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

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-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 uM): 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 (5-50uM) completely reversed the antagonism displayed by both quinoxalines and kynurenates. The interaction between glycine and the tested compounds appeared to be competitive in nature. 6 These data show that quinoxalines and kynurenates may antagonize the responses to Lglutamate by interacting with the glycine recognition sites of the NMDA receptor ion channel complex. IntoductionThe quinoxalinediones, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, also known as FG9065) and 6,7, dinitroquinoxaline-2,3-dione (DNQX, FG9041), have been reported to be selective, potent and competitive antagonists for the quisqualate and the kainate subtypes of excitatory amino acid receptors (Honore' et al., 1988;Fletcher et al., 1988), and have therefore been proposed and utilized as powerful tools for detailed investigations on the physiological role of non N-methyl-D-aspartate (NMDA) receptors (Blake et al

Effects of deletion of gria1 or gria2 genes encoding glutamatergic AMPA-receptor subunits on place preference conditioning in mice

“…While others have reported effects of AMPA-preferring antagonists on both the induction and expression of CPPs to drugs of abuse (Layer et al 1993;Cervo and Samanin 1995;Kaddis et al 1995;Tzschentke and Schmidt 1997), all of these findings could potentially be explained by non-specific effects of the compounds tested. Both CNQX and DNQX have affinity for the strychnine-insensitive glycine site of the NMDA receptor (Birch et al 1988;Kessler et al 1989;Pellegrini-Giampietro et al 1989;Sheardown et al 1990;Goldstein and Litwin 1993;Yoneda et al 1993), whilst GYKI 52466 shows functional antagonism of NMDA-induced seizures (Steppuhn and Turski 1993). Given the role that NMDA receptors (see Tzschentke 1998 for review), and modulation of the NMDA receptor via the glycine site , have in the induction of place preference conditioning, these earlier findings must be treated with caution.…”

Characterization of glutamate toxicity in cultured rat cerebellar granule neurons at reduced temperature

“…CNQX afforded potent neuroprotectant effects in response to glutamate challenge. Interpretation of this effect of CNQX is complicated somewhat by the ability of this compound to act as an antagonist at the strychnine-insensitive glycine site on NMDA receptors (34)(35)(36). Thus, in addition to acting as a non-NMDA receptor antagonist, CNQX is nearly equipotent as HA-966 in displacing […”

NMDA Receptor Contribution to the Climbing Fiber Response in the Adult Mouse Purkinje Cell

“…Although species differences cannot be completely excluded, examination of this study shows that it was done using CNQX as a specific blocker of AMPA receptors. CNQX has been widely described as being also an antagonist at NMDA-Rs, in part by competing with glycine at its modulatory site (Birch et al, 1988;Harris and Miller, 1989;Kessler et al, 1989;Pellegrini-Giampietro et al, 1989;Lester and Jahr, 1990;Mead and Stephens, 1999) and also with glutamate at its binding site (Lester and Jahr, 1990). In contrast, NBQX has no effect on NMDA currents (Sheardown et al, 1990).…”