The Stereoenantiomers of a Pinacidil Analog Open or Close Cloned ATP-sensitive K+ Channels
作者： Ulf Lange , Cornelia Löffler-Walz , Heinrich C. Englert , Annette Hambrock , Ulrich Russ
关键词: Pinacidil 、 K channels 、 Enantiomer 、 Stereochemistry 、 Katp channels 、 Coupling (electronics) 、 Patch clamp 、 Chemistry 、 Sulfonylurea receptor 、 Radioligand binding
摘要: Abstract ATP-dependent K+channels (KATP channels) are composed of pore-forming subunits Kir6.x and sulfonylurea receptors (SURs). Cyanoguanidines such as pinacidil P1075 bind to SUR enhance MgATP binding hydrolysis by SUR, thereby opening KATP channels. In the vasculature, openers channels produce vasorelaxation. Some novel cyanoguanidines, however, selectively reverse opener-induced vasorelaxation, suggesting that they might be channel blockers. Here we have analyzed interaction enantiomers a racemic cyanoguanidine blocker, PNU-94750, with Kir6.2/SUR patch clamp experiments, theR-enantiomer (PNU-96293) inhibited Kir6.2/SUR2 (IC50 ∼50 nm in whole cell configuration), whereas S-enantiomer (PNU-96179) was weak opener. Radioligand studies showed more potent it negatively allosterically coupled binding, theS-enantiomer weaker positively coupled. Binding experiments also suggested both bound site SUR. This is first report show modulator affect activity coupling opposite directions these effects apparently mediated same (opener)
sci-hub.se 参考文章(50)
K.M. Bray, U Quast, A specific binding site for K+ channel openers in rat aorta. Journal of Biological Chemistry. ,vol. 267, pp. 11689- 11692 ,(1992) , 10.1016/S0021-9258(19)49750-0
A. Lewis Farr, Oliver H. Lowry, Rose J. Randall, Nira J. Rosebrough, Protein Measurement with the Folin Phenol Reagent Journal of Biological Chemistry. ,vol. 193, pp. 265- 275 ,(1951)
Ulrich Russ, Annette Hambrock, Ferruh Artunc, Cornelia Löffler-Walz, Yoshiyuki Horio, Yoshihisa Kurachi, Ulrich Quast, Coexpression with the inward rectifier K(+) channel Kir6.1 increases the affinity of the vascular sulfonylurea receptor SUR2B for glibenclamide. Molecular Pharmacology. ,vol. 56, pp. 955- 961 ,(1999) , 10.1124/MOL.56.5.955
Sajida A. Khan, Kaushik D. Meisheri, Nicole R. Higdon, Jackson B. Hester, Pharmacological Characterization of Novel Cyanoguanidines as Vascular KATP Channel Blockers Journal of Pharmacology and Experimental Therapeutics. ,vol. 283, pp. 1207- 1213 ,(1997)
M.G. Garrino, J.C. Henquin, Highly potent and stereoselective effects of the benzoic acid derivative AZ‐DF 265 on pancreatic β‐cells British Journal of Pharmacology. ,vol. 93, pp. 61- 68 ,(1988) , 10.1111/J.1476-5381.1988.TB11405.X
Michael J. Coghlan, William A. Carroll, Murali Gopalakrishnan, Recent Developments in the Biology and Medicinal Chemistry of Potassium Channel Modulators: Update from a Decade of Progress Journal of Medicinal Chemistry. ,vol. 44, pp. 1627- 1653 ,(2001) , 10.1021/JM000484+
Annette Hambrock, Cornelia Löffler-Walz, Yoshihisa Kurachi, Ulrich Quast, Mg2+
and ATP dependence of KATP
channel modulator binding to the recombinant sulphonylurea receptor, SUR2B British Journal of Pharmacology. ,vol. 125, pp. 577- 583 ,(1998) , 10.1038/SJ.BJP.0702109
Lydia Aguilar-Bryan, Joseph Bryan, Molecular biology of adenosine triphosphate-sensitive potassium channels. Endocrine Reviews. ,vol. 20, pp. 101- 135 ,(1999) , 10.1210/EDRV.20.2.0361
Stephen J.H. Ashcroft, Frances M. Ashcroft, Properties and functions of ATP-sensitive K-channels. Cellular Signalling. ,vol. 2, pp. 197- 214 ,(1990) , 10.1016/0898-6568(90)90048-F
George Scatchard, The Attractions of Proteins for Small Molecules and Ions Annals of the New York Academy of Sciences. ,vol. 51, pp. 660- 672 ,(1949) , 10.1111/J.1749-6632.1949.TB27297.X