Antagonist pharmacology of kainate- and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-preferring receptors

Timothy J. Wilding, James E. Huettner

Research output: Contribution to journalArticlepeer-review

96 Scopus citations


Whole-cell recordings were used to study the antagonist pharmacology of two subtypes of non-N-methyl-D-aspartate glutamate receptors: the kainate-preferring subtype expressed by rat dorsal root ganglion (DRG) neurons and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring subtype expressed by neurons from rat cerebral cortex. A series of quinoxaline derivatives were tested for the ability to distinguish between AMPA and kainate receptors, as determined by differential potency. Of the nine compounds studied, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX) snowed the highest selectivity for AMPA-preferring receptors, whereas 5-chloro-7-trifluoromethyl-2,3-quinoxalinedione (ACEA-1011) showed the highest selectivity for the kainate-preferring subtype. NBQX blocked non-N-methyl-D-aspartate currents in cortical cells with a Kb of 0.3 μM, but in DRG neurons the Kb for NBQX was 3-fold higher (0.9 μM). ACEA-1011 also blocked the currents in DRG cells with a Kb of ∼1 μM, but in cortical neurons the Kb for this drug was 10-12 μM. Several additional compounds were tested for selective potency, including 5-nitro-6,7,8,9-tetrahydrobenzo[G]indole-2,3-dione-3-oxime, γ-D-glutamylaminomethylsulphonic acid, and derivatives of kynurenic acid and 1-benzazepine. 5-Nitro-6,7,8,9-tetrahydrobenzo[G]indole-2,3-dione-3-oxime displayed the highest selectivity in this group, blocking kainate receptors with a Kb of 6 μM while inhibiting AMPA receptors with a Kb of >100 μM. The remaining antagonists showed <3-fold selectivity between AMPA and kainate receptor subtypes. Our results suggest that most competitive antagonists block native AMPA and kainate receptors with approximately similar potencies, which is in marked contrast to the substantial differences in potency that have been observed with receptor agonists.

Original languageEnglish
Pages (from-to)540-546
Number of pages7
JournalMolecular pharmacology
Issue number3
StatePublished - Mar 1996

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