Differential modulation of the associated glycine recognition site by competitive N-methyl-D-aspartate receptor antagonists

JB Monahan, JP Biesterfeldt, WF Hood, RP Compton, AA Cordi, MI Vazquez, TH Lanthorn and PL Wood

Central Nervous System Diseases Research, G.D. Searle & Co., St. Louis, Missouri 63198.

The competitive N-methyl-D-aspartate (NMDA) receptor antagonist D-2- amino-5-phosphonopentanoate and two other five-atom linkage (C-5) omega- phosphono-alpha-amino acid analogs reduced [3H]glycine binding, in a dose-dependent manner, to a maximum of 45-55%, whereas seven-atom linkage (C-7) analogs had significantly less effect. The IC50 of the C- 5 antagonists for the inhibition of [3H]glycine binding closely paralleled their potency both in displacing NMDA-selective L- [3H]glutamate binding and in negatively modulating (+)-[3H]5-methyl- 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne maleate ([3H]MK- 801) binding. Additionally, reduction of glycine binding by the C-5 antagonists was reversed by both NMDA receptor agonists and C-7 competitive NMDA antagonists, providing evidence that the site of action of these C-5 antagonists is the NMDA recognition site, resulting in indirect modulation of the glycine site. These data imply a functional coupling between the NMDA and associated glycine recognition sites and, furthermore, suggest a differential interaction of C-5 and C- 7 competitive NMDA antagonists with the NMDA receptor complex.

Volume 37, Issue 6, pp. 780-784, 06/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics

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