Discovery of a new mexiletine-derived agonist of the hERG K+ channel

- MC450 is a new mexiletine-derived agonist of hERG K+ channel.
- MC450 increases the activation current of hERG K+ channel with an EC50 of 41 ± 4 μM
- MC450 primarily acts on the inactivation mechanism of hERG channel
- The hERG double mutant G628C/S631C is insensitive to MC450.

The human Ether-a-go-go Related Gene (hERG) potassium channel plays a central role in the rapid component (IKr) of cardiac action potential repolarization phase. A large number of structurally different compounds block hERG and cause a high risk of arrhythmias. Among the drugs that block hERG channel, a few compounds have been identified as hERG channel activators. Such compounds may be useful, at least in theory, for the treatment of long term QT syndrome.Here we describe a new activator of hERG channel, named MC450. This compound is a symmetric urea, derived from (R)-mexiletine. Using patch-clamp recordings, we found that MC450 increased the activation current of hERG channel, with an EC50 of 41 ± 4 μM. Moreover MC450 caused a depolarizing shift in the voltage dependence of inactivation from − 64.1 ± 1.2 mV (control), to − 35.9 ± 1.4 mV, whereas it had no effect on the voltage dependence of activation. Furthermore, MC450 slowed current inactivation and the effect of MC450 was attenuated by the inactivation-impaired double mutant G628C/S631C.

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