The N-methyl-D-aspartic acid (NMDA) ion channel complex has been implicated in excitotoxic events leading to neuronal degeneration. Glycine acts as a coagonist required for channel opening, making antagonists of the glycine site a promising approach to suppress glutamate excitotoxicity via the NMDA receptor. Previously reported partial agonists and antagonists include HA-966, quinoxalinediones, 2-carboxyindoles, and 5,7-dichlorokynurenic acid (5a). We report a new series of 3-phenyl-4-hydroxyquinolin-2(1H)-ones (7a-g) that show excellent inhibition of binding to the glycine site on the NMDA receptor complex. Synthesized via condensation, cyclization, and functional group modifications (e.g., HBr treatment for hydroxylation, hydrogenation for amination), their structures were confirmed by NMR, mass spectral, and microanalytical data. In [³H]glycine binding assays using rat cortical membranes, unsubstituted 7a had a Ki of 4.5 μM (similar to kynurenic acid, 5b: 5.4 μM), while 5,7-dichloro 7b was more potent (Ki 57 nM). Para-substitution in the 3-phenyl ring revealed potency order OH > NH₂ > H = OCH₃ >> CH₃ > NO₂, with 4'-hydroxy 7f being most potent (Ki 13 nM). Functional antagonism was demonstrated by inhibiting [³H]MK-801 binding (7f IC₅₀ 0.11 μM, more potent than 5a's 0.86 μM). In neonatal rat spinal cord, 7b and 7f selectively antagonized NMDA-induced responses (IC₅₀ ~2 μM) but not AMPA responses, with antagonism reversed by D-serine. QSAR analysis showed electron-donating substituents enhance binding affinity. These 3-phenyl-4-hydroxyquinolinones are potent and selective antagonists of the glycine site on the NMDA receptor complex; the 4'-hydroxy analog 7f has greater affinity than 5,7-dichlorokynurenic acid and better antagonism of NMDA-induced depolarizations. Expanded structure-activity relationships (SAR) will be reported in future work.