3-ACYL-4-HYDROXYQUINOLIN-2(1H)-ONES - SYSTEMICALLY ACTIVE ANTICONVULSANTS ACTING BY ANTAGONISM AT THE GLYCINE SITE OF THE N-METHL-D-ASPARTATE RECEPTOR COMPLEX

Most full antagonists at the glycine site of the NMDA receptor contain a carboxylic acid, which we believe to be detrimental to penetration of the blood-brain barrier. By consideration of a pharmacophore, novel antagonists at this site have been designed in which the anionic functionality is a vinylogous acid, in the form of a 4-hydroxyquinolin-2(1H)-one. In this series, a 3-substituent is necessary for binding, and correct manipulation of this group leads to compounds such as the 3- (3-hydroxyphenyl) propargyl ester 24 (L-701,273), with an IC50 for displacement of [H-3] -L-689,560 binding of 0. 17 muM and K(b) against NMDA in the cortical slice of 1.39 muM. Compounds were tested for their ability to prevent audiogenic seizure in DBA/2 mice; the most potent compound in this series is the cyclopropyl ketone 42 (L-701,252), with an ED50 of 4.1 mg/kg ip. A model is proposed for binding to the glycine site, in which an important interaction is of a putative receptor cation with the pi-system of the 3-substituent.