| Abstract
| - We report on a series of alkyl- and alkoxy-substituted1,4-dihydroquinoxaline-2,3-diones (QXs),prepared as a continuation of our structure−activity relationship(SAR) study of QXs asantagonists for the glycine site of theN-methyl-d-aspartate (NMDA) receptor. Thein vitropotency of these antagonists was determined by displacement of theglycine site radioligand[3H]-5,7-dichlorokynurenic acid([3H]DCKA) in rat brain cortical membranes. Ingeneral, methylis a good replacement for chloro or bromo in the 6-position, andalkoxy-substituted QXs havelower potencies than alkyl- or halogen-substituted QXs.Ethyl-substituted QXs are generallyless potent than methyl-substituted QXs, especially in the 6-positionof 5,6,7-trisubstitutedQXs. Fusion of a ring system at the 6,7-positions results in QXswith low potency. Severalmethyl-substituted QXs are potent glycine site antagonists that havesurprisingly high in vivoactivity in the maximal electroshock (MES) test in mice. Amongthese, 7-chloro-6-methyl-5-nitro QX (14g) (IC50 = 5 nM) and7-bromo-6-methyl-5-nitro QX (14f) (IC50 = 9nM) arecomparable in potency to 6,7-dichloro-5-nitro QX (2) (ACEA1021) as glycine site antagonists.QX 14g has an ED50 value of 1.2 mg/kg iv inthe mouse MES assay. Interestingly, alkyl QXswith log P values of 0.5 or less tend to be morebioavailable than QXs with higher log P values.QX 14g has 440-fold selectivity for NMDA vsα-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid (AMPA) receptors, as determined electrophysiologically understeady-state conditions inoocytes expressing rat cerebral cortex poly(A)+ RNA.Overall, 14g was found to have the bestcombination of in vitro and in vivo potency ofall the compounds tested in this and previousstudies on the QX series.
|
