Stereoselective interactions of the enantiomers of chromanol 293B with human voltage-gated potassium channels

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. Racemi c chromanol 293B is an inhibitor of both native I-Ks and its putative molec ular counterpart, the KvLQT1+minK ion channel complex. We synthesized the ( +)[3S,4R] and (-)-[3R,4S] enantiomers of chromanol 293B using chiral interm ediates of known absolute configuration and determined their relative poten cy to block recombinant human K+ channels that form the basis for the major repolarizing K+ currents in human heart, including KvLQT1+minK, human ethe r-a-go-go-related gene product (hERG), Kv1.5, and Kv4.3, corresponding to t he slow (I-Ks) rapid (I-Kr) and ultrarapid (I-Kur) delayed rectifier curren ts and the transient outward current (I-To), respectively. K+ channels were expressed in mammalian cells and currents were recorded using the whole-ce ll 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 th an (+)-[3S,4R]293B, indicating that the original stereochemical assignments were reversed. K+ current inhibition by (-)-293B was selective for KvLQT1minK over hERG, whereas the stereospecificity of block for KvLQT1+minK and Kv1.5 was preserved, with (-)293B more potent than (+)-293B for both channe l complexes. We conclude that the (-)-[3R,4S] enantiomer of chromanol 293B is a selective inhibitor of KvLQT1+minK and therefore a useful tool for stu dying I-Ks.