title: 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 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.
authors: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors: Nina E
authors: NE
authors: Ottosson
authors: Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.
authors: Xiongyu
authors: X
authors: Wu
authors: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors: Andreas
authors: A
authors: Nolting
authors: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors: Urban
authors: U
authors: Karlsson
authors: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors: Per-Eric
authors: PE
authors: Lund
authors: Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.
authors: Katinka
authors: K
authors: Ruda
authors: Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.
authors: Stefan
authors: S
authors: Svensson
authors: Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.
authors: Peter
authors: P
authors: Konradsson
authors: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors: Fredrik
authors: F
authors: Elinder
mesh_terms: D045784:Abietanes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology; D006219:Halogens / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D011522:Protons; D012117:Resins, Synthetic / Q000494:pharmacology*; D055672:Static Electricity; D014981:Xenopus
chemical_list: D045784:Abietanes; D006219:Halogens; D024642:Potassium Channels, Voltage-Gated; D011522:Protons; D012117:Resins, Synthetic; C013913:dehydroabietic acid