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.

Abstract

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-amino-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 (Kb approximately 6-8 nM) at the glycine site, moderate potency at non-NMDA receptors (Kb = 0.9-1.5 microM), 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 approximately 100-fold decrease in potency (10a,b,z), while removal of both halogens from 17a results in a approximately 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.