Competitive antagonism of glutamate receptor channels by substituted benzazepines in cultured cortical neurons

K. J. Swartz, W. J. Koroshetz, A. H. Rees, J. E. Huettner

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Whole-cell recordings from rat cortical neurons in dissociated cell culture were used to study the antagonism of glutamate receptors by several lipophilic benzazepine analogues of 2,5-dihydro-2,5-dioxo-3-hydroxy-1H- benzazepine (DDHB). DDHB and three substituted derivatives, 4-bromo-, 7- methyl-, and 8-methyl-DDHB, inhibited the activation of N-methyl-D-aspartate (NMDA) receptors at both the NMDA recognition site and the glycine allosteric site. In addition, all four compounds blocked the activation of non-NMDA receptors by kainate and L-glutamate. Antagonism by the four benzazepines was equivalent at holding potentials from -80 mV to +50 mV. Both the onset of and recovery from block of the agonist-gated currents were complete within seconds. Antagonist affinity was calculated from the displacement of steady state concentration-response curves for kainate, L-glutamate, glycine, and NMDA, based on the Gaddum-Schild relationship (dose ratio = 1 + [antagonist]/K(B)). The most potent blocker, 8-Me-DDHB, had an apparent dissociation constant (K(B)) of 470 nM at the glycine allosteric site and 27 μM at the NMDA recognition site. The apparent dissociation constant of 8- Me-DDHB for non-NMDA receptors was 6.4 μM when kainate was the agonist and 9.6 μM when L-glutamate was the agonist. Unsubstituted DDHB showed slightly higher affinity for the NMDA recognition site (K(B) = 16 μM) but was less potent than 8-Me-DDHB at the glycine allosteric site and at non-NMDA receptors (K(B) = 3 and 65 μM, respectively). At all three sites, the inhibitory actions of these benzazepine derivatives were consistent with a simple competitive mechanism of antagonism. In addition, the antagonist potency of the parent compound, DDHB, against kainate, NMDA, and glycine was equal to or greater than that of other bicyclic antagonists, including kynurenic acid, indole-2-carboxylic acid, and quinoxaline-2,3-dione. Substituted benzazepines represent a new class of glutamate receptor antagonists that show competitive action, significant potency at multiple sites, and a high degree of lipophilicity.

Original languageEnglish
Pages (from-to)1130-1141
Number of pages12
JournalMolecular pharmacology
Issue number6
StatePublished - 1992


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