Quinoxalines interact with the glycine recognition site of NMDA receptors: studies in guinea-pig myenteric plexus and in rat cortical membranes.
1. The effects of several quinoxalines, including 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6,7,dinitroquinoxaline-2,3-dione (DNQX), and of two kynurenates, kynurenate (KYNA) and 7-Clkynurenate (7-Cl-KYNA), have been evaluated on the N-methyl-D-aspartate (NMDA) receptors present in the guinea-pig ileum myenteric plexus preparation and on the strychnine-insensitive [3H]-glycine binding sites of cortical membranes. 2. Quinoxalines and kynurenates antagonized in a non-competitive manner L-glutamate-induced contraction. Their IC50s were (in microM): 5 for 7-Cl-KYNA, 7.5 for 6,7-Cl-3-hydroxy-2-quinoxaline carboxylate (6,7-Cl-HQCA), 20 for DNQX, 50 for CNQX, 76 for KYNA and 125 for 3-hydroxy-2-quinoxaline carboxylate (HQCA). 3. Glycine (5-50 microM) completely reversed the antagonism displayed by both quinoxalines and kynurenates. The interaction between glycine and the tested compounds appeared to be competitive in nature. 4. Quinoxalines and kynurenates displaced, in a concentration-dependent manner, [3H]-glycine from its strychnine-insensitive binding sites present in rat cortical membranes. Their IC50s for this action were (in microM): 0.45 for 7-Cl-KYNA, 0.6 for 6,7-Cl-HQCA, 2.4 for DNQX, 3.5 for CNQX, 20 for KYNA and 40 for HQCA. 5. When the IC50s for the displacement effect of [3H]-glycine binding were plotted against the IC50s obtained in the myenteric plexus, a significant correlation was found. 6. These data show that quinoxalines and kynurenates may antagonize the responses to L-glutamate by interacting with the glycine recognition sites of the NMDA receptor ion channel complex.
Pellegrini-Giampietro
D E
DE
Department of Preclinical and Clinical Pharmacology Mario Aiazzi Mancini, University of Florence, Italy.
Galli
A
A
Alesiani
M
M
Cherici
G
G
Moroni
F
F
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D005998:Glycine / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects; D007700:Kinetics; D007736:Kynurenic Acid / Q000494:pharmacology; D008297:Male; D009197:Myenteric Plexus / Q000187:drug effects / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D013331:Strychnine / Q000494:pharmacology
D007473:Ion Channels; D011810:Quinoxalines; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D007736:Kynurenic Acid; D013331:Strychnine; D005998:Glycine