SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF SUBSTITUTED 1,4-DIHYDROQUINOXALINE-2,3-DIONES - ANTAGONISTS OF N-METHYL-D-ASPARTATE (NMDA) RECEPTOR GLYCINE SITES AND NON-NMDA GLUTAMATE RECEPTORS

A series of mono-, di-, tri-, and tetrasubstituted 1,4-dihydroquinoxaline-2,3-diones (QXs) were synthesized and evaluated as antagonists at N-methyl-D-aspartate (NMDA)/glycine sites and alpha wamino-3-hydroxy-5-methylisoxazole-4-propionic acid-preferring non-NMDA receptors. Antagonist potencies were measured by electrical assays in Xenopus oocytes expressing rat whole brain poly(A)(+) RNA. Trisubstituted QXs 17a (ACEA 1021), 17b (ACEA 1031), 24a, and 27, containing a nitro group in the 5 position and halogen in the 6 and 7 positions, displayed high potency (K-b similar to 6-8 nM) at the glycine site, moderate potency at non-NMDA receptors (K-b = 0.9-1.5 mu M), and the highest (120-250-fold) selectivity in favor of glycine site antagonism over non-NMDA receptors. Tetrasubstituted QXs 17d,e were more than 100-fold weaker glycine site antagonists than the corresponding trisubstituted QXs with F being better tolerated than Cl as a substituent at the 8 position. Di-and monosubstituted QXs showed progressively weaker antagonism compared to trisubstituted analogues. For example, removal of the 5-nitro group of 17a results in a similar to 100-fold decrease in potency (10a,b,z), while removal of both halogens from 17a results in a similar to 3000-fold decrease in potency (10v). In terms of steady-state inhibition, most QX substitution patterns favor antagonism at NMDA/glycine sites over antagonism at non-NMDA receptors. Among the QXs tested, only 17i was slightly selective for non-NMDA receptors.