Planta Med 2015; 81 - PM_115
DOI: 10.1055/s-0035-1565492

The effect of diterpene alkaloids on the GIRK channels

BL Borcsa 1, T Kiss 2, D Csupor 1, P Orvos 2, 3, L Tálosi 3, J Hohmann 1
  • 1University of Szeged, Department of Pharmacognosy, Szeged, Hungary
  • 2University of Szeged, Faculty of Medicine, Department of Pharmacology and Pharmacotherapy, Szeged, Hungary
  • 3Rytmion Ltd., Szeged, Hungary

The GIRK (G protein-activated inwardly rectifying potassium channel) channel is a potential target in the treatment of atrial fibrillation. These channels are selectively expressed in the atrium and they are not present in the ventricle thus the electrical remodelling of atrial heart muscle might be achieved by their inhibition. Diterpene alkaloids isolated from Aconitum and Consolida species exert activity on Na+ and K+ channels and most of them are highly toxic. Depending on skeletal type and substitution pattern the binding affinity thereby the physiological activity may be diverse. Compounds with selective inhibitory activity on GIRK channels might be useful in the treatment of chronic atrial fibrillation. The aim of this work was the investigation of diterpene alkaloids on the GIRK channel.

Diterpene alkaloids were isolated from Ranunculaceae species. From A. anthora compounds 10-hydrox-8-O-methyltalatizamine (1), hetisinone (2), isothalatisidine (3), from A. moldavicum lycoctonine (4), gigactonine (5), ajacine (6), swatinine (7), from A. vulparia finetiadine (8), acovulparine (9), septentriodine (10), delcosine (11) and from C. orientalis takaosamine (12) were isolated. The electrophysiological effects of involved bisnor- (12), nor- (1, 3-11) and diterpene alkaloids (2) were investigated on stable transfected HEK-GIRK1/4 (Kir3.1 and Kir3.4) cell lines using automated patch clamp equipment (Patchliner, Nanion, 1 µM and 10 µM).

Compounds exerted low (5 – 27%) and moderate (30 – 45%) inhibition. Norditerpene alkaloids with aromatic moiety exerted higher activity. The highest activity was exerted by delcosine (11) (45 ± 1%) at 10 µM. These results may contribute to the understanding of the structure-activity relation of diterpene alkaloids on the GIRK channel.

Acknowledgment: This research was supported by the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of TÁMOP 4.2.4.A/2 – 11 – 1-2012 – 0001 'National Excellence Program'.