Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability.

Nina E Ottosson,Per-Eric Lund,Stefan Svensson,Katinka Ruda,Fredrik Elinder,Andreas Nolting,Xiongyu Wu,Peter Konradsson,Urban Karlsson

doi:10.1038/srep13278

Abstract

Voltage-gated ion channels generate cellular excitability, cause diseases when mutated, and act as drug targets in hyperexcitability diseases, such as epilepsy, cardiac arrhythmia and pain. Unfortunately, many patients do not satisfactorily respond to the present-day drugs. We found that the naturally occurring resin acid dehydroabietic acid (DHAA) is a potent opener of a voltage-gated K channel and thereby a potential suppressor of cellular excitability. DHAA acts via a non-traditional mechanism, by electrostatically activating the voltage-sensor domain, rather than directly targeting the ion-conducting pore domain. By systematic iterative modifications of DHAA we synthesized 71 derivatives and found 32 compounds more potent than DHAA. The most potent compound, Compound 77, is 240 times more efficient than DHAA in opening a K channel. This and other potent compounds reduced excitability in dorsal root ganglion neurons, suggesting that resin-acid derivatives can become the first members of a new family of drugs with the potential for treatment of hyperexcitability diseases.

Highlights

We have recently described a mechanism whereby polyunsaturated fatty acids (PUFAs) bind close to the VSD of different K channels and thereby electrostatically affect the charged voltage sensor in the VSD15–18
We investigated the effect of five naturally occurring and commercially available resin acids (Fig. 1a, pimaric acid, PiMA (1); isopimaric acid, Iso-PiMA (2); abietic acid, AA (3); dehydroabietic acid, DHAA (4); and podocarpic acid, PoCA (5)) at concentrations of 100 μ M with pH 7.4 on the genetically modified 3R Shaker K channel
To test if the compound effects reported in the present study apply to K channels expressed in mammalian cells, we investigated the effects of selected compounds (Compounds 13, 28, 29, 33, 55, and 77) on a Chinese hamster ovary (CHO) cell-line stably expressing the 3R Shaker K channel using whole-cell patch-clamp recordings

Summary

Introduction

We have recently described a mechanism whereby polyunsaturated fatty acids (PUFAs) bind close to the VSD of different K channels and thereby electrostatically affect the charged voltage sensor in the VSD15–18. The effect depends on (i) the number and geometry of the double bonds in the lipid tail[19], and (ii) the charge of the PUFA molecule – the direction of the shift of the conductance curve along the voltage axis depends on the sign of the charge[16] We refer to this as the lipoelectric mechanism[19]. In the present investigation we report on the discovery of twelve compounds more potent than the PUFA docosahexaenoic acid (DHA), previously the most potent lipoelectric compound identified We suggest that these compounds are good starting points to develop new drug candidates for the treatment of cardiac arrhythmia, epilepsy, and pain

Methods

Results

Conclusion