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-cyclohexyl-N-(3,3-diphenylpropyl)-acetamide hydrochloride (BIIA388Cl), which demonstrates 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 externally applied BIIA388Cl, while the transient A-current (I(A)) remained virtually unaffected. Block of I(DR) by the pre-applied BIIA388Cl 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 (τ=22 ms). The dose-response relationship for the blocking action of BIIA388Cl 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 depolarization was 120 nM. The blocking action of BIIA388Cl on I(A) was at least 200 times less potent. These data allow us to conclude that BIIA388Cl is an effective and selective blocker of I(DR). This current is the main pathway for the loss of intracellular potassium by depolarized neurons. Selective obstruction of this pathway could be useful for neuroprotection. Copyright (C) 2000 Elsevier Science Ltd.