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

Authors
  • Kiss, Tivadar1, 2
  • Borcsa, Botond1
  • Orvos, Péter3, 4
  • Tálosi, László1, 3
  • Hohmann, Judit1, 2
  • Csupor, Dezső1, 2
  • 1 Department of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Szeged, Hungary. , (Hungary)
  • 2 Interdisciplinary Centre for Natural Products, University of Szeged, Szeged, Hungary. , (Hungary)
  • 3 Rytmion Ltd., Szeged, Hungary. , (Hungary)
  • 4 Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary. , (Hungary)
Type
Published Article
Journal
Planta Medica
Publisher
Georg Thieme Verlag KG
Publication Date
Nov 01, 2017
Volume
83
Issue
17
Pages
1321–1328
Identifiers
DOI: 10.1055/s-0043-109556
PMID: 28472842
Source
Medline
License
Unknown

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.

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