title: The stereoenantiomers of a pinacidil analog open or close cloned ATP-sensitive K+ channels.
abstract: ATP-dependent K(+) channels (K(ATP) channels) are composed of pore-forming subunits Kir6.x and sulfonylurea receptors (SURs). Cyanoguanidines such as pinacidil and P1075 bind to SUR and enhance MgATP binding to and hydrolysis by SUR, thereby opening K(ATP) channels. In the vasculature, openers of K(ATP) channels produce vasorelaxation. Some novel cyanoguanidines, however, selectively reverse opener-induced vasorelaxation, suggesting that they might be K(ATP) channel blockers. Here we have analyzed the interaction of the enantiomers of a racemic cyanoguanidine blocker, PNU-94750, with Kir6.2/SUR channels. In patch clamp experiments, the R-enantiomer (PNU-96293) inhibited Kir6.2/SUR2 channels (IC(50) approximately 50 nm in the whole cell configuration), whereas the S-enantiomer (PNU-96179) was a weak opener. Radioligand binding studies showed that the R-enantiomer was more potent and that it was negatively allosterically coupled to MgATP binding, whereas the S-enantiomer was weaker and positively coupled. Binding experiments also suggested that both enantiomers bound to the P1075 site of SUR. This is the first report to show that the enantiomers of a K(ATP) channel modulator affect channel activity and coupling to MgATP binding in opposite directions and that these opposite effects are apparently mediated by binding to the same (opener) site of SUR.
authors.affiliation: Department of Pharmacology and Toxicology, University of Tübingen, Wilhelmstrasse 56, D-72074 Tübingen, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Lange
authors.forename: Cornelia
authors.initials: C
authors.lastname: Löffler-Walz
authors.forename: Heinrich C
authors.initials: HC
authors.lastname: Englert
authors.forename: Annette
authors.initials: A
authors.lastname: Hambrock
authors.forename: Ulrich
authors.initials: U
authors.lastname: Russ
authors.forename: Ulrich
authors.initials: U
authors.lastname: Quast
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D006801:Humans; D015640:Ion Channel Gating; D051379:Mice; D018408:Patch-Clamp Techniques; D020110:Pinacidil / Q000378:metabolism*; D015221:Potassium Channels / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D011869:Radioligand Assay; D013237:Stereoisomerism
chemical_list: D015221:Potassium Channels; D020110:Pinacidil; D000255:Adenosine Triphosphate