Abstract

Selective inhibitors of the slow component of the cardiac delayed rectifier K⁺ current, I_Ks, are of interest as novel class III antiarrhythmic agents and as tools for studying the physiologic roles of the I_Ks current. Racemic chromanol 293B is an inhibitor of both native I_Ks 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 (I_Ks), rapid (I_Kr), and ultrarapid (I_Kur) delayed rectifier currents and the transient outward current (I_To), 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 I_Ks.