Sensitivity of cardiac background inward rectifying K+ outward current (IK1) to the alkaloids lepadiformines A, B, and C

Journal of Natural Products
M P SauviatJ F Biard

Abstract

Three marine alkaloids, purified from Clavelina moluccensis, were structurally identified as lepadiformines A, B, and C and studied on frog atrial myocytes I(K1), using the patch-clamp technique. Lepadiformine A (0.4 to 3.3 microM) blocked I(K1) dose-dependently with an apparent dissociation constant (K(D)) equal to 1.42 microM and a stoichiometry of 0.77. The block is voltage-dependent, suggesting that lepadiformine A occupies a receptor site located at about two-thirds of the membrane depth. The shortening of the aliphatic chain at position C13 of lepadiformine B decreased the potency of the molecule to block I(K1) but not the affinity (K(D) = 1.56 microM) and stoichiometry (0.72). Additional deletion of the oxygenated side chain at C2 in lepadiformine C markedly decreased the inhibitory effect of the molecule. In conclusion, lepadiformine modulates I(K1) response in cardiac muscle. The oxygenated side chain in C2 is implicated in the affinity of lepadiformine, which behaved as an amine, for a receptor located near or inside the I(K1) pore, and the aliphatic chain length at position C13 is involved in the degree of I(K1) blockage.

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Citations

Jun 29, 2010·Journal of the American Chemical Society·Matthew A PerryScott D Rychnovsky
Mar 15, 2012·The Journal of Organic Chemistry·Matthew A PerryScott D Rychnovsky
Feb 6, 2008·Natural Product Reports·John W BluntMichèle R Prinsep
Dec 20, 2007·Beilstein Journal of Organic Chemistry·Ajoy KapatSundarababu Baskaran
Feb 4, 2014·Evidence-based Complementary and Alternative Medicine : ECAM·Kalimuthu Senthilkumar, Se-Kwon Kim
Nov 20, 2015·Organic Letters·Keisuke NishikawaYoshiki Morimoto
Nov 5, 2016·The Journal of Organic Chemistry·Sergey V TsukanovDaniel L Comins
Jan 18, 2017·Natural Products and Bioprospecting·Satheesh Kumar PalanisamyAngela Marino
Oct 13, 2006·Organic & Biomolecular Chemistry·Duanpen Lertpibulpanya, Stephen P Marsden
Mar 3, 2007·Angewandte Chemie·John J Caldwell, Donald Craig
Aug 14, 2008·Organic & Biomolecular Chemistry·Barry LygoChristopher Lumley
May 7, 2010·Natural Product Reports·Eugenia Marqués-LópezMathias Christmann
Dec 24, 2011·Natural Product Reports·John W BluntMichèle R Prinsep
Jan 7, 2014·Natural Product Reports·John W BluntMichèle R Prinsep
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