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Quinoxalines interact with the glycine recognition site of NMDA receptors: studies in guinea‐pig myenteric plexus and in rat cortical membranes
Author(s) -
PellegriniGiampietro Domenico E.,
Galli Alessandro,
Alesiani Marina,
Cherici Giovanna,
Moroni Flavio
Publication year - 1989
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1989.tb12675.x
Subject(s) - myenteric plexus , nmda receptor , guinea pig , neuroscience , receptor , glycine , membrane , biology , pharmacology , chemistry , medicine , endocrinology , biochemistry , amino acid , immunohistochemistry
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 [ 3 H]‐glycine binding sites of cortical membranes. 2 Quinoxalines and kynurenates antagonized in a non‐competitive manner L‐glutamate‐induced contraction. Their IC 50 s were (in μ m ): 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 μ m ) 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, [ 3 H]‐glycine from its strychnine‐insensitive binding sites present in rat cortical membranes. Their IC 50 s for this action were (in μ m ): 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 IC 50 s for the displacement effect of [ 3 H]‐glycine binding were plotted against the IC 50 s 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.