Identification of WB4101, an α₁-Adrenoceptor Antagonist, as a Sodium Channel Blocker

Sodium channels are important proteins in modulating neuronal membrane excitability. Genetic studies from patients and animals have indicated neuronal sodium channels play key roles in pain sensitization. We identified WB4101 (2-(2,6-Dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride), an antagonist of α₁-adrenoceptor, as a Nav1.7 inhibitor from a screen. The present study characterized the effects of WB4101 on sodium channels. We demonstrated that WB4101 inhibited both Nav1.7 and Nav1.8 channels with similar levels of potency. The half-inhibition concentrations (IC₅₀ values) of WB4101 were 11.6 ± 2.07 and 1.0 ± 0.07 µM for the resting and inactivated Nav1.7 channels, respectively, and 8.67 ± 1.31 and 0.91 ± 0.25 µM for the resting and inactivated Nav1.8 channels, respectively. WB4101 induced a hyperpolarizing shift in the voltage-dependent inactivation for both Nav1.7 (15 mV) and Nav1.8 (20 mV) channels. The IC₅₀ values for the open-state sodium channel were 2.50 ± 1.16 µM for Nav1.7 and 1.1 ± 0.2 µM for Nav1.8, as determined by the block of persistent late currents in inactivation-deficient Nav1.7 and Nav1.8 channels, respectively. Consistent with the state-dependent block, the drug also displayed use-dependent inhibitory properties on both wild-type Nav1.7 and Nav1.8 channels, which were removed by the local anesthetic-insensitive mutations but still existed in the inactivation-deficient channels. Further, the state-dependent inhibition on sodium channels induced by WB4101 was demonstrated in dorsal root ganglion neurons. In conclusion, the present study identified WB4101 as a sodium channel blocker with an open-state-dependent property, which may contribute to WB4101's analgesic action.