Arylbenzazepines are potent modulators for the delayed rectifier K+ channel: A potential mechanism for their neuroprotective effects

Abstract

(±) SKF83959, like many other arylbenzazepines, elicits powerful neuroprotection in vitro and in vivo. The neuroprotective action of the compound was found to partially depend on its D1-like dopamine receptor agonistic activity. The precise mechanism for the (±) SKF83959-mediated neuroprotection remains elusive. We report here that (±) SKF83959 is a potent blocker for delayed rectifier K+ channel. (±) SKF83959 inhibited the delayed rectifier K+ current (IK) dose-dependently in rat hippocampal neurons. The IC50 value for inhibition of IK was 41.9±2.3μM (Hill coefficient = 1.81±0.13, n = 6), whereas that for inhibition of IA was 307.9±38.5 μM (Hill coefficient = 1.37±0.08, n = 6). Thus, (±) SKF83959 is 7.3-fold more potent in suppressing IK than IA. Moreover, the inhibition of IK by (±) SKF83959 was voltage-dependent and not related to dopamine receptors. The rapidly onset of inhibition and recovery suggests that the inhibition resulted from a direct interaction of (±) SKF83959 with the K+ channel. The intracellular application of (±) SKF83959 had no effects of on IK, indicating that the compound most likely acts at the outer mouth of the pore of K+ channel. We also tested the enantiomers of (±) SKF83959, R-(+) SKF83959 (MCL-201), and S-(-) SKF83959 (MCL-202), as well as SKF38393; all these compounds inhibited IK. However, (±) SKF83959, at either 0.1 or 1 mM, exhibited the strongest inhibition on the currents among all tested drug. The present findings not only revealed a new potent blocker of IK, but also provided a novel mechanism for the neuroprotective action of arylbenzazepines such as (±) SKF83959. © 2009 Chen et al.