title: Allosteric modulation of the glutamate site on the NMDA receptor by four novel glycine site antagonists.
abstract: Using radioligand binding studies, we have investigated the binding properties of four 4-hydroxy-2-quinolones, a novel series of selective antagonists for the glycine site on the N-methyl-D-aspartate (NMDA) receptor. L-701,324, L-703,717, L-698,532 and L-695,902 inhibited [3H]L-689,560 (glycine site antagonist) binding to rat cortex/hippocampus P2 membranes with IC50 values of 1.97, 4.47, 209 and 6448 nM, respectively, whilst also inhibiting non-equilibrium [3H]dizocilpine binding to the NMDA receptor ion-channel. All four compounds partially inhibited L-[3H]glutamate (approximately 50% inhibition; agonist) binding and enhanced [3H]cis-4-phosphonomethyl-2-piperidine carboxylate ([3H]CGS-19755; 41-81% enhancement; 'C-5' antagonist) and [3H]3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonate ([3H]CPP; 28-66% enhancement; 'C-7' antagonist) binding to the glutamate recognition site of the NMDA receptor with EC50 values similar to those observed for [3H]L-689,560 binding. These results provide further evidence for allosteric interactions between the glutamate and glycine recognition sites of the NMDA receptor complex, and as the 4-hydroxy-2-quinolones are 'full' antagonists at the glycine site, indicate that these interactions are not caused by the intrinsic activity of a compound.
authors.affiliation: Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.
authors.forename: S
authors.initials: S
authors.lastname: Grimwood
authors.forename: J J
authors.initials: JJ
authors.lastname: Kulagowski
authors.forename: I M
authors.initials: IM
authors.lastname: Mawer
authors.forename: M
authors.initials: M
authors.lastname: Rowley
authors.forename: P D
authors.initials: PD
authors.lastname: Leeson
authors.forename: A C
authors.initials: AC
authors.lastname: Foster
mesh_terms: D000495:Allosteric Site / Q000187:drug effects; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D018684:Glycine Agents / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D011869:Radioligand Assay; D051381:Rats; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism*; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018684:Glycine Agents; D017470:Receptors, Glutamate; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate