STRUCTURE-ACTIVITY-RELATIONSHIPS OF 3-HYDROXY-2(1H)-QUINOLINONES AS N-METHYL-D-ASPARTATE (GLYCINE SITE) RECEPTOR ANTAGONISTS

Two series of 3-hydroxy-2(1H)-quinolinones (3a-s, 4a-v) were prepared and structure-activity relationships for binding affinity to the N-met hyl-D-aspartate (glycine site) receptor measured. Despite the structur al similarity to glycine antagonists of the quinoxalinedioned type, su rprisingly, the SARs for compounds 3a-s more closely follow those of t he kynurenic acids. Thus the most potent compounds, 3r (IC50 = 6.3 nM) and 4v (IC50 = 7.6 nM), possessed chlorines at both 5 and 7 positions , and a suitable hydrogen-bond acceptor (ethoxycarbonyl or N,N'dialkyl -ureido) at the 4-position.