Abstract
Aconitum diterpene alkaloids are known for their remarkable toxicity, which is due to their
effect on ion channels. Activation of voltage-gated Na+ channels is the major cause of their cardiotoxicity, however, influence on K+ channels may also play a role in the overall effect.
Here we report the synthesis of a series of lipo-alkaloids, including four new compounds,
based on the 14-benzoylaconine structure, which is the core of a vast number of diterpene
alkaloids naturally occurring in Aconitum species. The activities of these compounds were measured in vitro on K+ ion channels using the whole-cell patch-clamp technique. Structure-activity analysis
was carried out based on the data of 51 compounds (32 genuine diterpene alkaloids,
5 fatty acids, and 14 lipo-alkaloids). Depending on their substitution, these compounds
exert different activities on GIRK (G protein-coupled inwardly-rectifying potassium
channel) and hERG (human ether-à-go-go-related gene) channels. Fatty acids and diterpene
alkaloids show lower activity on the GIRK channel than lipo-alkaloids. Lipo-alkaloids
also have less pronounced hERG inhibitory activity compared to the cardiotoxic aconitine.
Considering the GIRK/hERG selectivity as an indicator of perspective therapeutic applicability,
lipo-alkaloids are significantly more selective than the genuine diterpene alkaloids.
14-Benzoyl-8-O-eicosa-8Z,11Z,14Z-trienoate and 14-benzoyl-8-O-eicosa-11Z,14Z,17Z-trienoate are strong and selective inhibitors of GIRK channels, thus, they are promising
subjects for further studies to develop diterpene alkaloid-based antiarrhythmic pharmacons.
Key words
Aconitum species - lipo-alkaloid - diterpene alkaloid - hERG - GIRK
