Abstract
GBR-12909 (vanoxerine) is a potent highly selective dopamine transporter antagonist. It was initially developed for treatment of Parkinson's disease and while safe in man, lacked efficacy. Although a potent hERG blocker, the drug exhibits multiple ion channel effects including frequency-dependence. The drug effectively terminated induced, sustained atrial fibrillation (AF) and atrial flutter in a canine model of sterile pericarditis. Subsequently the drug terminated AF in a Phase 2B ascending dose trial. Previous in vitro measurements used protocols that did not address the issue of the late Nav1.5 current which is important in understanding safety of a potent hERG blocker. Peak and late sodium currents were measured in HEK-293 cells stably expressing the human Nav1.5 channel. Peak currents were measured using a step-ramp protocol consisting of a 40 ms step to −15 mV (where the peak current was measured), a 180 ms step to +30 mV and a 200 ms ramp to the holding potential of −80 mV (1 Hz stimulating frequency). The effect of the drug was parameterized with a single binding isotherm having an IC50 of 29 ± 3 nM (95% CI: 22-37) and a Hill coefficient of 0.91 ± 0.10 (95% CI: 0.68-1.18) (seven cells, three concentrations). We also evaluated the effect of GBR-19209 on currents increased using the sea-anemone toxin ATX-II as a surrogate of the late sodium current. The calculated IC50 and Hill coefficients from five cells and five concentrations were 93 ± 9 nM (95% CI: 7-117) and 1.57 ± 0.24 (95% CI: 1.05-2.67), respectively. Thus, GBR-12909 block is at least sixty times more potent than ranolazine's (IC50 = 6 µM).The combination of potent peak and late sodium block may explain the antiarrhythmic and safe profile of the drug.
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call