TY - JOUR T1 - Identification of WB4101, an alpha1-adrenoceptor antagonist, as a sodium channel blocker JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.117.111252 SP - mol.117.111252 AU - Min Li AU - Ying Wu AU - Beiyan Zou AU - Xiaoliang Wang AU - Min Li AU - Haibo Yu Y1 - 2018/01/01 UR - http://molpharm.aspetjournals.org/content/early/2018/06/08/mol.117.111252.abstract N2 - Sodium channels are important proteins in modulating neuronal membrane excitability. Genetic studies from patients and animals indicated neuronal sodium channels play key roles in pain sensitization. We have identified WB4101, an antagonist of alpha1-adrenoceptor, as a Nav1.7 inhibitor from a screen. Present study was to characterize the effects of WB4101 on sodium channels. We demonstrated that WB4101 inhibited both Nav1.7 and Nav1.8 channels with similar level of potencies. The half-inhibition concentrations (IC50s) of WB4101 were 11.6±2.07μM and 1.0±0.07μM for the resting and inactivated Nav1.7 channels, respectively, and 8.67±1.31μM and 0.91±0.25μM for the resting and inactivated Nav1.8 channels, respectively. WB4101 induced significant hyperpolarizing shift in the voltage-dependent inactivation for both Nav1.7 (15mV) and Nav1.8 (20mV) channels. The IC50 for the open state sodium channel was 2.50±1.16μM for Nav1.7 and 1.1±0.2μM 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 significant 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, present study identified WB4101 as a sodium channel blocker with an open-state dependent property, which may be contributing to WB4101’s analgesic action. ER -