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. Author manuscript; available in PMC: 2022 Oct 1.
Published in final edited form as: Br J Pharmacol. 2021 Jun 21;178(19):3905–3923. doi: 10.1111/bph.15531

Figure 1. BW-031 inhibition of human Nav1.7 channels and sodium channels in iPSC-derived nociceptors.

Figure 1.

(a) Chemical structures of lidocaine, QX-314 and BW-031. (b) Whole-cell patch clamp recordings illustrating use-dependent inhibition of hNav1.7 channels expressed in HEK 293 cells by 30 μM intracellular QX-314 (blue) or BW-031 (red) or with the use-dependent protocol run with control intracellular solution (black). hNav1.7 current was evoked by 20-ms depolarizations from −100 to −20 mV. After an initial stimulation at 0.05 Hz, trains of depolarizations at frequencies from 0.33 to 10 Hz were delivered, each for 1 minute (0.33 to 3 Hz) or 30 seconds (5 and 10 Hz), with a 1 minute rest between trains. (c) Dose-dependent inhibition by various intracellular concentrations of QX-314 (blue) and BW-031 (red). Mean±SD (n=6 for 3, 10, 30, 100, and 300 μM QX-314; n=6 for 3, 10, 30, and 100 μM BW-031, n=5 for 300 μM BW-031). Solid lines, best fits to (1/1 + [Drug]/IC50), where [Drug] is the QX-314 or BW-031 concentration and IC50 is the half-blocking concentration, with IC50=66 μM for QX-314 and IC50=9.5 μM for BW-031. Current was quantified during the final slow (0.05 Hz) stimulation following the higher-frequency trains of stimulation. (d) Use-dependent inhibition of hNav1.7 channels (same voltage protocol as (a) by 100 μM intracellular BW-031 (red) contrasted with the same voltage protocol in control (black) or after application of 100 μM extracellular BW-031 (green). (e) Collected results for relative current remaining after the use-dependent pulse sequence for recordings of hNav1.7 currents with intracellular solution with no compound (black, n=37), intracellular 100 μM QX-314 (blue, n=6), intracellular 100 μM BW-031 (red, n=6), and extracellular 100 μM BW-031 (green, n=6). Asterisks indicate P<0.05. (f) Use-dependent inhibition (same protocol as in (a) and (d) of native Nav currents in hiPSC-derived nociceptors by 100 μM intracellular QX-314 (blue) or 100 μM intracellular BW-031 (red), and Nav currents in control neurons with compound-free intracellular solution with the same voltage protocol (black). (g) Collected results for relative current remaining after the use-dependent pulse sequence for recordings of Nav currents in hiPSC-derived nociceptors with intracellular solution containing no compound (black, n=4), intracellular 100 μM QX-314 (blue, n=5) and intracellular 100 μM BW-031 (red, n=5). Asterisks indicate P<0.05.