title: Comparative patch clamp studies on the kinetics and selectivity of glutamate receptor antagonism by 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) and 1-(4-amino-phenyl)-4-methyl-7,8-methyl-endioxyl-5H-2,3-benzodiaze pine (GYKI 52466).
abstract: The glutamate antagonistic effects of NBQX [2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline] and GYKI 52466 [1-(4-amino-phenyl)-4-methyl-7,8-methyl-endioxyl-5H-2,3-benzodiaze pine] were compared on inward current responses of cultured superior collicular and hippocampal neurones with the whole cell patch clamp technique. Both NBQX (8 microM) and GYKI 52466 (33 microM) selectively reduced responses to AMPA [(S)-alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid, 50 microM] and kainate (50 microM) whilst having little effect on responses to NMDA (N-methyl-D-aspartate, 100 microM). The effects of the two antagonists on the kinetics of AMPA (50 microM) responses were, however, very different--NBQX dramatically slowed the rise time of responses so that peak currents (IC50 60.4 +/- 4.2 nM) were markedly more effected than desensitized plateau currents (IC50 706 +/- 99 nM) whereas GYKI 52466 antagonized plateau responses (IC50 4.44 +/- 0.21 microM) somewhat more than peak responses (IC50 6.87 +/- 0.46 microM) and had only marginal effects on kinetics. In fact, low concentrations of NBQX (50-250 nM) actually potentiated plateau AMPA responses--an effect likely to be due to a reduction in the degree of AMPA-induced desensitization. Similar effects on response kinetics, were seen with kainate such that the IC50s for NBQX in antagonizing initial and plateau components of current responses to kainate 400 microM were 18.1 +/- 2.9 nM and 298 +/- 27 nM respectively whereas the IC50s for GYKI 52466 against kainate 50 microM were 17.3 +/- 1.8 microM and 15.5 +/- 3.3 microM respectively. These differences are likely to be due to the different modes of action of the two antagonists--NBQX shifted kainate concentration responses curves to the right in a parallel fashion indicative of competitive antagonism whereas the effects of GYKI 52466 were largely noncompetitive. There was, however, some indication for a small allosteric influence of GYKI 52466 on the affinity of the glutamate recognition site of the AMPA/kainate receptor. Estimation of Kbs using the Cheng-Prussoff relationship revealed little difference in the affinity of NBQX in antagonizing plateau responses to AMPA (Kb 23.2 nM) and kainate (Kb 57.1 nM) and indicate that the effects of these two agonists are mediated at a common receptor under the experimental conditions used. Moreover, the differential effects of NBQX on peak and plateau components of AMPA (50 microM) responses was associated with a desensitization-induced, paradoxical increase in the agonist affinity and was probably not due to any change in the affinity of NBQX.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Pharmacology, Merz+Co. GmbH & Co., Frankfurt am Main, Germany.
authors.forename: C G
authors.initials: CG
authors.lastname: Parsons
authors.forename: R
authors.initials: R
authors.lastname: Gruner
authors.forename: J
authors.initials: J
authors.lastname: Rozental
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines / Q000494:pharmacology*; D002478:Cells, Cultured; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology; D007700:Kinetics; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D013477:Superior Colliculi / Q000166:cytology / Q000502:physiology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D014151:Anti-Anxiety Agents; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D018091:Receptors, AMPA; C061950:GYKI 52466; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D001569:Benzodiazepines; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007608:Kainic Acid