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Jean R. Wrathall - One of the best experts on this subject based on the ideXlab platform.
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2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline (NBQX) increases fibroblast growth factor mRNA levels after contusive spinal cord injury
Brain Research, 1998Co-Authors: Paolo Follesa, Jean R. Wrathall, Italo MocchettiAbstract:We have previously demonstrated that the glutamatergic receptor (AMPA) antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline (NBQX) reduces functional deficits in a standardized rat model of contusive spinal cord injury (SCI). NBQX not only acted to protect neurons from excitotoxicity but also, unexpectedly, enhanced sparing of white matter including axons of descending pathways. We have therefore investigated mechanisms through which NBQX could produce beneficial effects for white matter. We report here that NBQX elicits a rapid and selective induction of FGF2 mRNA levels in injured spinal cord. This novel effect could contribute to the therapeutic properties of NBQX in the treatment of SCI.
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Evaluation of cardiorespiratory parameters in rats after spinal cord trauma and treatment with NBQX, an antagonist of excitatory amino acid receptors.
Neuroscience letters, 1996Co-Authors: Yang D. Teng, Jean R. WrathallAbstract:2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), a selective antagonist of amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptors, ameliorates functional deficits and tissue loss after experimental contusive spinal cord injury (SCI). Data suggest that NBQX acts via local receptors at the injury site. However, potential systemic effects of NBQX could also modify consequences of SCI. We therefore examined effects of therapeutic doses of NBQX on cardiorespiratory parameters (CRP) including: mean arterial pressure, heart rate, respiratory rate and arterial blood gas. We found no significant effect on these CRP of either focal microinjection or intravenous administration of NBQX at doses that are therapeutic for SCI, in either uninjured rats, or rats after SCI. The results support the hypothesis that NBQX affects SCI by acting locally rather than through systemic effects and demonstrate NBQX treatment paradigms without adverse effects on CRP.
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Amelioration of functional deficits from spinal cord trauma with systemically administered NBQX, an antagonist of non-N-methyl-D-aspartate receptors
Experimental neurology, 1996Co-Authors: Jean R. Wrathall, Yang D. Teng, David ChoiniereAbstract:Abstract Excitatory amino acid (EAA) receptors play a significant role in delayed neuronal death after ischemic and traumatic injury to the CNS. Recent data based on focal microinjection experiments have demonstrated that 2,3-dihydro-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), a highly selective and potent antagonist of non- N -methyl- D -aspartate ionotropic EAA receptors, i.e., those preferring α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) or kainate, can reduce histopathology and functional deficits after traumatic spinal cord injury (SCI). Thus, non-NMDA receptors at or near the injury site appear to be important in secondary injury processes that contribute significantly to the consequences of SCI. We have now examined the effects of systemic NBQX, using intravenous infusion, the most commonly used and temporally efficient clinical mode of drug administration. Standardized contusive SCI was produced at the T8 vertebral level in Sprague–Dawley rats. Beginning at 15 min postinjury, NBQX was administered intravenously at 1 mg/kg/min for 30 min. Behavioral tests of hindlimb functional deficits were performed at 1 day and weekly for 1 month after SCI. Spinal cord tissue was then examined morphometrically to compare lesion size and amount of spared tissue. We found that intravenous administration of NBQX significantly reduced functional impairment after SCI. The effects included more rapid and extensive recovery of hindlimb reflexes, more rapid establishment of a reflex bladder, and a more rapid and greater degree of recovery of coordinated use of hindlimbs in open field locomotion, swimming, and maintaining position on an inclined plane. The profile of effects was similar to that seen with focal microinjection of NBQX, suggesting that even with systemic administration, the drug acts mainly at the injury site. Further, the results support a therapeutic potential for NBQX, or similar drugs that antagonize non-NMDA receptors and inhibit secondary injury processes after SCI.
Tage Honoré - One of the best experts on this subject based on the ideXlab platform.
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The NBQX Story
Excitatory Amino Acids, 1997Co-Authors: Lars Nordholm, Malcolm J. Sheardown, Tage HonoréAbstract:Publisher Summary This chapter discusses pharmacology of 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline (NBQX). NBQX is the first selective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist to demonstrate neuroprotective properties in animal models of focal and global cerebral ischemia. NBQX potently increased the focal seizure threshold and inhibited seizure spread from the focus. It protected against seizure induced by maximal electroshock (MES) and pentylenetetrazol. NBQX treatment did not reverse the Parkinsonism nor changed the responses to the selective D 2 dopamine receptor agonist (+)-PHNO or the partial dopamine D 1 receptor agonist CY208-243 in two Parkinsonian monkeys. NBQX can reduce the hippocampal CA1 neuronal loss observed following severe cerebral trauma, suggesting a further potential clinical use for AMPA antagonists in head injury. It is suggested that NBQX be administered in relatively high doses to get an anti-ischemic effect. It is observed that NBQX is as efficacious as the N -methyl- D -aspartate (NMDA) antagonists in most models of focal ischemia and does not seem to have the psychotomimetic side-effect problem.
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characterization of the metabotropic glutamate receptor in mouse cerebellar granule cells lack of effect of 2 3 dihydroxy 6 nitro 7 sulphamoylbenzo f quinoxaline NBQX
European Journal of Pharmacology, 1993Co-Authors: Peter D Suzdak, Malcolm J. Sheardown, Tage HonoréAbstract:Abstract The ability of excitatory amino acids to stimulate phosphoinositide hydrolysis in mouse cerebellar granule cells was characterized. Quisqualic acid (EC50 = 2 μM), ibotenic acid (EC50 = 15 μM), kainic acid (EC50 = 30 μM), glutamate (EC50 = 51 μM) and (1S,3R)-1-amino-cyclo-pentane-1,3-dicarboxylic acid (t-ACPD) (EC50 = 175 μM) dose-dependently stimulated phosphoninositide hydrolysis. The stimulation of phosphoinositide hydrolysis was dose-dependently blocked by 2-amino-3-phosphonopropionic acid (L-AP3) and pertussis toxin, but was unaffected by other excitatory amino acid agonists or antagonists. These data suggest that the pharmacology of excitatory amino acid-stimulated phosphoinositide hydrolysis in the mouse cerebellar granule cells is mediated through the G protein coupled metabotropic glutamate receptor. The overall pharmacology of the metabotropic receptor present in mouse cerebellar granule cells differs from that of previously reported tissue preparations such as rat cerebellar granule cells. In addition, the effect of the α-amino-3-hydroxyl-5-methyl-1-isoxazole-4-propionic acid (AMPA) receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulphamoylbenzo(F)quinoxaline (NBQX), on excitatory amino acid-stimulated phosphoinositide hydrolysis was also examined. NBQX was without effect on either basal phosphoinositide hydrolysis or excitatory amino acid-stimulated phosphoinositide hydrolysis, suggesting that the neuroprotective effect of NBQX is not mediated through the metabotropic glutamate receptor.
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Protection against post-ischemic behavioral pathology by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) in the gerbil
Neuroscience letters, 1991Co-Authors: Martin Edward Judge, Malcolm J. Sheardown, Poul Jacobsen, Tage HonoréAbstract:The neuroprotective effects of NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline) were assessed on hippocampal CA1 neuronal loss and locomotor hyperactivity following transient bilateral carotid artery occlusion (BCAO) in the gerbil. NBQX, a selective blocker of the AMPA glutamate receptor subtype, was injected 1 h after 5 or 10 min BCAO, or sham surgery. Both 5 and 10 min ischemia produced equivalent hyperactivity 3 days post ischemia and CA1 neuronal loss on Day 4, while activity was unchanged in the sham-operated group. NBQX protected from both hippocampal damage and post-ischemic hyperactivity. These results demonstrate that NBQX can protect from behavioral pathology induced by global cerebral ischemia.
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The AMPA receptor antagonist NBQX has antiparkinsonian effects in monoamine-depleted rats and MPTP-treated monkeys.
Annals of Neurology, 1991Co-Authors: Thomas Klockgether, Don M. Gash, Lechoslaw Turski, Roger Kurlan, Tage Honoré, Zhiming Zhang, J. Timothy GreenamyreAbstract:Abnormally increased subthalamic nucleus output to the internal pallidal segment and the reticular part of the substantia nigra plays a critical pathophysiological role in the development of parkinsonism. Because synaptic transmission of subthalamic output is glutamatergic and mediated, in part, by the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptor, AMPA receptor antagonists may possess antiparkinsonian properties. We report that in monoamine-depleted rats, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) (Novo-Nordisk, Copenhagen, Denmark)--a selective antagonist of the AMPA subtype of glutamate receptor--suppressed muscular rigidity but had no effect on akinesia. NBQX microinjected into the subthalamic nucleus, internal pallidal segment, and reticular part of the substantia nigra, but not into the laterodorsal neostriatum of the rats, stimulated locomotor activity and reduced muscular rigidity. In aged Rhesus monkeys with bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, intramuscular NBQX produced clinically apparent improvement in akinesia, tremor, posture, and gross motor skills. NBQX also potentiated the antiparkinsonian effects of L-3,4-dihydroxyphenylalanine in both rats and monkeys. Blockade of excitatory synaptic transmission by AMPA receptor antagonists may provide a new therapeutic strategy for Parkinson's disease (PD).
Brian S. Meldrum - One of the best experts on this subject based on the ideXlab platform.
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The effect of the non-NMDA receptor antagonists GYKI 52466 and NBQX and the competitive NMDA receptor antagonist d-CPPene on the development of amygdala kindling and on amygdala-kindled seizures
Epilepsy research, 1994Co-Authors: Nick Dürmüller, Mike Craggs, Brian S. MeldrumAbstract:Abstract A competitive (NBQX) and a non-competitive (GYKI 52466) AMPA antagonist and a competitive NMDA antagonist ( d -CPPene) were tested against the development of kindling and against fully kindled seizures in amygdalakindled rats. GYKI 52466, 10 mg/kg given i.p. 5 min prior to electrical stimulation in fully kindled animals, reduces both the cortical after-discharge duration and the behavioural seizure score. GYKI 52466, 20 mg/kg, reduces seizure score and after-discharge duration significantly (after 5–30 min) but the animals show severe motor side effects and an irregular cortical and hippocampal EEG. Administration of GYKI 52466, 10 mg/kg, prior to kindling stimulation on days 3–8, does not slow the development of kindling. NBQX, 20 mg/kg or 40 mg/kg i.p., 30 min prior to stimulation, significantly reduces the seizure score in fully kindled animals. NBQX 20 mg/kg i.p. has no effect on the development of kindling. d -CPPene, 8 mg/kg or 12 mg/kg, 120 min prior to stimulation reduces the behavioural seizure score in fully kindled animals. d -CPPene, 8 mg/kg on days 3–8, delays the development of kindling. NMDA receptors play a key role in the kindling process. Expression of kindled seizures involves non-NMDA and NMDA receptors.
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The non-NMDA antagonists, NBQX and GYKI 52466, protect against cortical and striatal cell loss following transient global ischaemia in the rat
Brain research, 1992Co-Authors: Eliane Le Pillet, B. Arvin, C. Moncada, Brian S. MeldrumAbstract:Abstract The cerebroprotective action of non-NMDA receptor blockade has been assessed in a model of transient global ischaemia using NBQX, 2,3-dihydro-6-nitro-7-sulphomoyl-benzo(F)quinoxaline, and GYKI 52466, 1-(amino-phenyl)-4-methyl-7,8-methylendioxy-5H-2,3-benzodiazepine. HCl. In Wistar rats, prioir cauterisation of the vertebral arteries was followed by occlussion of the common carotid arteries for 20 min, with a 7 day survival period before histological evaluation. NBQX, 40 mg/kg, or GYKI 52466, 40 mg/kg, was administered intravenously starting directly after the end of carotid occlusion and ending 3 h later. Both compounds produced significant protection against selective cell loss in the striatum and cortex. Less consistent changes were seen in the hippocampus; protection by NBQX was significant in CA3 but neither compound produced significant protection in CA1. This pattern of protection is interpreted in terms of a blockade of glutamate's action at non-NMDA receptors limited to the initial 3 h of reperfusion.
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The anticonvulsant effect of the non-NMDA antagonists, NBQX and GYKI 52466, in mice
Epilepsy research, 1991Co-Authors: Astrid G. Chapman, Stuart E. Smith, Brian S. MeldrumAbstract:The excitatory amino acid antagonists, NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline) and GYKI 52466 (1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine) that act on non-NMDA receptors, provide potent anticonvulsant protection against AMPA [RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-induced seizures in Swiss mice and against sound-induced seizures in seizure-susceptible DBA/2 mice. Maximal anticonvulsant protection is observed 5-30 min after the i.p. administration of NBQX and 5-15 min after the i.p. administration of GYKI 52466 in DBA/2 mice. The ED50 values for the protection against AMPA-induced seizures by NBQX (30 min, i.p.) and GYKI 52466 (15 min, i.p.) are 23.6 (11.6-48.0) and 18.5 (11.5-29.5) mumol/kg, respectively. The ED50 values at 15 min for the protection against sound-induced seizures in DBA/2 mice are 31.3 (24.9-39.4) mumol/kg (NBQX, i.p.), 37.8 (21.2-67.4) mumol/kg (NBQX, i.v.) and 13.7 (11.5-16.5) mumol/kg (GYKI 52466, i.p.). In DBA/2 mice the therapeutic index (ratio of ED50 values for impaired rotarod performance and anticonvulsant action) is 6.6 for NBQX (15 and 30 min, i.p.) and 2.0 for GYKI 52466 (15 min, i.p.).
Angela De Sarro - One of the best experts on this subject based on the ideXlab platform.
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anticonvulsant activity of 5 7dcka NBQX and felbamate against some chemoconvulsants in dba 2 mice
Pharmacology Biochemistry and Behavior, 1996Co-Authors: Giovambattista De Sarro, Ennio Ongini, Rosalia Bertorelli, Umberto Aguglia, Angela De SarroAbstract:Abstract The anticonvulsant effects of felbamate (10–300 mg/kg, intraperitoneally, IP), and those of two representative antagonists of the excitatory amino acid receptors, 5–7dichlorokynurenic acid (5–7DCKA; 0.6–30 nmol/mouse, intracerebroventricularly, ICV), and 2,3-dihydroxy-6 nitro-7-sulfamoylbenzo(F)quinoxoline (NBQX; 1.1–33.6 mg/kg, IP) were studied in the DBA/2 mice. All drugs protected the animals from sound-induced seizures. The drugs were also effective against seizures induced by stimulation of the excitatory amino acid receptor complex using the agonists N -methyl-D-aspartate (NMDA) or α-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA). In separate studies, felbamate protected mice from seizures induced by ICV administration of the activator of dihydropyridine-sensitive calcium channels, methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl) pyridine-5-carboxylate (Bay k 8644), with ED 50 values of 26 and 46.9 mg/kg for tonus and clonus, respectively. Using Bay k 8644, NBQX (1–40 mg/kg IP) was uneffective, while 5,7DCKA (5–90 nmol/mouse, ICV) protected mice against tonus. Moreover, felbamate prevented seizures induced by blocking voltage-dependent K + channels using α-dendrotoxin, with ED 50 values of 22.6 mg/kg for tonus and of 34.8 mg/kg for clonus. Conversely, 5,7DCKA or NBQX did not significantly antagonize seizures induced by α-dendrotoxin. The present data indicate that felbamate is an effective anticonvulsant drug in DBA/2 mice with a broader anticonvulsant spectrum than 5,7DCKA and NBQX.
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Anticonvulsant activity of 5,7DCKA, NBQX, and felbamate against some chemoconvulsants in DBA/2 mice.
Pharmacology biochemistry and behavior, 1996Co-Authors: Giovambattista De Sarro, Ennio Ongini, Rosalia Bertorelli, Umberto Aguglia, Angela De SarroAbstract:Abstract The anticonvulsant effects of felbamate (10–300 mg/kg, intraperitoneally, IP), and those of two representative antagonists of the excitatory amino acid receptors, 5–7dichlorokynurenic acid (5–7DCKA; 0.6–30 nmol/mouse, intracerebroventricularly, ICV), and 2,3-dihydroxy-6 nitro-7-sulfamoylbenzo(F)quinoxoline (NBQX; 1.1–33.6 mg/kg, IP) were studied in the DBA/2 mice. All drugs protected the animals from sound-induced seizures. The drugs were also effective against seizures induced by stimulation of the excitatory amino acid receptor complex using the agonists N -methyl-D-aspartate (NMDA) or α-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA). In separate studies, felbamate protected mice from seizures induced by ICV administration of the activator of dihydropyridine-sensitive calcium channels, methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl) pyridine-5-carboxylate (Bay k 8644), with ED 50 values of 26 and 46.9 mg/kg for tonus and clonus, respectively. Using Bay k 8644, NBQX (1–40 mg/kg IP) was uneffective, while 5,7DCKA (5–90 nmol/mouse, ICV) protected mice against tonus. Moreover, felbamate prevented seizures induced by blocking voltage-dependent K + channels using α-dendrotoxin, with ED 50 values of 22.6 mg/kg for tonus and of 34.8 mg/kg for clonus. Conversely, 5,7DCKA or NBQX did not significantly antagonize seizures induced by α-dendrotoxin. The present data indicate that felbamate is an effective anticonvulsant drug in DBA/2 mice with a broader anticonvulsant spectrum than 5,7DCKA and NBQX.
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fenbufen pretreatment potentiates the anticonvulsant activity of cppene and NBQX in dba 2 mice
Journal of Pharmacy and Pharmacology, 1994Co-Authors: Giovambattista De Sarro, Stefania Renne, F Nava, Angela De SarroAbstract:— The anticonvulsant activity of 3-((±)-2-carboxypiperazin-4-yl)-***l-propenyl-***l-phosphonic acid (CPPene) and 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxoline (NBQX), two excitatory amino acid antagonists, was studied against audiogenic seizures in DBA/2 mice, following intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration. Maximal anticonvulsant protection was observed 15–30 min following NBQX and 45–180 min after CPPene. Coadministration with fenbufen (20mgkg-1, i.p.), a non-steroidal anti-inflammatory agent, enhanced and prolonged the anticonvulsant actions of CPPene and NBQX and also potentiated and prolonged the impairment of rotarod performance. The enhancement of the anticonvulsant activity and the prolonged impairment of rotarod performance suggests that fenbufen may have some pharmacokinetic interactions with CPPene and NBQX and that fenbufen is able to increase the brain levels of these excitatory amino acid antagonists. In particular, fenbufen was able to exert a major degree of potentiation of effects of NBQX rather than those of CPPene, suggesting that the chemical structures of these excitatory amino acid antagonists are responsible for the different degree of interactions between CPPene or NBQX and fenbufen. NBQX appears to have a notable similarity with quinolones whilst CPPene does not. Additionally fenbufen may displace CPPene and NBQX from plasma binding sites or inhibit the renal excretion. The present data are also consistent with previous studies showing pharmacokinetic interactions between fenbufen and quinolones.
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Fenbufen pretreatment potentiates the anticonvulsant activity of CPPene and NBQX in DBA/2 mice
Journal of Pharmacy and Pharmacology, 1994Co-Authors: Giovambattista De Sarro, Stefania Renne, F Nava, Angela De SarroAbstract:— The anticonvulsant activity of 3-((±)-2-carboxypiperazin-4-yl)-***l-propenyl-***l-phosphonic acid (CPPene) and 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxoline (NBQX), two excitatory amino acid antagonists, was studied against audiogenic seizures in DBA/2 mice, following intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration. Maximal anticonvulsant protection was observed 15–30 min following NBQX and 45–180 min after CPPene. Coadministration with fenbufen (20mgkg-1, i.p.), a non-steroidal anti-inflammatory agent, enhanced and prolonged the anticonvulsant actions of CPPene and NBQX and also potentiated and prolonged the impairment of rotarod performance. The enhancement of the anticonvulsant activity and the prolonged impairment of rotarod performance suggests that fenbufen may have some pharmacokinetic interactions with CPPene and NBQX and that fenbufen is able to increase the brain levels of these excitatory amino acid antagonists. In particular, fenbufen was able to exert a major degree of potentiation of effects of NBQX rather than those of CPPene, suggesting that the chemical structures of these excitatory amino acid antagonists are responsible for the different degree of interactions between CPPene or NBQX and fenbufen. NBQX appears to have a notable similarity with quinolones whilst CPPene does not. Additionally fenbufen may displace CPPene and NBQX from plasma binding sites or inhibit the renal excretion. The present data are also consistent with previous studies showing pharmacokinetic interactions between fenbufen and quinolones.
Jean M. Lepagnol - One of the best experts on this subject based on the ideXlab platform.
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Competitive inhibition by NBQX of kainate/AMPA receptor currents and excitatory synaptic potentials: importance of 6-nitro substitution.
European journal of pharmacology, 1992Co-Authors: John C.r. Randle, Thierry Guet, Alexis A. Cordi, Jean M. LepagnolAbstract:Abstract We evaluated the inhibitory potencies at excitatory amino acid receptors of 2,3-dihydroxy-7-sulfamoyl-benzo[f]quinoxaline (BQX) and its 6-nitro derivative, NBQX. Currents activated by kainate or (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) in two-electrode voltage-clamp recordings of Xenopus oocytes injected with rat cortex mRNA were inhibited by BQX and NBQX: the apparent K i values versus kainate were 14 μM and 78 nM, respectively, and versus AMPA were 23 μM and 63 nM, respectively. Thus, to a degree even more marked than with other quinoxalinedione derivatives, 6-nitro substitution of BQX to yield NBQX increases potency (200-fold) at the non-NMDA ionotropic receptor, but does not conter selectivity for kainate or AMPA. Schild analysis of the NBQX inhibition of the kainate and AMPA currents yielded pA 2 values of 7.17 ± 0.05 and 7.05 ± 0.10, respectively, and slopes near unity confirming the competitive nature of the inhibition. Neither BQX nor NBQX significantly inhibited the current activated by glycine plus NMDA. The selectivity ratio of NBQX (> 5000-fold) is by far the greatest of any quinoxalinedione derivative antagonist of the kainate/AMPA receptor. BQX and NBQX also inhibited the excitatory postsynaptic field potentials mediated by kainate/AMPA receptors in the CA1 region of hippocampal slices after stimulation of the Schaffer collateral-commissural pathways with IC 50 values of 130 and 0.90 μM, respectively. The 10-fold differences between the IC 50 values in hippocampal slices and the K i values in Xenopus oocytes correlate closely with data for other quinoxalinedione derivative antagonists.
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competitive inhibition by NBQX of kainate ampa receptor currents and excitatory synaptic potentials importance of 6 nitro substitution
European Journal of Pharmacology, 1992Co-Authors: John C.r. Randle, Thierry Guet, Alexis A. Cordi, Jean M. LepagnolAbstract:Abstract We evaluated the inhibitory potencies at excitatory amino acid receptors of 2,3-dihydroxy-7-sulfamoyl-benzo[f]quinoxaline (BQX) and its 6-nitro derivative, NBQX. Currents activated by kainate or (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) in two-electrode voltage-clamp recordings of Xenopus oocytes injected with rat cortex mRNA were inhibited by BQX and NBQX: the apparent K i values versus kainate were 14 μM and 78 nM, respectively, and versus AMPA were 23 μM and 63 nM, respectively. Thus, to a degree even more marked than with other quinoxalinedione derivatives, 6-nitro substitution of BQX to yield NBQX increases potency (200-fold) at the non-NMDA ionotropic receptor, but does not conter selectivity for kainate or AMPA. Schild analysis of the NBQX inhibition of the kainate and AMPA currents yielded pA 2 values of 7.17 ± 0.05 and 7.05 ± 0.10, respectively, and slopes near unity confirming the competitive nature of the inhibition. Neither BQX nor NBQX significantly inhibited the current activated by glycine plus NMDA. The selectivity ratio of NBQX (> 5000-fold) is by far the greatest of any quinoxalinedione derivative antagonist of the kainate/AMPA receptor. BQX and NBQX also inhibited the excitatory postsynaptic field potentials mediated by kainate/AMPA receptors in the CA1 region of hippocampal slices after stimulation of the Schaffer collateral-commissural pathways with IC 50 values of 130 and 0.90 μM, respectively. The 10-fold differences between the IC 50 values in hippocampal slices and the K i values in Xenopus oocytes correlate closely with data for other quinoxalinedione derivative antagonists.
