FIGURE 4.

A and B, time course of Nav1.7 current block by the non-amidated and amidated variants of compounds 2670 and D1I in HEK293 cells stably expressing the human Nav1.7 channel. The manual whole-cell patch clamp technique was used to record Nav1.7 currents. Nav1.7 currents were evoked by a 15-ms step depolarization to 0 mV every 10 s from a holding potential of −90 mV. Currents were normalized to the maximum amplitude of control peak current. Data presented as normalized peak current amplitude versus time. The time of compound application is indicated by solid line. C and D, effect of amidation for 2670 and D1I illustrated in selectivity plots. Amidation increases potency for both compounds on Nav1.7 but also on Nav1.2 and Nav1.6. Improvement in potency is accompanied by selectivity benefits against Nav1.2 but not Nav1.6.