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Vol. 294, Issue 3, 955-962, September 2000

Stereoselective Interactions of the Enantiomers of Chromanol 293B with Human Voltage-Gated Potassium Channels1

Iris C.-H. Yang, Michael W. Scherz, Anthony Bahinski, Paul B. Bennett and Katherine T. Murray

Departments of Pharmacology and Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee (I.C.-H.Y., P.B.B., K.T.M.); and Cardiovascular Research Department, Procter & Gamble Pharmaceuticals, Mason, Ohio (M.W.S., A.B.)

Selective inhibitors of the slow component of the cardiac delayed rectifier K+ current, IKs, are of interest as novel class III antiarrhythmic agents and as tools for studying the physiologic roles of the IKs current. Racemic chromanol 293B is an inhibitor of both native IKs and its putative molecular counterpart, the KvLQT1+minK ion channel complex. We synthesized the (+)-[3S,4R] and (-)-[3R,4S] enantiomers of chromanol 293B using chiral intermediates of known absolute configuration and determined their relative potency to block recombinant human K+ channels that form the basis for the major repolarizing K+ currents in human heart, including KvLQT1+minK, human ether-a-go-go-related gene product (hERG), Kv1.5, and Kv4.3, corresponding to the slow (IKs), rapid (IKr), and ultrarapid (IKur) delayed rectifier currents and the transient outward current (ITo), respectively. K+ channels were expressed in mammalian cells and currents were recorded using the whole-cell patch-clamp technique. We found that the physicochemical properties and relative potency of the enantiomers differed from those reported previously, with (-)-[3R,4S]293B nearly 7-fold more potent in block of KvLQT1+minK than (+)-[3S,4R]293B, indicating that the original stereochemical assignments were reversed. K+ current inhibition by (-)-293B was selective for KvLQT1+minK over hERG, whereas the stereospecificity of block for KvLQT1+minK and Kv1.5 was preserved, with (-)-293B more potent than (+)-293B for both channel complexes. We conclude that the (-)-[3R,4S] enantiomer of chromanol 293B is a selective inhibitor of KvLQT1+minK and therefore a useful tool for studying IKs.

1 This work was supported by a grant from Procter and Gamble Pharmaceuticals.

0022-3565/00/2943-0955$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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