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

In this study, we examined the effects of a novel, water-soluble, putative competitive AMPA receptor antagonist, 1,2,3,6,7, 8-hexahydro-3-(hydroxyimino)-N,N,7-trimethyl-2-oxobenzo[2,1- b:3, 4-c']dipyrrole-5-sulfonamide (NS-257) on AMPA, kainate and NMDA receptors using the two-electrode voltage-clamp technique in Xenopus oocytes. All glutamate receptor subtypes were inhibited by NS-257 in a voltage-independent way. When kainate was applied to oocytes injected with total mouse brain mRNA, mainly AMPA receptors were activated. The antagonistic effects of NS-257 on these kainate-induced currents were concentration-dependent and competitive. In the same way, NS-257 blocked kainate-induced currents recorded from oocytes expressing homomeric GluR-1 receptors. In our experiments higher concentrations (>1 microM) 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 competitive fashion, kainate responses recorded from homomeric GluR-6 receptors were blocked in a mixed competitive-noncompetitive manner. This mixed antagonistic action of NS-257 might have been caused by preincubating oocytes with concanavalin A, which blocks desensitization of kainate receptors. Although NS-257 appeared to be a less potent AMPA receptor antagonist then other known antagonists like NBQX, its main advantage over all other reported compounds so far is its higher aqueous solubility which still represents the major weakness of the other AMPA receptor antagonists, especially for clinical use.