Quinoxalines interact with the glycine recognition site of NMDA receptors: studies in guinea‐pig myenteric plexus and in rat cortical membranes

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Abstract
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-Cl-kynurenate (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 μm): 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 μm) 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 μm): 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.