Arylbenzazepines Are Potent Modulators for the Delayed Rectifier K Channel: A Potential Mechanism for Their Neuroprotective EffectsReportar como inadecuado




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± 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±2.3 µM 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.



Autor: Xue-Qin Chen, Jing Zhang, John L. Neumeyer, Guo-Zhang Jin, Guo-Yuan Hu, Ao Zhang , Xuechu Zhen

Fuente: http://plos.srce.hr/



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