The pore and gate regions of voltage-gated cation channels have been often targeted with drugs acting as channel modulators.In contrast, the voltage sensing domains (VSD) was practically not exploited for therapeutic purposes, though it is the target of gating-modifier toxins and its paddle motif is a modular and transferable structure.We recently designed novel diphenylamine carboxylates that are powerful Kv7.2 channel openers or blockers.Here we show that NH17 and NH29, two new Kv7.2 channel blocker and opener, respectively, act as gating modifiers.Mutagenesis and modeling data suggest that in Kv7.2, NH29 docks to the extemal groove formed by the interface of helices S1,S2 and S4 in a way, which stabilizes the interaction between two conserved charged residues in S2,and S4, known to interact electrostatically, in the open state of Kv channels.Reflecting the promiscuous nature of the VSD, NH29 is also a potent blocker of TRPV1 channels.Interestingly, mutations in linker S3-S4 of the TRPV1 VSD are significantly more resistant to the inhibitory effect of NH29.While compound NH17 potently blocks Kv7.2 channels, it sensitizes the TRPV1 current activated by capsaicin.Mutations in linker S3-S4 switch the TRPV1 sensitizing action of NH17 to a potent inhibition.Subtle modifications in the VSD or in the chemical structure of the molecule drastically change the attributes of the gating-modifier, thereby stabilizing the channel in either the closed or the open state.Data indicate that the novel compounds may operate via a voltage-sensor trapping mechanism similar to that suggested for gating-modifier toxins.