Electrophysiological Characterization of 14-benzoyltalatisamine, a Selective Blocker of the Delayed Rectifier K+ Channel Found in Virtual Screening.
From: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu-Chong-Zhi Road, Shanghai 201203, PR China.
European journal of pharmacology
- Publish Date: Feb 2006
- ISSN: 0014-2999
- Volume: 531
- Issue: 1-3
- Pages: 47-53
- Medium: Print
- Language: English
- Citation (JAMA): Song Ming-Ke, Liu Hong, Jiang Hua-Liang, et al. Electrophysiological Characterization of 14-benzoyltalatisamine, a Selective Blocker of the Delayed Rectifier K+ Channel Found in Virtual Screening.. Eur. J. Pharmacol. Feb 2006;531:47-53
Abstract
14-Benzoyltalatisamine is a potent and selective blocker of the delayed rectifier K+ channel found in a computational virtual screening study. The compound was found to block the K+ channel from the extracellular side. However, it is unclear whether 14-benzoyltalatisamine shares the same block mechanism with tetraethylammonium (TEA). In order to elucidate how the hit compound found by the virtual screening interacts with the outer vestibule of the K+ channel, the effects of 14-benzoyltalatisamine and TEA on the delayed rectifier K+ current of rat dissociated hippocampal neurons were compared using whole-cell voltage-clamp recording. External application of 14-benzoyltalatisamine and TEA reversibly inhibited the current with IC50 values of 10.1+/-2.2 microM and 1.05+/-0.21 mM, respectively. 14-Benzoyltalatisamine exerted voltage-dependent inhibition, markedly accelerated the decay of the current, and caused a significant hyperpolarizing shift of the steady-state activation curve, whereas TEA caused voltage-independent inhibition, without affecting the kinetic parameters of the current. The blockade by 14-benzoyltalatisamine, but not by TEA, was significantly diminished in a high K+ (60 mM) external solution. The potency of 14-benzoyltalatisamine was markedly reduced in the presence of 15 mM TEA. The results suggest that 14-benzoyltalatisamine bind to the external pore entry of the delayed rectifier K+ channel with partial insertion into the selectivity filter, which is in conformity with that predicted by the molecular docking model in the virtual screening.
Mesh Headings (Keywords): Aconitine, Animals, Delayed Rectifier Potassium Channels, Dose-Response Relationship, Drug, Membrane Potentials, Molecular Structure, Potassium, Potassium Channel Blockers, Pyramidal Cells, Rats, Rats, Sprague-Dawley, Tetraethylammonium, Time Factors
Check for Full Text / PubMed Unique Identifier (PMID): 16442097
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