ALLOSTERIC MODULATION OF THE GLUTAMATE SITE ON THE NMDA RECEPTOR BY 4NOVEL GLYCINE SITE ANTAGONISTS

Using radioligand binding studies, we have investigated the binding pr operties of four 4-hydroxy-2-quinolones, a novel series of selective a ntagonists for the glycine site on the N-methyl-D-aspartate (NMDA) rec eptor. L-701,324, L-703,717, L-698,532 and L-695,902 inhibited [H-3]L- 689,560 (glycine site antagonist) binding to rat cortex/hippocampus P- 2 membranes with IC50 values of 1.97, 4.47, 209 and 6448 nM, respectiv ely, whilst also inhibiting non-equilibrium [H-3]dizocilpine binding t o the NMDA receptor ion-channel. All four compounds partially inhibite d L-[H-3]glutamate (similar to 50% inhibition; agonist) binding and en hanced [H-3]cis-4-phosphonomethyl-2-piperidine carboxylate ([H-3]CGs-1 9755; 41-81% enhancement; 'C-5' antagonist) and 3]3-(2-carboxypiperazi n-4-yl)-propyl-1-phosphonate ([H-3]CPP; 28-66% enhancement; 'C-7' anta gonist) binding to the glutamate recognition site of the NMDA receptor with EC(50) values similar to those observed for [H-3]L-689,560 bindi ng. These results provide further evidence for allosteric interactions between the glutamate and glycine recognition sites of the NMDA recep tor complex, and as the 4-hydroxy-2-quinolones are 'full' antagonists at the glycine site, indicate that these interactions are not caused b y the intrinsic activity of a compound.