Fig. 1.
A-803467 is a selective blocker of Nav1.8 channels. (A) Chemical structure of A-803467. (B) Block of recombinant and native Nav1.8 currents by 100 nM A-803467. Current records were generated during voltage steps to 0 mV in control and after application of A-803467 (100 nM) for human Nav1.8 or native DRG TTX-R currents. Holding potentials were set at −100 mV, and each test pulse was preceded by an 8-s prepulse to −40 mV, followed by 20 ms at −100 mV before a 20-ms depolarization to 0 mV. [Scale bars, 0.3 nA and 5 ms (Nav1.8) and 1.5 nA and 5 ms (TTX-R).] (C) Representative concentration–response curves were generated after application of different concentrations of A-803467 and assessment of current block for human Nav1.8 (IC50 = 8 ± 1 nM), and TTX-R currents (IC50 = 140 ± 14 nM) in rat DRG cells and hNav1.2, hNav1.3, hNav1.5, and hNav1.7. Data represent means ± SEM from at least three separate experiments. Percent inhibition was calculated as 1 − (test current/(control current + wash current/2)) and plotted vs. test concentration. Concentration-effect curves were fit by using the Hill equation to estimate IC50 values and Hill coefficients. For hNav1.2, 1.3, 1.5, and 1.7, Hill coefficients were set to 0.7 as was found for Nav1.8. Holding potentials for selectivity targets were −60 mV for hNav1.2, 1.3, and 1.7 and −90 mV for hNav1.5.