IDENTIFICATION OF -2-ARYL-1H-PYRAZOLO[3,4-C]QUINOLINE-1,4(2H)-DIONES AS NOVEL HIGH-AFFINITY GLYCINE SITE N-METHYL-D-ASPARTATE ANTAGONISTS

Almost all of the exisiting known antagonists at the glycine site of t he N-methyl-D-aspartate (NMDA) receptor have a low propensity for cros sing the blood-brain barrier. It has been suggested that in many cases this may be due to the presence of a carboxylic acid which is a commo n feature of most of the potent full antagonists at this receptor. In this study, 2-aryl-1H-pyrazolo[3,4-c]quinoline-1,4(2H)-diones were fou nd to have high-affinity binding at the glycine receptor. In particula r, structure-activity studies identified yphenyl)-1H-pyrazolo[3,4-c]qu inoline-1,4(2H)-dione as the most potent of a series of analogues with an IC50 of 3.3 nM. The measured pK(a) values in this class of compoun ds (typically 4.0) indicate they are of equivalent acidity to carboxyl ic acids. Functional antagonism was demonstrated by inhibition of NMDA -evoked responses in rat cortical slices. Anticonvulsant activity in D BA/2 mice was achieved after dosing by direct injection into the cereb ral ventricles, but no activity was seen after systemic administration , suggesting low brain penetration with this class of antagonists.