New channel blocker BIIA388CL blocks delayed rectifier, but not A-type potassium current in central neurons

A new substance (R,S)-(3,4-dihydro-6,7-dimethoxyisoquinoline-1-yl)-2-cycloh exyl-N-(3,3-diphenylpropyl)-acetamide hydrochloride (BIIA388C1), which demo nstrates neuroprotective properties in animal models, was examined for its action on K+ currents in acutely isolated rat hippocampal neurons using the patch-clamp/concentration clamp techniques in the whole-cell configuration . The delayed rectifier K+-current (I-DR) was strongly inhibited by externa lly applied BIIA388C1, while the transient A-current (I-A) remained virtual ly unaffected. Block of I-DR by the pre-applied BIIA388C1 was revealed as a rapid decay of the current indicating direct interaction of the drug with the open state of the channel. The removal of the block upon repolarization was also rapid (tau =22 ms). The dose-response relationship for the blocki ng action of BIIA388C1 revealed an IC50 value of 300 nM for the peak I-DR, whereas the IC50 value for I-DR measured 300 ms after the onset of depolari zation was 120 nM. The blocking action of BIIA388C1 on I-A was at least 200 times less potent. These data allow us to conclude that BIIA388C1 is an ef fective and selective blocker of I-DR. This current is the main pathway for the loss of intracellular potassium by depolarized neurons. Selective obst ruction of this pathway could be useful for neuroprotection. (C) 2000 Elsev ier Science Ltd. All rights reserved.