5,7-Dichlorokynurenic acid, a potent and selective competitive antagonist of the glycine site on NMDA receptors.
Fourteen substituted derivatives of kynurenic acid were compared for their ability to block ionic currents evoked by N-methyl-D-aspartate (NMDA) plus glycine, or kainate, in voltage-clamped Xenopus oocytes injected with rat brain messenger RNA. Among these analogues there was an excellent correlation between the Ki for displacing [3H]glycine binding to rat brain membranes, and the ability to inhibit ionic currents evoked by glycine/NMDA in Xenopus oocytes. In the oocyte 5,7-dichlorokynurenic acid (5,7-DCK) was a competitive blocker of the glycine recognition site on NMDA receptors, and was more potent (KB 65 nM in Schild analysis) and selective (509-fold more potent vs glycine than kainate) than the prototype glycine antagonist, 7-chlorokynurenic acid, 5,7-DCK also reduced NMDA-induced neuron injury in rat cortical cell cultures.
McNamara
D
D
Department of Pharmacology, University of North Carolina, Chapel Hill 27599.
Smith
E C
EC
Calligaro
D O
DO
O'Malley
P J
PJ
McQuaid
L A
LA
Dingledine
R
R
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D005071:Evoked Potentials / Q000187:drug effects; D005260:Female; D005998:Glycine / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000008:administration & dosage / Q000235:genetics; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013329:Structure-Activity Relationship; D014981:Xenopus
D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D007736:Kynurenic Acid; C066192:5,7-dichlorokynurenic acid; D005998:Glycine