文摘
Human ether-à-go-go-related gene (hERG) has an important role in the repolarization of the cardiac action potential. Sophocarpine and sophoridine are quinolizidine alkaloids and their structures are similar. Our aim was to investigate the effects of sophocarpine or sophoridine on hERG-encoded K+ channels and the underlying structure–activity relationships. The effects of sophocarpine and sophoridine were examined on stably expressed hERG channels in HEK293 cells using a whole-cell patch clamp technique and Western blot analysis. The oil–water partition coefficients of sophocarpine and sophoridine were determined by a validated RP-HPLC method. At 300 µM, fractional block was 60.9 ± 1.4 % for sophocarpine versus 41.9 ± 2.0 % for sophoridine. Compared with sophocarpine, voltage-dependence of hERG channels inhibition by sophoridine was more notable. Sophoridine altered the activation properties, but not sophocarpine. Sophocarpine shifted the inactivation curve in a negative direction, but not sophoridine. Both drugs had no significant effect on the expression of hERG protein. The partition coefficients for the n-octanol/water system of sophocarpine and sophoridine at 37 °C were 16.03 ± 0.42 and 1.94 ± 0.03, respectively. In summary, sophocarpine and sophoridine are low potency blockers of hERG channels that functions by changing the channel kinetics, and sophocarpine is a more potent blocker of hERG K+ channels than sophoridine, which may be due to higher hydrophobic nature of sophocarpine compared with sophoridine. Sophocarpine may have a higher binding affinity for the inactivate state. In contrast, sophoridine has a higher binding affinity for the open state. Both drugs have no effect on the generation and trafficking of hERG protein.
