The Stereoenantiomers of a Pinacidil Analog Open or Close
Cloned ATP-sensitive K+ Channels*
Ulf
Lange,
Cornelia
Löffler-Walz,
Heinrich C.
Englert
,
Annette
Hambrock,
Ulrich
Russ, and
Ulrich
Quast§
From the Department of Pharmacology and Toxicology, University of
Tübingen, Wilhelmstrasse 56, D-72074 Tübingen, Germany and
Aventis Pharma Deutschland GmbH,
D-65926 Frankfurt, Germany
ATP-dependent K+
channels (KATP 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 KATP channels. In the vasculature, openers of KATP channels produce
vasorelaxation. Some novel cyanoguanidines, however, selectively
reverse opener-induced vasorelaxation, suggesting that they might be
KATP 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
(IC50 ~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
KATP 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.
*
This work was supported by Deutsche Forschungsgemeinschaft
Grants Qu 100/2-4 (to A. H. and U. Q.) and Qu100/3-1 (to U. Q.); by
the fortüne program of the Medical Faculty of the
University of Tübingen (to U. L.); and by the Federal Ministry
of Education, Science, Research, and Technology Grant Fö 01KS9602
and the Interdisciplinary Center of Clinical Research (IZKF)
Tübingen.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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