Resin-acid Derivatives As Potent Electrostatic Openers of Voltage-gated K Channels and Suppressors of Neuronal Excitability

Overview

Journal Sci Rep

Specialty Science

Date 2015 Aug 25

PMID 26299574

Citations 11

Authors

Nina E Ottosson

Xiongyu Wu

Andreas Nolting

Urban Karlsson

Per-Eric Lund

Katinka Ruda

Stefan Svensson

Peter Konradsson

Fredrik Elinder

Affiliations

Soon will be listed here.

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.

Citing Articles

Carboxyl-group compounds activate voltage-gated potassium channels via a distinct mechanism.

Ronnelid O, Elinder F J Gen Physiol. 2024; 156(7).

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Therapeutic role of voltage-gated potassium channels in age-related neurodegenerative diseases.

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Resin-acid derivatives bind to multiple sites on the voltage-sensor domain of the Shaker potassium channel.

Ejneby M, Gromova A, Ottosson N, Borg S, Estrada-Mondragon A, Yazdi S J Gen Physiol. 2021; 153(4).

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Coupling stabilizers open K1-type potassium channels.

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