Differential antagonism of alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid-preferring and kainate-preferring receptors by 2,3-benzodiazepines.

Whole-cell recordings were used to study the antagonism of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring and kainate-preferring receptors by 2,3-benzodiazepines. Current through kainate-preferring receptors was recorded in rat dorsal root ganglion (DRG) neuron-s, whereas AMPA receptor current was measured in cultured neurons from rat cerebral cortex. In both cell types 2,3-benzodiazepines produced noncompetitive inhibition; however, antagonist potency was much higher against AMPA-preferring receptors than against kainate receptors. The most potent compound, 1-(4-aminophenyl)-3-methylcarbamyl-4-methyl-7,8- methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine (GYKI 53655), blocked AMPA receptor currents with an IC50 of approximately 1 microM. A second benzodiazepine, 1-(4-aminophenyl)-4-methyl-7,8- methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466), was about 20-fold less potent at AMPA receptors (IC50 = 18 microM). Both drugs were markedly weaker against kainate currents in DRG neurons. At 200 microM, the highest concentration tested, GYKI 53655 and GYKI 52466 produced only 30-40% inhibition in DRG cells, suggesting that for both compounds the IC50 against kainate receptors is > 200 microM. Our study suggests that GYKI 53655, at a concentration of approximately 10 microM, should produce > 90% block of AMPA-preferring receptors but < 5% inhibition of kainate-preferring receptors. Because the antagonism by this drug is noncompetitive, its effectiveness should not be influenced by phasic changes in transmitter concentration, making it an ideal compound for functional studies of the role of kainate and AMPA receptors in synaptic transmission.

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