Planta Med
DOI: 10.1055/s-0043-109556
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Diterpene Lipo-Alkaloids with Selective Activities on Cardiac K+ Channels

Tivadar Kiss1, 2, Botond Borcsa1, Péter Orvos3, 4, László Tálosi1, 3, Judit Hohmann1, 2, Dezső Csupor1, 2
  • 1Department of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Szeged, Hungary
  • 2Interdisciplinary Centre for Natural Products, University of Szeged, Szeged, Hungary
  • 3Rytmion Ltd., Szeged, Hungary
  • 4Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
Further Information

Publication History

received 13 February 2017
revised 27 March 2017

accepted 15 April 2017

Publication Date:
04 May 2017 (eFirst)

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.