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Fabrício G. Menezes - One of the best experts on this subject based on the ideXlab platform.
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theoretical and experimental investigation of acidity of the glutamate receptor antagonist 6 7 dinitro 1 4 dihydroquinoxaline 2 3 dione and its possible implication in glua2 binding
Journal of Physical Chemistry A, 2017Co-Authors: Gutto R. S. De Freitas, Sara E. Coelho, Norberto K. V. Monteiro, Jannyely Moreira Neri, Lívia Nunes Cavalcanti, Josiel B. Domingos, Davi S. Vieira, Miguel A. F. De Souza, Fabrício G. MenezesAbstract:The acidity of organic compounds is highly relevant to understanding several biological processes. Although the relevance and challenges in estimating pKa values of organic acids is recognized by several reported works in the literature, there is a lack in determining the acidity of amides. This paper presents an experimental/theoretical combined investigation on the acid dissociation of the compound 6,7-dinitro-1,4-dihydroquinoxaline-2,3-dione (DNQX), a well-established antagonist of ionotropic glutamate receptor GluA2. DNQX was synthesized, and its two acidic constants were determined by UV–vis spectroscopy. The experimental pKa of 6.99 ± 0.02 and 10.57 ± 0.01 indicate that DNQX mainly exists as an anionic form (DNQXA1) in physiological media, which was also confirmed by 1H NMR analysis. Five computational methods were applied for estimating the theoretical pKa values of DNQX, including B3LYP, M06-2X, ωB97XD, and CBS-QB3, which were able to provide reasonable estimates for pKa associated with DNQX. Mole...
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Theoretical and Experimental Investigation of Acidity of the Glutamate Receptor Antagonist 6,7-Dinitro-1,4-dihydroquinoxaline-2,3-dione and Its Possible Implication in GluA2 Binding
2017Co-Authors: Gutto R. S. De Freitas, Sara E. Coelho, Norberto K. V. Monteiro, Jannyely Moreira Neri, Lívia Nunes Cavalcanti, Josiel B. Domingos, Davi S. Vieira, Miguel A. F. De Souza, Fabrício G. MenezesAbstract:The acidity of organic compounds is highly relevant to understanding several biological processes. Although the relevance and challenges in estimating pKa values of organic acids is recognized by several reported works in the literature, there is a lack in determining the acidity of amides. This paper presents an experimental/theoretical combined investigation on the acid dissociation of the compound 6,7-dinitro-1,4-dihydroquinoxaline-2,3-dione (DNQX), a well-established antagonist of ionotropic glutamate receptor GluA2. DNQX was synthesized, and its two acidic constants were determined by UV–vis spectroscopy. The experimental pKa of 6.99 ± 0.02 and 10.57 ± 0.01 indicate that DNQX mainly exists as an anionic form (DNQXA1) in physiological media, which was also confirmed by 1H NMR analysis. Five computational methods were applied for estimating the theoretical pKa values of DNQX, including B3LYP, M06-2X, ωB97XD, and CBS-QB3, which were able to provide reasonable estimates for pKa associated with DNQX. Molecular dynamics studies have demonstrated that DNQXA1′ binds more effectively to the pocket of the GluA2 than neutral DNQX, and this fact is coherent to the interactions between amidic oxygens and Arg845 being the main interactions of this host–guest system. Moreover, interaction of GluA2 with endogenous glutamate is stronger than that with DNQXA1, which is in agreement with literature. To the best of our knowledge, we report herein an unprecedented approach involving acidity of the antagonist DNQX, as well as the possible implications in binding to GluA2
Norman J. Uretsky - One of the best experts on this subject based on the ideXlab platform.
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induction of locomotor activity by the glutamate antagonist DNQX injected into the ventral tegmental area
Brain Research, 1996Co-Authors: Asad Dalia, Norman J. Uretsky, Lane J. WallaceAbstract:DNQX, an antagonist of AMPA/kainate receptors, was injected into the ventral tegmental area (VTA) to test the hypothesis that AMPA/kainate receptors in this brain region might be involved in regulation of locomotor activity. Bilateral injection of 1 μg DNQX into the VTA increased locomotor activity. In addition, unilateral injection of DNQX into this site produced contraversive turning, which was potentiated by coadministration of amphetamine (1 mg/kg, i.p.). These results suggest that a glutamatergic afferent to the VTA is tonically active in inhibiting locomotor activity. The locomotor stimulation produced by DNQX was not associated with a change in DOPAC/DA level in the nucleus accumbens or the striatum. However, the locomotor stimulation produced by DNQX was markedly attenuated following blockade of dopaminergic receptors by haloperidol (0.5 mg/kg, s.c.) or following dopamine depletion induced by reserpine plus α-methyl-para-tyrosine pretreatment. These results suggest that a basal activation of dopaminergic receptors is required for expression of the locomotor activity elicited by DNQX.
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effects of the ampa kainate receptor antagonist DNQX in the nucleus accumbens on drug induced conditioned place preference
Brain Research, 1993Co-Authors: Richard T Layer, Norman J. Uretsky, Lane J. WallaceAbstract:Abstract Activation of AMPA/kainate glutamatergic receptors in the nucleus accumbens may be a component of the mechanism of drug induced reward. To test this hypothesis, 6,7-dinitroquinoxaline-2,3-dione (DNQX), an α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA)/kainate glutamatergic receptor antagonist, was injected into the nucleus accumbens before the administration of amphetamine or morphine during the training phase (acquisition) of a conditioned place preference paradigm. Rats were then tested for place preference in the absence of drugs. In other experiments, DNQX was given before testing for place preference (expression) but not during the training phase. Bilateral injection of DNQX (1 μg/0.5 μl/side) inhibited acquisition of place preference to amphetamine (1 mg/kg) but not morphine (10 mg/kg). During acquisition, DNQX marginally attenuated the locomotor stimulation elicited by amphetamine during the first but not subsequent training sessions, while the combination of morphine plus DNQX produced marked akinesia during each training session. When given prior to testing, DNQX inhibited the expression of place preference induced by amphetamine and morphine but did not affect locomotor activity. The results suggest that activation of AMPA/kainate receptors is involved in the primary reward stimulation (acquisition of place preference) of amphetamine but not morphine and in behaviors elicited by memory of primary reward stimulation (expression of place preference) for both drugs. Furthermore, locomotor activity during conditioning is not necessary for acquisition of place preference.
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ampa kainic acid glutamate receptor antagonism in the zona incerta dorsal to the subthalamic nucleus inhibits amphetamine induced stereotypy but not locomotor activity
Brain Research, 1992Co-Authors: Donna E Supko, Norman J. Uretsky, Lane J. WallaceAbstract:The effect of 6,7-dinitroquinoxaline-2,3-dione (DNQX), an alpha-amino-3- hydroxy-5-methyl-4-isoxazole-propionate (AMPA)/kainic acid glutamate receptor antagonist, injected into the zona incerta (ZI) was investigated to determine whether the behavioral responses to systemic amphetamine involve AMPA/kainic acid receptors in this brain region. Rats were injected bilaterally in the ZI with either vehicle or DNQX (1 microgram/0.5 microliter) and immediately given a systemic injection of D-amphetamine (0.5, 1.0 or 10.0 mg/kg, s.c.). Locomotor activity was recorded for 1 h. DNQX did not significantly affect hypermotility stimulated with 0.5 and 1.0 mg/kg amphetamine, but markedly increased the level of locomotor activity elicited by the higher dose, 10 mg/kg. To test the hypothesis that the enhanced locomotor response to high dose amphetamine was due to an inhibition of stereotyped behavior, the effect of DNQX in the ZI on amphetamine and apomorphine-induced stereotypy was investigated. DNQX significantly inhibited stereotypy induced by amphetamine (10 mg/kg) and apomorphine (1 mg/kg), with the onset of inhibition of amphetamine-induced stereotypy corresponding to the onset of enhanced locomotor activity. Ibotenic acid lesions of the ZI produced similar results, having an insignificant effect on locomotor activity stimulated by low dose amphetamine (1 mg/kg) and an attenuation of apomorphine-induced stereotypy which was of a magnitude comparable to that produced by DNQX. Thus, the AMPA/kainic acid subtypes of glutamate receptors in the ZI may be involved in the regulation of motor function mediated via striatal output but not mesolimbically generated locomotor activity.
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alpha amino 3 hydroxy 5 methylisoxazole 4 propionate kainate receptor antagonists in the nucleus accumbens and ventral pallidum decrease the hypermotility response to psychostimulant drugs
Journal of Pharmacology and Experimental Therapeutics, 1992Co-Authors: David L. Willins, Lane J. Wallace, Duane D Miller, Norman J. UretskyAbstract:The purpose of this study was to determine the role of alpha-amino-3-hydroxy- 5-methylisoxazole-4-propionate (AMPA)/kainate excitatory amino acid receptors in the nucleus accumbens and the ventral pallidum in the hypermotility responses to amphetamine, caffeine and scopolamine. To accomplish this, we determined the effects of intracranial injections of 6,7-dinitroquinoxaline-2,3-dione (DNQX) and gamma-D-glutamylaminomethyl-sulfonate (GAMS), which inhibit the responses to AMPA, quisqualate and kainate in electrophysiological and behavioral studies. The bilateral administration of either DNQX (1 micrograms/0.5 microliters) or GAMS (5 micrograms/0.5 microliters) into the nucleus accumbens inhibited the locomotor stimulation produced by amphetamine (0.5 mg/kg s.c.) but not by caffeine (20 mg/kg s.c.) or scopolamine (0.5 mg/kg s.c.). However, the bilateral administration of either of the two antagonists into the ventral pallidum inhibited the response to all three stimulants. The administration of 6-amino-7-fluroquinoxaline-2,3-dione, a chemical analog of DNQX that does not bind to AMPA receptors, into either the nucleus accumbens or the ventral pallidum did not inhibit the locomotor stimulation produced by amphetamine. Neither DNQX nor GAMS injected into either the nucleus accumbens or the ventral pallidum produced significant changes in the locomotor activity of animals not injected with the stimulants. These results suggest that activation of AMPA/kainate receptors in the nucleus accumbens is important in the stimulation of locomotion produced by amphetamine, whereas activation of these receptors in the ventral pallidum is involved in the hypermotility response to all three central nervous system stimulants.
Lane J. Wallace - One of the best experts on this subject based on the ideXlab platform.
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induction of locomotor activity by the glutamate antagonist DNQX injected into the ventral tegmental area
Brain Research, 1996Co-Authors: Asad Dalia, Norman J. Uretsky, Lane J. WallaceAbstract:DNQX, an antagonist of AMPA/kainate receptors, was injected into the ventral tegmental area (VTA) to test the hypothesis that AMPA/kainate receptors in this brain region might be involved in regulation of locomotor activity. Bilateral injection of 1 μg DNQX into the VTA increased locomotor activity. In addition, unilateral injection of DNQX into this site produced contraversive turning, which was potentiated by coadministration of amphetamine (1 mg/kg, i.p.). These results suggest that a glutamatergic afferent to the VTA is tonically active in inhibiting locomotor activity. The locomotor stimulation produced by DNQX was not associated with a change in DOPAC/DA level in the nucleus accumbens or the striatum. However, the locomotor stimulation produced by DNQX was markedly attenuated following blockade of dopaminergic receptors by haloperidol (0.5 mg/kg, s.c.) or following dopamine depletion induced by reserpine plus α-methyl-para-tyrosine pretreatment. These results suggest that a basal activation of dopaminergic receptors is required for expression of the locomotor activity elicited by DNQX.
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effects of the ampa kainate receptor antagonist DNQX in the nucleus accumbens on drug induced conditioned place preference
Brain Research, 1993Co-Authors: Richard T Layer, Norman J. Uretsky, Lane J. WallaceAbstract:Abstract Activation of AMPA/kainate glutamatergic receptors in the nucleus accumbens may be a component of the mechanism of drug induced reward. To test this hypothesis, 6,7-dinitroquinoxaline-2,3-dione (DNQX), an α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA)/kainate glutamatergic receptor antagonist, was injected into the nucleus accumbens before the administration of amphetamine or morphine during the training phase (acquisition) of a conditioned place preference paradigm. Rats were then tested for place preference in the absence of drugs. In other experiments, DNQX was given before testing for place preference (expression) but not during the training phase. Bilateral injection of DNQX (1 μg/0.5 μl/side) inhibited acquisition of place preference to amphetamine (1 mg/kg) but not morphine (10 mg/kg). During acquisition, DNQX marginally attenuated the locomotor stimulation elicited by amphetamine during the first but not subsequent training sessions, while the combination of morphine plus DNQX produced marked akinesia during each training session. When given prior to testing, DNQX inhibited the expression of place preference induced by amphetamine and morphine but did not affect locomotor activity. The results suggest that activation of AMPA/kainate receptors is involved in the primary reward stimulation (acquisition of place preference) of amphetamine but not morphine and in behaviors elicited by memory of primary reward stimulation (expression of place preference) for both drugs. Furthermore, locomotor activity during conditioning is not necessary for acquisition of place preference.
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ampa kainic acid glutamate receptor antagonism in the zona incerta dorsal to the subthalamic nucleus inhibits amphetamine induced stereotypy but not locomotor activity
Brain Research, 1992Co-Authors: Donna E Supko, Norman J. Uretsky, Lane J. WallaceAbstract:The effect of 6,7-dinitroquinoxaline-2,3-dione (DNQX), an alpha-amino-3- hydroxy-5-methyl-4-isoxazole-propionate (AMPA)/kainic acid glutamate receptor antagonist, injected into the zona incerta (ZI) was investigated to determine whether the behavioral responses to systemic amphetamine involve AMPA/kainic acid receptors in this brain region. Rats were injected bilaterally in the ZI with either vehicle or DNQX (1 microgram/0.5 microliter) and immediately given a systemic injection of D-amphetamine (0.5, 1.0 or 10.0 mg/kg, s.c.). Locomotor activity was recorded for 1 h. DNQX did not significantly affect hypermotility stimulated with 0.5 and 1.0 mg/kg amphetamine, but markedly increased the level of locomotor activity elicited by the higher dose, 10 mg/kg. To test the hypothesis that the enhanced locomotor response to high dose amphetamine was due to an inhibition of stereotyped behavior, the effect of DNQX in the ZI on amphetamine and apomorphine-induced stereotypy was investigated. DNQX significantly inhibited stereotypy induced by amphetamine (10 mg/kg) and apomorphine (1 mg/kg), with the onset of inhibition of amphetamine-induced stereotypy corresponding to the onset of enhanced locomotor activity. Ibotenic acid lesions of the ZI produced similar results, having an insignificant effect on locomotor activity stimulated by low dose amphetamine (1 mg/kg) and an attenuation of apomorphine-induced stereotypy which was of a magnitude comparable to that produced by DNQX. Thus, the AMPA/kainic acid subtypes of glutamate receptors in the ZI may be involved in the regulation of motor function mediated via striatal output but not mesolimbically generated locomotor activity.
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alpha amino 3 hydroxy 5 methylisoxazole 4 propionate kainate receptor antagonists in the nucleus accumbens and ventral pallidum decrease the hypermotility response to psychostimulant drugs
Journal of Pharmacology and Experimental Therapeutics, 1992Co-Authors: David L. Willins, Lane J. Wallace, Duane D Miller, Norman J. UretskyAbstract:The purpose of this study was to determine the role of alpha-amino-3-hydroxy- 5-methylisoxazole-4-propionate (AMPA)/kainate excitatory amino acid receptors in the nucleus accumbens and the ventral pallidum in the hypermotility responses to amphetamine, caffeine and scopolamine. To accomplish this, we determined the effects of intracranial injections of 6,7-dinitroquinoxaline-2,3-dione (DNQX) and gamma-D-glutamylaminomethyl-sulfonate (GAMS), which inhibit the responses to AMPA, quisqualate and kainate in electrophysiological and behavioral studies. The bilateral administration of either DNQX (1 micrograms/0.5 microliters) or GAMS (5 micrograms/0.5 microliters) into the nucleus accumbens inhibited the locomotor stimulation produced by amphetamine (0.5 mg/kg s.c.) but not by caffeine (20 mg/kg s.c.) or scopolamine (0.5 mg/kg s.c.). However, the bilateral administration of either of the two antagonists into the ventral pallidum inhibited the response to all three stimulants. The administration of 6-amino-7-fluroquinoxaline-2,3-dione, a chemical analog of DNQX that does not bind to AMPA receptors, into either the nucleus accumbens or the ventral pallidum did not inhibit the locomotor stimulation produced by amphetamine. Neither DNQX nor GAMS injected into either the nucleus accumbens or the ventral pallidum produced significant changes in the locomotor activity of animals not injected with the stimulants. These results suggest that activation of AMPA/kainate receptors in the nucleus accumbens is important in the stimulation of locomotion produced by amphetamine, whereas activation of these receptors in the ventral pallidum is involved in the hypermotility response to all three central nervous system stimulants.
Gutto R. S. De Freitas - One of the best experts on this subject based on the ideXlab platform.
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theoretical and experimental investigation of acidity of the glutamate receptor antagonist 6 7 dinitro 1 4 dihydroquinoxaline 2 3 dione and its possible implication in glua2 binding
Journal of Physical Chemistry A, 2017Co-Authors: Gutto R. S. De Freitas, Sara E. Coelho, Norberto K. V. Monteiro, Jannyely Moreira Neri, Lívia Nunes Cavalcanti, Josiel B. Domingos, Davi S. Vieira, Miguel A. F. De Souza, Fabrício G. MenezesAbstract:The acidity of organic compounds is highly relevant to understanding several biological processes. Although the relevance and challenges in estimating pKa values of organic acids is recognized by several reported works in the literature, there is a lack in determining the acidity of amides. This paper presents an experimental/theoretical combined investigation on the acid dissociation of the compound 6,7-dinitro-1,4-dihydroquinoxaline-2,3-dione (DNQX), a well-established antagonist of ionotropic glutamate receptor GluA2. DNQX was synthesized, and its two acidic constants were determined by UV–vis spectroscopy. The experimental pKa of 6.99 ± 0.02 and 10.57 ± 0.01 indicate that DNQX mainly exists as an anionic form (DNQXA1) in physiological media, which was also confirmed by 1H NMR analysis. Five computational methods were applied for estimating the theoretical pKa values of DNQX, including B3LYP, M06-2X, ωB97XD, and CBS-QB3, which were able to provide reasonable estimates for pKa associated with DNQX. Mole...
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Theoretical and Experimental Investigation of Acidity of the Glutamate Receptor Antagonist 6,7-Dinitro-1,4-dihydroquinoxaline-2,3-dione and Its Possible Implication in GluA2 Binding
2017Co-Authors: Gutto R. S. De Freitas, Sara E. Coelho, Norberto K. V. Monteiro, Jannyely Moreira Neri, Lívia Nunes Cavalcanti, Josiel B. Domingos, Davi S. Vieira, Miguel A. F. De Souza, Fabrício G. MenezesAbstract:The acidity of organic compounds is highly relevant to understanding several biological processes. Although the relevance and challenges in estimating pKa values of organic acids is recognized by several reported works in the literature, there is a lack in determining the acidity of amides. This paper presents an experimental/theoretical combined investigation on the acid dissociation of the compound 6,7-dinitro-1,4-dihydroquinoxaline-2,3-dione (DNQX), a well-established antagonist of ionotropic glutamate receptor GluA2. DNQX was synthesized, and its two acidic constants were determined by UV–vis spectroscopy. The experimental pKa of 6.99 ± 0.02 and 10.57 ± 0.01 indicate that DNQX mainly exists as an anionic form (DNQXA1) in physiological media, which was also confirmed by 1H NMR analysis. Five computational methods were applied for estimating the theoretical pKa values of DNQX, including B3LYP, M06-2X, ωB97XD, and CBS-QB3, which were able to provide reasonable estimates for pKa associated with DNQX. Molecular dynamics studies have demonstrated that DNQXA1′ binds more effectively to the pocket of the GluA2 than neutral DNQX, and this fact is coherent to the interactions between amidic oxygens and Arg845 being the main interactions of this host–guest system. Moreover, interaction of GluA2 with endogenous glutamate is stronger than that with DNQXA1, which is in agreement with literature. To the best of our knowledge, we report herein an unprecedented approach involving acidity of the antagonist DNQX, as well as the possible implications in binding to GluA2
Miguel A. F. De Souza - One of the best experts on this subject based on the ideXlab platform.
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theoretical and experimental investigation of acidity of the glutamate receptor antagonist 6 7 dinitro 1 4 dihydroquinoxaline 2 3 dione and its possible implication in glua2 binding
Journal of Physical Chemistry A, 2017Co-Authors: Gutto R. S. De Freitas, Sara E. Coelho, Norberto K. V. Monteiro, Jannyely Moreira Neri, Lívia Nunes Cavalcanti, Josiel B. Domingos, Davi S. Vieira, Miguel A. F. De Souza, Fabrício G. MenezesAbstract:The acidity of organic compounds is highly relevant to understanding several biological processes. Although the relevance and challenges in estimating pKa values of organic acids is recognized by several reported works in the literature, there is a lack in determining the acidity of amides. This paper presents an experimental/theoretical combined investigation on the acid dissociation of the compound 6,7-dinitro-1,4-dihydroquinoxaline-2,3-dione (DNQX), a well-established antagonist of ionotropic glutamate receptor GluA2. DNQX was synthesized, and its two acidic constants were determined by UV–vis spectroscopy. The experimental pKa of 6.99 ± 0.02 and 10.57 ± 0.01 indicate that DNQX mainly exists as an anionic form (DNQXA1) in physiological media, which was also confirmed by 1H NMR analysis. Five computational methods were applied for estimating the theoretical pKa values of DNQX, including B3LYP, M06-2X, ωB97XD, and CBS-QB3, which were able to provide reasonable estimates for pKa associated with DNQX. Mole...
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Theoretical and Experimental Investigation of Acidity of the Glutamate Receptor Antagonist 6,7-Dinitro-1,4-dihydroquinoxaline-2,3-dione and Its Possible Implication in GluA2 Binding
2017Co-Authors: Gutto R. S. De Freitas, Sara E. Coelho, Norberto K. V. Monteiro, Jannyely Moreira Neri, Lívia Nunes Cavalcanti, Josiel B. Domingos, Davi S. Vieira, Miguel A. F. De Souza, Fabrício G. MenezesAbstract:The acidity of organic compounds is highly relevant to understanding several biological processes. Although the relevance and challenges in estimating pKa values of organic acids is recognized by several reported works in the literature, there is a lack in determining the acidity of amides. This paper presents an experimental/theoretical combined investigation on the acid dissociation of the compound 6,7-dinitro-1,4-dihydroquinoxaline-2,3-dione (DNQX), a well-established antagonist of ionotropic glutamate receptor GluA2. DNQX was synthesized, and its two acidic constants were determined by UV–vis spectroscopy. The experimental pKa of 6.99 ± 0.02 and 10.57 ± 0.01 indicate that DNQX mainly exists as an anionic form (DNQXA1) in physiological media, which was also confirmed by 1H NMR analysis. Five computational methods were applied for estimating the theoretical pKa values of DNQX, including B3LYP, M06-2X, ωB97XD, and CBS-QB3, which were able to provide reasonable estimates for pKa associated with DNQX. Molecular dynamics studies have demonstrated that DNQXA1′ binds more effectively to the pocket of the GluA2 than neutral DNQX, and this fact is coherent to the interactions between amidic oxygens and Arg845 being the main interactions of this host–guest system. Moreover, interaction of GluA2 with endogenous glutamate is stronger than that with DNQXA1, which is in agreement with literature. To the best of our knowledge, we report herein an unprecedented approach involving acidity of the antagonist DNQX, as well as the possible implications in binding to GluA2