Characterization of the anticonvulsant and neuroprotectant BIIR 561 CL in vitro: effects on native and recombinant alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors

BIIR 561 CL is a novel blocker of AMPA receptors and voltage-dependent sodi um channels. In this study we further describe the effects of BIIR 561 CL o n AMPA receptor-mediated membrane currents in rodent. neurons, as well as i n cells expressing recombinant human GluR1/2 receptors in more detail. BIIR 561 CL suppressed responses to kainate in neuronal cultures from rat c ortex with an IC50 of 9.8 muM. Similar effects were observed using acutely dissociated neurons from the CA1 region of rat hippocampus (IC50=9.5 muM). Inhibition of kainate responses by BIIR 561 CL was prevented by preapplicat ion of GYKI 53655, suggesting that both non-competitive inhibitors bind to a common site of the receptor. The effect of 10 muM BIIR 561 CL on kainate-induced currents was dependent on extracellular pH, with more pronounced block (84.1%) under acidic condit ions (pH(extern)=6.4), compared to only 30.1% at a pH(extern) of 8.4. Thus, it can be hypothesized that BIIR 561 CL inhibits AMPA receptors in ischaem ic brain regions more effectively than in healthy tissue. BIIR 561 CL inhibited responses to 1 mM glutamate in cells expressing recom binant human GluR1/2 receptors with similar potency, as compared to kainate responses in rat neurons (IC50=17.3 muM). The reference compound NBQX had an IC50 of 25.2 nM. None of the two compounds affected the glutamate-induce d receptor desensitization sit any tested concentration. The block by BIIR 561 CL was not use-dependent and had fast on- and off-kinetics (tau (on)=6. 8 s; tau (off)=1.3 s in hGluR1/2 receptors With 30 muM BIIR 561 CL). Thus, BIIR 561 CL can be anticipated to have a promising profile for the tr eatment of neurological disorders like brain ischaemia and head trauma.