GYKI 52466, a 2,3-benzodiazepine, is a highly selective, noncompetitive antagonist of AMPA/kainate receptor responses.

In whole-cell voltage-clamp recordings from cultured rat hippocampal neurons, the 2,3-benzodiazepine GYKI 52466 was a potent antagonist of kainate- and AMPA-activated currents (IC50 values, 7.5 and 11 microM, respectively), but was inactive against N-methyl-D-aspartate (NMDA) or gamma-aminobutyric acid responses. The block produced by GYKI 52466 occurred in a noncompetitive fashion, was voltage independent, and failed to show use dependence, indicating an allosteric blocking mechanism. In kinetic experiments with kainate as the agonist, the GYKI 52466 binding and unbinding rates were 1.6 x 10(5) M-1 s-1 and 3.2 s-1, respectively. GYKI 52466 also suppressed non-NMDA receptor-mediated spontaneous synaptic currents via a postsynaptic action. Non-competitive AMPA/kainate antagonists such as GYKI 52466 could offer advantages over competitive antagonists in the treatment of glutamate-associated neurological disorders, particularly under conditions in which high levels of the amino acid would render the competitive antagonists relatively ineffective. Moreover, the results demonstrate the existence of a novel recognition site for an atypical benzodiazepine on non-NMDA receptors.