Vernakalant (Hydrochloride)

Vernakalant hydrochloride is a mixed voltage- and frequency-dependent Na⁺ and atria-preferred K⁺ channel blocker. IC₅₀ for block by Vernakalant of wild-type and mutant Kv1.5 channels Fractional block is 13.35±0.93 μM, 0.61±0.03 μM, and 1.63±0.09 μM for Kv1.5 channel^wt, Kv1.5 channel^I508F, Kv1.5 channel^T479A, respectively. IC50 & Target: IC50: 13.35±0.93 μM (Kv1.5 channel^wt), 0.61±0.03 μM (^I508F), 1.63±0.09 μM (Kv1.5 channel ^T479A)^[1] In Vitro: Block of Kv1.5 by Vernakalant Hydrochloride is mediated after channel activation, because Vernakalant causes a relatively rapid onset of block of channel current upon depolarization but little evidence of resting or “tonic” block of the channel. In the presence of 10 μM Vernakalant, rapid block is apparent after channel opening, and a steady-state current level is rapidly reached. The most important effect is the reduction in potency for Vernakalant centered at I502A, which had an IC₅₀ of 329±19 μM (n=4-10), compared with a control IC₅₀ of 13.4±0.9 μM (n=5-23), which is a 25-fold decrease in potency. V505A, I508A, T480A, and C500A showed lesser reductions in potency on Kv1.5, of between 3- and 4-fold. I508Y in our experiments increased the IC₅₀ for Vernakalant on Kv1.5 to 24.7 μM, again similar to the reported value for hERG^[1].