Differential modulation of the associated glycine recognition site by competitive N-methyl-D-aspartate receptor antagonists.
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.
Monahan
J B
JB
Central Nervous System Diseases Research, G.D. Searle & Co., St. Louis, Missouri 63198.
Biesterfeldt
J P
JP
Hood
W F
WF
Compton
R P
RP
Cordi
A A
AA
Vazquez
M I
MI
Lanthorn
T H
TH
Wood
P L
PL
D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D005998:Glycine / Q000378:metabolism*; D008297:Male; D016202:N-Methylaspartate; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects* / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000596:Amino Acids; D009943:Organophosphorus Compounds; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D001224:Aspartic Acid; D016202:N-Methylaspartate; C056639:2-amino-5-phosphopentanoic acid; D014633:Valine; D005998:Glycine