LAUSR

Abstract Despite the importance of the hERG channel in drug discovery and the sizable number of antagonist molecules discovered, only a few hERG agonists have been discovered. Here we report a novel hERG agonist; SKF‐32802 and a structural analog of the agonist NS3623, SB‐335573. These were discovered through a similarity search of published hERG agonists. SKF‐32802 incorporates an amide linker rather than NS3623's urea, resulting in a compound with a different mechanism of action. We find that both compounds decrease the time constant of open channel kinetics, increase the amplitude of the envelope of tails assay, mildly increased the amplitude of the IV curve, bind the hERG channel in either open or closed states, increase the plateau of the voltage dependence of activation and modulate the effects of the hERG antagonist, quinidine. Neither compound affects inactivation nor deactivation kinetics, a property unique among hERG agonists. Additionally, SKF‐32802 induces a leftward shift in the voltage dependence of activation. Our structural models show that both compounds make strong bridging interactions with multiple channel subunits and are stabilized by internal hydrogen bonding similar to NS3623, PD‐307243 and RPR26024. While SB‐335573 binds in a nearly identical fashion as NS3623, SKF‐32802 makes an additional hydrogen bond with neighboring threonine 623. In summary, SB‐335573 is a type 4 agonist which increases open channel probability while SKF‐32802 is a type 3 agonist which induces a leftward shift in the voltage dependence of activation. Graphical abstract Figure. No Caption available.