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

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 m

SUBMITTER: Ottosson NE 

PROVIDER: S-EPMC4547393 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature