Planta Med 2017; 83(17): 1321-1328
DOI: 10.1055/s-0043-109556
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

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

Tivadar Kiss
1   Department of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Szeged, Hungary
2   Interdisciplinary Centre for Natural Products, University of Szeged, Szeged, Hungary
,
Botond Borcsa
1   Department of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Szeged, Hungary
,
Péter Orvos
3   Rytmion Ltd., Szeged, Hungary
4   Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
,
László Tálosi
1   Department of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Szeged, Hungary
3   Rytmion Ltd., Szeged, Hungary
,
Judit Hohmann
1   Department of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Szeged, Hungary
2   Interdisciplinary Centre for Natural Products, University of Szeged, Szeged, Hungary
,
Dezső Csupor
1   Department of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Szeged, Hungary
2   Interdisciplinary Centre for Natural Products, University of Szeged, Szeged, Hungary
› Author Affiliations
Further Information

Publication History

received 13 February 2017
revised 27 March 2017

accepted 15 April 2017

Publication Date:
04 May 2017 (online)

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.

 
  • References

  • 1 Pharmacopoeia of the Peopleʼs Republic of China. Vol. I. 10th ed. Beijing: Peopleʼs Medical Publishing House; 2010
  • 2 Friese J, Gleitz J, Gutser UT, Heubach JF, Matthiesen T, Wilffert B, Selve N. Aconitum sp. alkaloids: the modulation of voltage-dependent Na+ channels, toxicity and antinociceptive properties. Eur J Pharmacol 1997; 337: 165-174
  • 3 Chan TYK, Kelly SP. Aconite poisoning. Med J Aust 1990; 153: 499
  • 4 Ameri A. The effects of Aconitum alkaloids on the central nervous system. Prog Neurobiol 1998; 56: 211-235
  • 5 Liu Q, Zhuo L, Liu L, Zhu S, Sunnassee A, Liang M, Zhou L, Liu Y. Seven cases of fatal aconite poisoning: forensic experience in China. Forensic Sci Int 2011; 212: e5-e9
  • 6 Dzhakhangirov FN, Sultankhodzhaev MN, Tashkhodzhaev B, Salimov BT. Diterpenoid alkaloids as a new class of antiarrhythmic agents. Structure-activity relationship. Chem Nat Compd 1997; 33: 190-202
  • 7 Wang YP, Chen WZ, Wang XL, Hua Z. Inhibition of guan-fu base A on delayed rectifier current (Ik) in guinea pig ventricular myocytes. Yao Xue Xue Bao 1996; 31: 581-584
  • 8 Wright SN. Irreversible block of human heart (hH1) sodium channels by the plant alkaloid lappaconitine. Mol Pharmacol 2001; 59: 183-192
  • 9 Vakhitova YV, Farafontova EI, Khisamutdinova RY, Yunusov VM, Tsypysheva IP, Yunusov MS. A study of the mechanism of the antiarrhythmic action of allapinin. Russ J Bioorganic Chem 2013; 39: 92-101
  • 10 Song MK, Liu H, Jiang HL, Yue JM, Hu GY. Electrophysiological characterization of 14-benzoyltalatisamine, a selective blocker of the delayed rectifier K+ channel found in virtual screening. Eur J Pharmacol 2006; 531: 47-53
  • 11 Chen WZ, Dong YL, Zhang YF, Ding GS. Anti-arrhythmia effects of guan-fu base A. Zhongguo Yao Li Xue Bao 1983; 4: 247-250
  • 12 Wang YP, Chen WZ, Sun WK, Wu JX. Hemodynamic actions of guan-fu base A in anesthetized rats. Zhongguo Yao Li Xue Bao 1992; 13: 231-234
  • 13 Tai CJ, El-Shazly M, Wu TY, Lee KT, Csupor D, Hohmann J, Chang FR, Wu YC. Clinical aspects of Aconitum preparations. Planta Med 2015; 81: 1017-1028
  • 14 Huang X, Yang Y, Zhu J, Dai Y, Pu J. The effects of a novel anti-arrhythmic drug, acehytisine hydrochloride, on the human ether-a-go-go related gene K+ channel and its trafficking. Basic Clin Pharmacol Toxicol 2009; 104: 145-154
  • 15 Sanguinetti MC, Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia. Nature 2006; 440: 463-469
  • 16 Dobrev D, Friedrich A, Voigt N, Jost N, Wettwer E, Christ T, Knaut M, Ravens U. The G protein-gated potassium current I(K,ACh) is constitutively active in patients with chronic atrial fibrillation. Circulation 2005; 112: 3697-3706
  • 17 Hashimoto N, Yamashita T, Tsuruzoe N. Tertiapin, a selective IKACh blocker, terminates atrial fibrillation with selective atrial effective refractory period prolongation. Pharmacol Res 2006; 54: 136-141
  • 18 Li Y, Tu D, Xiao H, Du Y, Zou A, Liao Y, Dong S. Aconitine blocks HERG and Kv1.5 potassium channels. J Ethnopharmacol 2010; 131: 187-195
  • 19 Xie S, Jia Y, Liu A, Dai R, Huang L. Hypaconitine-induced QT prolongation mediated through inhibition of KCNH2 (hERG) potassium channels in conscious dogs. J Ethnopharmacol 2015; 166: 375-379
  • 20 Huang X, Yang Y, Zhu J, Xu D, Peng J, Liu J. Comparative effects of guanfu base A and guanfu base G on hERG K+ channel. J Cardiovasc Pharmacol 2012; 59: 77-83
  • 21 Forgo P, Borcsa B, Csupor D, Fodor L, Berkecz R, Molnár VA, Hohmann J. Diterpene alkaloids from Aconitum anthora and assessment of the hERG-inhibiting ability of Aconitum alkaloids. Planta Med 2011; 77: 368-373
  • 22 Kiss T, Orvos P, Bánsághi S, Forgo P, Jedlinszki N, Tálosi L, Hohmann J, Csupor D. Identification of diterpene alkaloids from Aconitum napellus subsp. firmum and GIRK channel activities of some Aconitum alkaloids. Fitoterapia 2013; 90: 85-93
  • 23 Borcsa B, Csupor D, Forgo P, Widowitz U, Bauer R, Hohmann J. Aconitum lipo-alkaloids-semisynthetic products of the traditional medicine. Nat Prod Commun 2011; 6: 527-536
  • 24 Csupor D, Wenzig EM, Zupkó I, Wölkart K, Hohmann J, Bauer R. Qualitative and quantitative analysis of aconitine-type and lipo-alkaloids of Aconitum carmichaelii roots. J Chromatogr A 2009; 1216: 2079-2086
  • 25 Borcsa B, Widowitz U, Csupor D, Forgo P, Bauer R, Hohmann J. Semisynthesis and pharmacological investigation of lipo-alkaloids prepared from aconitine. Fitoterapia 2011; 82: 365-368
  • 26 Borcsa B, Kiss T, Csupor D, Orvos P, Tálosi L, Hohmann J. The effect of diterpene alkaloids on the GIRK channels. Planta Med 2015; 81: 1546-1547
  • 27 Borcsa B, Fodor L, Csupor D, Forgo P, Molnár A, Hohmann J. Diterpene alkaloids from the roots of Aconitum moldavicum and assessment of Nav 1.2 sodium channel activity of Aconitum alkaloids. Planta Med 2014; 80: 231-236
  • 28 Csupor D, Forgo P, Csedő K, Hohmann J. C19 and C20 diterpene alkaloids from Aconitum toxicum Rchb. Helv Chim Acta 2006; 89: 2981-2986
  • 29 Csupor D, Forgo P, Wenzig EM, Bauer R, Hohmann J. Bisnorditerpene, norditerpene, and lipo-alkaloids from Aconitum toxicum . J Nat Prod 2008; 71: 1779-1782
  • 30 Csupor D, Forgo P, Zupkó I, Szabó P, Hohmann J. Anthranoyl-substituted norditerpene alkaloids from Aconitum vulparia Rchb. and their cytotoxic activities. Z Naturforsch 2007; 62?b: 135-141
  • 31 Hohmann J, Forgo P, Hajdú Z, Varga E, Máthé I. Norditerpenoid alkaloids from Consolida orientalis and complete 1H and 13C NMR signal assignments of some lycoctonine-type alkaloids. J Nat Prod 2002; 65: 1069-1072
  • 32 Bai Y, Desai HK, Pelletier SW. Long-chain fatty acid esters of some norditerpenoid alkaloids. J Nat Prod 1994; 57: 963-970
  • 33 Hashimoto N, Yamashita T, Tsuruzoe N. Characterization of in vivo and in vitro electrophysiological and antiarrhythmic effects of a novel IKACh blocker, NIP-151: a comparison with an IKr-blocker dofetilide. J Cardiovasc Pharmacol 2008; 51: 162-169
  • 34 Polonchuk L. Toward a new gold standard for early safety: automated temperature-controlled hERG test on the PatchLiner®. Front Pharmacol 2012; 3: 3