A)-7-SUBSTITUTED-1,4-DIHYDROQUINOXALINE-2,3-DIONES - NOVEL, SYSTEMICALLY ACTIVE AND BROAD-SPECTRUM ANTAGONISTS FOR NMDA GLYCINE, AMPA, AND KAINATE RECEPTORS/

A group of za-7-substituted-1,4-dihydroquinoxaline-2,3-diones (QXs) an d the corresponding 5-(N-oxyaza)-7-substituted QXs were prepared and e valuated as antagonists of ionotropic glutamate receptors. The in vitr o potency of these QXs was determined by inhibition of [H-3]- 5,7-dich lorokynurenic acid ([H-3]DCKA) binding to N-methyl-D-aspartate (NMDA)/ glycine receptors, lpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([H-3]AMPA) binding to AMPA receptors, and [H-3]kainate ([H-3]KA) binding to KA receptors in rat brain membranes. 5-(N-Oxyaza)-QXs 12a- e all have low micromolar or submicromolar potency for NMDA/glycine re ceptors and low micromolar potencies for AMPA and KA receptors. QXs 12 a-e display 2-12-fold selectivity for NMDA/glycine receptors compared to AMPA receptors, and similar to 2-fold difference between AMPA and K A potency. In contrast to other QXs that either show high selectivity for NMDA (such as ACEA 1021) or AMPA (such as NBQX) receptors, these m olecules are broad spectrum antagonists of ionotropic glutamate recept ors. 7-Nitro-5-(N-oxyaza)-QX (12e) is the most potent inhibitor among 12a-e, having IC50 values of 0.69, 1.3, and 2.4 mu M at NMDA, AMPA, an d KA receptors, respectively. In functional assays on glutamate recept ors expressed in oocytes by rat cerebral cortex poly(A(+)) RNA, 7-chlo ro-5-(N-oxyaza)-QX (12a) and 7-nitro-5-(N-oxyaza)-QX (12e) have K-b va lues of 0.63 and 0.31 mu M for NMDA/glycine receptors, and are 6- and 4-fold selective for NMDA over AMPA receptors, respectively. 5-(N-Oxya za)-7-substituted-QXs 12a-e all have surprisingly high in vivo potency as anticonvulsants in a mouse maximal electroshock-induced seizure (M ES) model. 7-Chloro-5-(N-oxyaza)-QX (12a), 7-bromo-5-(N-oxyaza)-QX (12 b), and 7-methyl-5-(N-oxyaza)-QX (12c) have ED50 values of 0.82, 0.87, and 0.97 mg/kg iv, respectively. The high in vivo potency of QXs 12a- e is particularly surprising given their low log P values (similar to- 2.7). Separate studies indicate that QXs 12a and 12e are also active i n vivo as neuroprotectants and also have antinociceptive activity in a nimal pain models. In terms of in vivo activity, these 5-(N-oxyaza)-7- substituted-QXs are among the most potent broad spectrum ionotropic gl utamate antagonists reported.