{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T11:07:29Z","timestamp":1778843249078,"version":"3.51.4"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,8,24]],"date-time":"2015-08-24T00:00:00Z","timestamp":1440374400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,8,24]],"date-time":"2015-08-24T00:00:00Z","timestamp":1440374400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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.<\/jats:p>","DOI":"10.1038\/srep13278","type":"journal-article","created":{"date-parts":[[2015,8,24]],"date-time":"2015-08-24T11:10:17Z","timestamp":1440414617000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability"],"prefix":"10.1038","volume":"5","author":[{"given":"Nina E","family":"Ottosson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiongyu","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Nolting","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Urban","family":"Karlsson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Per-Eric","family":"Lund","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katinka","family":"Ruda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Svensson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Konradsson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fredrik","family":"Elinder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,8,24]]},"reference":[{"key":"BFsrep13278_CR1","doi-asserted-by":"crossref","unstructured":"Ashcroft, F. M. Ion channels and disease (1st ed.). San Diego, CA: Academic press., (2000).","DOI":"10.1016\/B978-012065310-2\/50023-0"},{"key":"BFsrep13278_CR2","doi-asserted-by":"crossref","unstructured":"Mosh\u00e9, S. L., Perucca, E., Ryvlin, P. & Tomson, T. Epilepsy: new advances. Lancet, 10.1016\/s0140-6736(14)60456-6 (2014).","DOI":"10.1016\/S0140-6736(14)60456-6"},{"key":"BFsrep13278_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.14581\/jer.14001","volume":"4","author":"SK Lee","year":"2014","unstructured":"Lee, S. K. Treatment strategy for the patient with hippocampal sclerosis who failed to the first antiepileptic drug. Journal of epilepsy research 4, 1\u20136 (2014).","journal-title":"Journal of epilepsy research"},{"key":"BFsrep13278_CR4","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1016\/s1474-4422(08)70108-x","volume":"7","author":"SU Schuele","year":"2008","unstructured":"Schuele, S. U. & L\u00fcders, H. O. Intractable epilepsy: management and therapeutic alternatives. The Lancet. Neurology 7, 514\u2013524, 10.1016\/s1474-4422(08)70108-x (2008).","journal-title":"The Lancet. Neurology"},{"key":"BFsrep13278_CR5","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1126\/science.280.5360.69","volume":"280","author":"DA Doyle","year":"1998","unstructured":"Doyle, D. A. et al. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280, 69\u201377 (1998).","journal-title":"Science"},{"key":"BFsrep13278_CR6","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1038\/nature06265","volume":"450","author":"S Long","year":"2007","unstructured":"Long, S., Tao, X., Campbell, E. & MacKinnon, R. Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. Nature 450, 376\u2013458 (2007).","journal-title":"Nature"},{"key":"BFsrep13278_CR7","doi-asserted-by":"publisher","first-page":"8552","DOI":"10.1073\/pnas.1116938109","volume":"109","author":"U Henrion","year":"2012","unstructured":"Henrion, U. et al. Tracking a complete voltage-sensor cycle with metal-ion bridges. Proc. Natl. Acad. Sci. USA. 109, 8552\u20138559, 10.1073\/pnas.1116938109 (2012).","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"BFsrep13278_CR8","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1085\/jgp.201210873","volume":"140","author":"E Vargas","year":"2012","unstructured":"Vargas, E. et al. An emerging consensus on voltage-dependent gating from computational modeling and molecular dynamics simulations. The Journal of general physiology 140, 587\u2013594, 10.1085\/jgp.201210873 (2012).","journal-title":"The Journal of general physiology"},{"key":"BFsrep13278_CR9","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1085\/jgp.69.4.497","volume":"69","author":"B Hille","year":"1977","unstructured":"Hille, B. Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. The Journal of general physiology 69, 497\u2013515 (1977).","journal-title":"The Journal of general physiology"},{"key":"BFsrep13278_CR10","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1016\/j.neuron.2010.08.021","volume":"67","author":"W Catterall","year":"2010","unstructured":"Catterall, W. Ion channel voltage sensors: structure, function and pathophysiology. Neuron 67, 915\u2013943 (2010).","journal-title":"Neuron"},{"key":"BFsrep13278_CR11","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1124\/mol.104.010793","volume":"67","author":"TV Wuttke","year":"2005","unstructured":"Wuttke, T. V., Seebohm, G., Bail, S., Maljevic, S. & Lerche, H. The New Anticonvulsant Retigabine Favors Voltage-Dependent Opening of the Kv7.2 (KCNQ2) Channel by Binding to Its Activation Gate. Mol. Pharmacol. 67, 1009\u20131017, 10.1124\/mol.104.010793 (2005).","journal-title":"Mol. Pharmacol."},{"key":"BFsrep13278_CR12","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1016\/S0896-6273(00)80306-2","volume":"18","author":"KJ Swartz","year":"1997","unstructured":"Swartz, K. J. & MacKinnon, R. Hanatoxin modifies the gating of a voltage-dependent K+ channel through multiple binding sites. Neuron 18, 665\u2013673 (1997).","journal-title":"Neuron"},{"key":"BFsrep13278_CR13","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1085\/jgp.201210914","volume":"141","author":"M Milescu","year":"2013","unstructured":"Milescu, M., Lee, H. C., Bae, C. H., Kim, J. I. & Swartz, K. J. Opening the shaker K+ channel with hanatoxin. The Journal of general physiology 141, 203\u2013216, 10.1085\/jgp.201210914 (2013).","journal-title":"The Journal of general physiology"},{"key":"BFsrep13278_CR14","doi-asserted-by":"publisher","first-page":"15637","DOI":"10.1073\/pnas.0911294107","volume":"107","author":"A Peretz","year":"2010","unstructured":"Peretz, A. et al. Targeting the voltage sensor of Kv7.2 voltage-gated K+ channels with a new gating-modifier. Proc. Natl. Acad. Sci. USA. 107, 15637\u201315642, 10.1073\/pnas.0911294107 (2010).","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"BFsrep13278_CR15","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1085\/jgp.201110599","volume":"137","author":"SI B\u00f6rjesson","year":"2011","unstructured":"B\u00f6rjesson, S. I. & Elinder, F. An electrostatic potassium channel opener targeting the final voltage sensor transition. J. Gen. Physiol. 137, 563\u2013640 (2011).","journal-title":"J. Gen. Physiol."},{"key":"BFsrep13278_CR16","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1016\/j.bpj.2009.10.026","volume":"98","author":"SI B\u00f6rjesson","year":"2010","unstructured":"B\u00f6rjesson, S. I., Parkkari, T., Hammarstr\u00f6m, S. & Elinder, F. Electrostatic tuning of cellular excitability. Biophys. J. 98, 396\u2013403 (2010).","journal-title":"Biophys. J."},{"key":"BFsrep13278_CR17","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1085\/jgp.201311087","volume":"143","author":"N Ottosson","year":"2014","unstructured":"Ottosson, N., Liin, S. & Elinder, F. Drug-induced ion channel opening tuned by the voltage sensor charge profile. J. Gen. Physiol. 143, 173\u2013182, 10.1085\/jgp.201311087 (2014).","journal-title":"J. Gen. Physiol."},{"key":"BFsrep13278_CR18","doi-asserted-by":"publisher","first-page":"5714","DOI":"10.1073\/pnas.1503488112","volume":"112","author":"SI Liin","year":"2015","unstructured":"Liin, S. I. et al. Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac IKs channel. Proc. Natl. Acad. Sci. USA. 112, 5714\u20135719, 10.1073\/pnas.1503488112 (2015).","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"BFsrep13278_CR19","doi-asserted-by":"publisher","first-page":"2242","DOI":"10.1529\/biophysj.108.130757","volume":"95","author":"SI B\u00f6rjesson","year":"2008","unstructured":"B\u00f6rjesson, S. I., Hammarstr\u00f6m, S. & Elinder, F. Lipoelectric modification of ion channel voltage gating by polyunsaturated fatty acids. Biophys. J. 95, 2242\u20132253 (2008).","journal-title":"Biophys. J."},{"key":"BFsrep13278_CR20","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.eplepsyres.2008.03.013","volume":"80","author":"X-p Xu","year":"2008","unstructured":"Xu, X.-p. et al. Polyunsaturated fatty acids and cerebrospinal fluid from children on the ketogenic diet open a voltage-gated K channel: a putative mechanism of antiseizure action. Epilepsy Res. 80, 57\u2013123 (2008).","journal-title":"Epilepsy Res."},{"key":"BFsrep13278_CR21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s002329900578","volume":"172","author":"A Leaf","year":"1999","unstructured":"Leaf, A., Kang, J. X., Xiao, Y. F., Billman, G. E. & Voskuyl, R. A. The antiarrhythmic and anticonvulsant effects of dietary N-3 fatty acids. The Journal of membrane biology 172, 1\u201311 (1999).","journal-title":"The Journal of membrane biology"},{"key":"BFsrep13278_CR22","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1124\/mol.62.4.836","volume":"62","author":"Y Imaizumi","year":"2002","unstructured":"Imaizumi, Y. et al. Molecular basis of pimarane compounds as novel activators of large-conductance Ca(2+)-activated K(+) channel alpha-subunit. Mol. Pharmacol. 62, 836\u2013846, 10.1124\/mol.62.4.836 (2002).","journal-title":"Mol. Pharmacol."},{"key":"BFsrep13278_CR23","doi-asserted-by":"publisher","first-page":"2818","DOI":"10.1016\/S0031-9422(00)97289-3","volume":"10","author":"T Norin","year":"1971","unstructured":"Norin, T. & Winell, B. Diterpenoids of cones from two Cedrus species. Phytochemistry 10, 2818\u20132821 (1971).","journal-title":"Phytochemistry"},{"key":"BFsrep13278_CR24","unstructured":"Beath, O. A. On Abietic Acid and Related Resin Acids from Oleoresin of American Conifers. (University of Wisconsin\u2013Madison, 1912)."},{"key":"BFsrep13278_CR25","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1021\/cr60131a004","volume":"42","author":"HH Zeiss","year":"1948","unstructured":"Zeiss, H. H. The chemistry of the resin acids. Chem. Rev. 42, 163\u2013187 (1948).","journal-title":"Chem. Rev."},{"key":"BFsrep13278_CR26","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1007\/s12013-008-9032-5","volume":"52","author":"SI B\u00f6rjesson","year":"2008","unstructured":"B\u00f6rjesson, S. I. & Elinder, F. Structure, function and modification of the voltage sensor in voltage-gated ion channels. Cell Biochem. Biophys. 52, 149\u2013223 (2008).","journal-title":"Cell Biochem. Biophys."},{"key":"BFsrep13278_CR27","doi-asserted-by":"crossref","unstructured":"Sascha, R. et al. Effects of antiarrhythmic drugs on cloned cardiac voltage-gated potassium channels expressed in Xenopus oocytes. Naunyn. Schmiedebergs Arch. Pharmacol. 362, 10.1007\/s002100000257 (2000).","DOI":"10.1007\/s002100000257"},{"key":"BFsrep13278_CR28","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.tins.2013.12.002","volume":"37","author":"C Tsantoulas","year":"2014","unstructured":"Tsantoulas, C. & McMahon, S. B. Opening paths to novel analgesics: the role of potassium channels in chronic pain. Trends Neurosci. 37, 146\u2013158, 10.1016\/j.tins.2013.12.002 (2014).","journal-title":"Trends Neurosci."},{"key":"BFsrep13278_CR29","doi-asserted-by":"publisher","first-page":"8014","DOI":"10.1016\/j.bmc.2006.07.042","volume":"14","author":"T Tashima","year":"2006","unstructured":"Tashima, T. et al. Design, synthesis and BK channel-opening activity of hexahydrodibenzazepinone derivatives. Bioorg. Med. Chem. 14, 8014\u20138031, 10.1016\/j.bmc.2006.07.042 (2006).","journal-title":"Bioorg. Med. Chem."},{"key":"BFsrep13278_CR30","doi-asserted-by":"publisher","first-page":"8642","DOI":"10.1016\/j.bmc.2010.09.072","volume":"18","author":"Y-M Cui","year":"2010","unstructured":"Cui, Y.-M. et al. Design, synthesis and characterization of BK channel openers based on oximation of abietane diterpene derivatives. Bioorg. Med. Chem. 18, 8642\u20138659, 10.1016\/j.bmc.2010.09.072 (2010).","journal-title":"Bioorg. Med. Chem."},{"key":"BFsrep13278_CR31","doi-asserted-by":"publisher","first-page":"6386","DOI":"10.1016\/j.bmcl.2008.10.078","volume":"18","author":"Y-M Cui","year":"2008","unstructured":"Cui, Y.-M. et al. Novel oxime and oxime ether derivatives of 12, 14-dichlorodehydroabietic acid: design, synthesis and BK channel-opening activity. Bioorg. Med. Chem. Lett. 18, 6386\u20136389, 10.1016\/j.bmcl.2008.10.078 (2008).","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"BFsrep13278_CR32","doi-asserted-by":"publisher","first-page":"3552","DOI":"10.1073\/pnas.1114321109","volume":"109","author":"G Gessner","year":"2012","unstructured":"Gessner, G. et al. Molecular mechanism of pharmacological activation of BK channels. Proc. Natl. Acad. Sci. USA. 109, 3552\u20133557, 10.1073\/pnas.1114321109 (2012).","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"BFsrep13278_CR33","doi-asserted-by":"publisher","first-page":"4822","DOI":"10.1073\/pnas.1222003110","volume":"110","author":"T Hoshi","year":"2013","unstructured":"Hoshi, T., Tian, Y., Xu, R., Heinemann, S. & Hou, S. Mechanism of the modulation of BK potassium channel complexes with different auxiliary subunit compositions by the omega-3 fatty acid DHA. Proc. Natl. Acad. Sci. USA. 110, 4822\u20134827, 10.1073\/pnas.1222003110 (2013).","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"BFsrep13278_CR34","doi-asserted-by":"publisher","first-page":"4816","DOI":"10.1073\/pnas.1221997110","volume":"110","author":"T Hoshi","year":"2013","unstructured":"Hoshi, T. et al. Omega-3 fatty acids lower blood pressure by directly activating large-conductance Ca2+-dependent K+ channels. Proc. Natl. Acad. Sci. USA. 110, 4816\u20134821, 10.1073\/pnas.1221997110 (2013).","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"BFsrep13278_CR35","doi-asserted-by":"crossref","unstructured":"Tigerholm, J., B\u00f6rjesson, S., Lundberg, L., Elinder, F. & Frans\u00e9n, E. Dampening of hyperexcitability in CA1 pyramidal neurons by polyunsaturated fatty acids acting on voltage-gated ion channels. PLoS ONE 7, 10.1371\/journal.pone.0044388 (2012).","DOI":"10.1371\/journal.pone.0044388"},{"key":"BFsrep13278_CR36","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1016\/0092-8674(87)90494-6","volume":"50","author":"A Kamb","year":"1987","unstructured":"Kamb, A., Iverson, L. E. & Tanouye, M. A. Molecular characterization of Shaker, a Drosophila gene that encodes a potassium channel. Cell 50, 405\u2013413 (1987).","journal-title":"Cell"},{"key":"BFsrep13278_CR37","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1126\/science.2122519","volume":"250","author":"T Hoshi","year":"1990","unstructured":"Hoshi, T., Zagotta, W. & Aldrich, R. Biophysical and molecular mechanisms of Shaker potassium channel inactivation. Science 250, 533\u2013541 (1990).","journal-title":"Science"},{"key":"BFsrep13278_CR38","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.vascn.2012.10.005","volume":"67","author":"K Ido","year":"2013","unstructured":"Ido, K. et al. Screening quality for Ca2+-activated potassium channel in IonWorks Quattro is greatly improved by using BAPTA-AM and ionomycin. J. Pharmacol. Toxicol. Methods 67, 16\u201324, 10.1016\/j.vascn.2012.10.005 (2013).","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"BFsrep13278_CR39","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.vascn.2007.09.002","volume":"57","author":"AR Harmer","year":"2008","unstructured":"Harmer, A. R. et al. Optimisation and validation of a medium-throughput electrophysiology-based hNav1.5 assay using IonWorks. J. Pharmacol. Toxicol. Methods 57, 30\u201341, 10.1016\/j.vascn.2007.09.002 (2008).","journal-title":"J. Pharmacol. Toxicol. Methods"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep13278","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep13278.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep13278.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T22:16:06Z","timestamp":1672956966000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep13278"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,8,24]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,10,16]]}},"alternative-id":["BFsrep13278"],"URL":"https:\/\/doi.org\/10.1038\/srep13278","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,8,24]]},"assertion":[{"value":"21 April 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 July 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 August 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Two patent applications based on these results have been submitted by N.E.O., X.W., P.K. and F.E. as inventors.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"13278"}}