COMPETITIVE-INHIBITION BY NBQX OF KAINATE AMPA RECEPTOR CURRENTS AND EXCITATORY SYNAPTIC POTENTIALS - IMPORTANCE OF 6-NITRO SUBSTITUTION

We evaluated the inhibitory potencies at excitatory amino acid receptors of 2,3-dihydroxy-7-sulfamoyl-benzo[f]quinoxaline (BQX) and its 6-nitro derivative, NBQX. Currents activated by kainate or (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) in two-electrode voltage-clamp recordings of Xenopus oocytes injected with rat cortex mRNA were inhibited by BQX and NBQX: the apparent K(i) values versus kainate were 14-mu-M and 78 nM, respectively, and versus AMPA were 23-mu-M and 63 nM, respectively. Thus, to a degree even more marked than with other quinoxalinedione derivatives, 6-nitro substitution of BQX to yield NBQX increases potency (200-fold) at the non-NMDA ionotropic receptor, but does not confer selectivity for kainate or AMPA. Schild analysis of the NBQX inhibition of the kainate and AMPA currents yielded pA2 values of 7.17 +/- 0.05 and 7.05 +/- 0.10, respectively, and slopes near unity confirming the competitive nature of the inhibition. Neither BQX nor NBQX significantly inhibited the current activated by glycine plus NMDA. The selectivity ratio of NBQX (> 5000-fold) is by far the greatest of any quinoxalinedione derivative antagonist of the kainate/AMPA receptor. BQX and NBQX also inhibited the excitatory postsynaptic field potentials mediated by kainate/AMPA receptors in the CAI region of hippocampal slices after stimulation of the Schaffer collateral-commissural pathways with IC50 values of 130 and 0.90-mu-M, respectively. The 10-fold differences between the IC50 values in hippocampal slices and the K(i) values in Xenopus oocytes correlate closely with data for other quinoxalinedione derivative antagonists.