Short biaryl sulfonamides activate the WT Shaker KV channel expressed in X. laevis oocytes. (A) Representative plot of the steady-state current amplitude at −30 mV during wash-in and wash-out of a sulfonamide compound (100 µM of Cmpd 5). Holding voltage, −80 mV; pulse length, 100 ms; pulse frequency, 0.1 Hz. (B) Representative current traces in control solution (black) and after application of 100 µM Cmpd 5 (red). Holding voltage, −80 mV; test-step voltage, −35 mV. (C) G(V) curve for the cell shown in B. The arrow denotes the shift in voltage dependence (ΔVG(V) = −10.8 mV) measured at 10% of the maximum conductance in control (dotted line; see Materials and methods for a detailed description). The continuous curves are best fitted to Eq. 2; the exponent n was fixed to 4; the slope s was constrained to be equal for the two sets of data; and V1/2 was shifted −11.7 mV. (D–F) Representative effects on the G(V) curve for Cmpds 4, 6, and 7. The shifts are −0.8, −13.2, and −1.2 mV, respectively, measured by Eq. 2. (G) Summary of the dose-dependent effect of 11 selected sulfonamides on ΔVG(V) of the WT Shaker KV channel. n = 3–6. Mean ± SEM. The compounds are color coded depending on their effect on ΔVG(V): red for no significant effect, black for significant but small effect, and blue for significant prominent effect. The effect of 100 µM Cmpd 2 could not be determined, as application of the compound resulted in massive cell leakage. A two-tailed t test was used to compare effects to a hypothetical value of 0. *, P < 0.05; **, P < 0.01. The remaining data points had P > 0.05. (H) Molecular structures of the two compounds selected for further investigation.
