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 domain (VSD) was practically not exploited for therapeutic purposes, though it is the target of gatingmodifier toxins. 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 external 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 Kv channel open state. Interestingly, NH29 is also a potent blocker of TRPV1 channels, while the Kv7.2 channel blocker, NH17, activates TRPV1. Our data mutagenesis and docking data suggest that the VSD of TRPV1 is also important for the effects of NH29 and NH17. Thus, 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.