Fig. 1.
VX-548 is less potent on human Nav1.8 channels at 37 °C than 21 °C. (A) Dose–response for inhibition of human Nav1.8 currents at 21 °C, mean ± SD. Measurements from 49 cells, 40 exposed to a single concentration and 9 to first a low (0.03, 0.3, or 1 nM) then a high (3, 10, or 30 nM) concentration; n = 6 for 0 (relative current measured after 10 min of exposure to control drug-free solution containing 0.1% DMSO), 4 for 0.003 nM, 7 for 0.01 nM, 8 for 0.03 nM, 9 for 0.1 nM, 5 for 0.3 nM, 5 for 1 nM, 5 for 3 nM, 5 for 10 nM, 4 for 30 nM. (B) Dose–response at 37 °C, mean ± SD. Measurements from 43 cells, 24 exposed to a single concentration and 19 to first a lower (0.03 or 1 nM) then a higher (3, 10, or 30 nM) concentration; n = 6 for 0 (relative current measured after 10 min of exposure to control drug-free solution containing 0.1% DMSO), 6 for 0.03 nM, 7 for 0.1 nM, 15 for 0.3 nM, 8 for 1 nM, 8 for 3 nM, 9 for 10 nM, 3 for 30 nM. Fitted curves: Imax/[1 + (Drug)/Kd], where both Imax and Kd were allowed to vary and the fit included weighting of data points by SD. 21 °C: Imax = 1.00, Kd = 0.072 nM. 37 °C: Imax = 0.99, Kd = 0.38 nM.