STRUCTURE-ACTIVITY RELATIONSHIPS OF 4-HYDROXY-3-NITROQUINOLIN-2(1H)-ONES AS NOVEL ANTAGONISTS AT THE GLYCINE SITE OF N-METHYL-D-ASPARTATE RECEPTORS

A series of 4-hydroxy-3-nitroquinolin-2(1H)-ones (HNQs) was synthesize d by nitration of the corresponding 2,4-quinolinediols. The HNQs were evaluated as antagonists at the glycine site of NMDA receptors by inhi bition of [H-3]DCKA binding to rat brain membranes. Selected HNQs were also tested for functional antagonism by electrophysiological assays in Xenopus oocytes expressing either 1a/2C subunits of NMDA receptors or rat brain AMPA receptors. The structure-activity relationships (SAR ) of HNQs showed that substitutions in the 5-, 6-, and 7-positions in general increase potency while substitutions in the 8-position cause a sharp reduction in potency. Among the HNQs tested, 5,6,7-trichloro HN Q (8i) was the most potent antagonist with an IC50 of 220 nM in [H-3]D CKA binding assay and a K-b of 79 nM from electrophysiological assays. Measured under steady-state conditions HNQ 8i is 240-fold selective f or NMDA over AMPA receptors. The SAR of HNQs was compared with those o f 1,4-dihydroquinoxaline-2,3-diones (QXs) and 1,2,3,4-tetrahydroquinol ine-2,3,4-trione 3-oximes (QTOs). In general, HNQs have similar potenc ies to QXs with the same benzene ring substitution pattern but are abo ut 10 times less active than the corresponding QTOs. HNQs are more sel ective for NMDA receptors than the corresponding QXs and QTOs. The sim ilarity of the SAR of HNQs, QXs, and QTOs suggested that these three c lasses of antagonists might bind to the glycine site in a similar mann er. With appropriate substitutions, HNQs represent a new class of pote nt and highly selective NMDA receptor glycine site antagonists.