arylbenzazepines are potent modulators for the delayed rectifier k+ channel a potential mechanism for their neuroprotective effectsarylbenzazepines强有力的调节器的延迟整流k +通道潜在的神经保护作用的机制.pdfVIP

Arylbenzazepines Are Potent Modulators for the Delayed Rectifier K+ Channel: A Potential Mechanism for Their Neuroprotective Effects 1 2 3 1 1 2 Xue-Qin Chen , Jing Zhang , John L. Neumeyer , Guo-Zhang Jin , Guo-Yuan Hu , Ao Zhang *, Xuechu Zhen1* 1 State Key laboratory of Drug Research, Department of Pharmacology II, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China, 2 Synthetic Organic Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China, 3 Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, United States of America Abstract (6) 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 (6) SKF83959-mediated neuroprotection remains elusive. We report here that ( 6) SKF83959 is a potent blocker for delayed rectifier K+ channel. (6) SKF83959 inhibited the delayed rectifier K+ current (I ) dose-dependently in rat K hippocampal neurons. The IC50 value for inhibition of IK was 41.9 62.3 mM (Hill coefficient = 1.8160.13, n = 6), whereas that for inhibition of IA was 307.9 638.5 mM (Hill coefficient = 1.3760.08, n = 6). Thus, (6) SKF83959 is 7.3-fold more potent in suppressing I than I . Moreover, the inhibition of I by (6) SKF83959 was voltage-dependent and not related to dopamine K A K receptors. The rapidl