This mixed antagonis tic action of NS-257 might have been caused by preincubating oocytes with c oncanavalin A, which blocks desensitization of kainate receptors. Although NS-257 appeared to be a less potent AMPA receptor antagonist then other kno wn antagonists like NBQX, its main advantage over all other reported compou nds so far is its higher aqueous solubility which still represents the majo r weakness of the other AMPA receptor antagonists, especially for clinical use. (C) 1999 Elsevier Science B.V. All rights reserved.