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Konradsson, Peter
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Publications (10 of 76) Show all publications
Rautio, T., Vangerven, D., Dahlén, J., Watanabe, S., Kronstrand, R., Vikingsson, S., . . . Gréen, H. (2023). In vitro metabolite identification of acetylbenzylfentanyl, benzoylbenzylfentanyl, 3-fluoro-methoxyacetylfentanyl, and 3-phenylpropanoylfentanyl using LC-QTOF-HRMS together with synthesized references. Drug Testing and Analysis, 15(7), 711-729
Open this publication in new window or tab >>In vitro metabolite identification of acetylbenzylfentanyl, benzoylbenzylfentanyl, 3-fluoro-methoxyacetylfentanyl, and 3-phenylpropanoylfentanyl using LC-QTOF-HRMS together with synthesized references
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2023 (English)In: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611, Vol. 15, no 7, p. 711-729Article in journal (Refereed) Published
Abstract [en]

Acetylbenzylfentanyl, benzoylbenzylfentanyl, 3-fluoro-methoxyacetylfentanyl, and 3-phenylpropanoylfentanyl are fentanyl analogs that have been reported to the European Monitoring Centre for Drugs and Drug Addiction in recent years. The aim of this study was to identify metabolic pathways and potential biomarker metabolites of these fentanyl analogs. The compounds were incubated (5 mu M) with cryopreserved hepatocytes for up to 5 h in vitro. Metabolites were analyzed with liquid chromatography-quadrupole time of flight-high-resolution mass spectrometry (LC-QTOF-HRMS). The experiments showed that acetylbenzylfentanyl, benzoylbenzylfentanyl, and 3-phenylpropanoylfentanyl were mainly metabolized through N-dealkylation (forming nor-metabolites) and 3-fluoro-methoxyacetylfentanyl mainly through demethylation. Other observed metabolites were formed by mono-/dihydroxylation, dihydrodiol formation, demethylation, dehydrogenation, amide hydrolysis, and/or glucuronidation. The experiments showed that a large number of metabolites of 3-phenylpropanoylfentanyl were formed. The exact position of hydroxy groups in formed monohydroxy metabolites could not be established solely based upon recorded MSMS spectra of hepatocyte samples. Therefore, potential monohydroxy metabolites of 3-phenylpropanoylfentanyl, with the hydroxy group in different positions, were synthesized and analyzed together with the hepatocyte samples. This approach could reveal that the beta position of the phenylpropanoyl moiety was highly favored; beta-OH-phenylpropanoylfentanyl was the most abundant metabolite after the nor-metabolite. Both metabolites have the potential to serve as biomarkers for 3-phenylpropanoylfentanyl. The nor-metabolites of acetylbenzylfentanyl, benzoylbenzylfentanyl, and 3-fluoro-methoxyacetylfentanyl do also seem to be suitable biomarker metabolites, as do the demethylated metabolite of 3-fluoro-methoxyacetylfentanyl. Identified metabolic pathways and formed metabolites were in agreement with findings in previous studies of similar fentanyl analogs.

Place, publisher, year, edition, pages
WILEY, 2023
Keywords
fentanyl analogs; hepatocytes; metabolite synthesis; new psychoactive substances
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:liu:diva-192492 (URN)10.1002/dta.3454 (DOI)000935058600001 ()36756728 (PubMedID)
Note

Funding Agencies|Eurostars-2 Joint Programme (European Commission) [E! 113377]; European Unions Horizon 2020 research and innovation program; Swedens Innovation Agency VINNOVA [2019-03566]; Strategic Research Area in Forensic Sciences (Strategiomradet forensiska vetenskaper) at Linkoeping University

Available from: 2023-03-21 Created: 2023-03-21 Last updated: 2024-10-23Bibliographically approved
Lee, I.-M., Huang, T.-Y., Yang, F.-L., Johansson, V., Hsu, C.-R., Hsieh, P.-F., . . . Wu, S.-H. (2022). A hexasaccharide from capsular polysaccharide of carbapenem-resistant Klebsiella pneumoniae KN2 is a ligand of Toll-like receptor 4. Carbohydrate Polymers, 278, Article ID 118944.
Open this publication in new window or tab >>A hexasaccharide from capsular polysaccharide of carbapenem-resistant Klebsiella pneumoniae KN2 is a ligand of Toll-like receptor 4
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2022 (English)In: Carbohydrate Polymers, ISSN 0144-8617, E-ISSN 1879-1344, Vol. 278, article id 118944Article in journal (Refereed) Published
Abstract [en]

Klebsiella pneumoniae serotype KN2 is a carbapenem-resistant strain and leads to the health care-associated in-fections, such as bloodstream infections. Its capsular polysaccharide (CPS) was isolated and cleaved by a specific enzyme from a bacteriophage into a hexasaccharide-repeating unit. With GC-MS, NMR, and Mass analyses, the structure of KN2 CPS was determined to be {-> 3)-beta-D-Glcp-(1 -> 3)-[alpha-D-GlcpA-(1 -> 4)-beta-D-Glcp-(1 -> 6)]-alpha-D-Galp- (1 -> 6)-beta-D-Galp-(1 -> 3)-beta-D-Galp-(1 ->}(n). We demonstrated that 1 mu g/mL CPS could stimulate J774A.1 murine macrophages to release tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in vitro. Also, we proved that KN2 CPS induced the immune response through Toll-like receptor 4 (TLR4) in the human embryonic kidney (HEK)-293 cells. Strikingly, the hexasaccharide alone shows the same immune response as the CPS, suggesting that the hexasaccharide can shape the adaptive immunity to be a potential vaccine adjuvant. The glucuronic acid (GlcA) on other polysaccharides can affect the immune response, but the GlcA-reduced KN2 CPS and hex-asaccharide still maintain their immunomodulatory activities.

Place, publisher, year, edition, pages
ELSEVIER SCI LTD, 2022
Keywords
K. pneumoniae; Capsular polysaccharide; Bacteriophage glycosidase; Toll-like receptor 4
National Category
Organic Chemistry
Identifiers
urn:nbn:se:liu:diva-183779 (URN)10.1016/j.carbpol.2021.118944 (DOI)000760879600002 ()34973762 (PubMedID)
Note

Funding Agencies|Ministry of Science and Technology, Taiwan (MOST) [109-2923-M-001-008, 109-2113-M-001-004]

Available from: 2022-03-25 Created: 2022-03-25 Last updated: 2024-10-25
Rautio, T., Thornell, J., Gréen, H., Konradsson, P., Dahlén, J. & Wu, X. (2022). An improved procedure for the synthesis of fourteen 4-OH and 3-MeO-4OH metabolites of fentanyl analogues from two intermediates on multi-gram scale. Synthetic Communications, 52(3), 392-401
Open this publication in new window or tab >>An improved procedure for the synthesis of fourteen 4-OH and 3-MeO-4OH metabolites of fentanyl analogues from two intermediates on multi-gram scale
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2022 (English)In: Synthetic Communications, ISSN 0039-7911, E-ISSN 1532-2432, Vol. 52, no 3, p. 392-401Article in journal (Refereed) Published
Abstract [en]

Fentanyl analogues have appeared on the recreational drug market during the last ten years and caused many fatal overdoses around the world due to their high potencies. Their metabolites are of great interest for toxicology, metabolism and identification studies. According to the literature, fentanyl analogues with similar structures have similar metabolism profile. Therefore, a synthetic route that enables synthesis of the corresponding metabolites for several fentanyl analogues would be valuable. Fentanyl analogue metabolites are often polar and tailing on silica gel. Hence, the purification of these substances could be challengeable. In this work, a general synthetic route was developed and described for the multi-gram scale synthesis of 14 potential metabolites of seven fentanyl analogues. The synthetic route is concise and optimized, does not require any use of silica gel purification and is therefore convenient for large-scale synthesis. The overall yields of the metabolites were in the range of 25-57%.

Place, publisher, year, edition, pages
Taylor & Francis Inc, 2022
Keywords
Fentanyl analogues; key intermediate; metabolite; multigram scale
National Category
Organic Chemistry
Identifiers
urn:nbn:se:liu:diva-182626 (URN)10.1080/00397911.2022.2026396 (DOI)000745881500001 ()
Note

Funding Agencies|Strategic Research Area Forensic Sciences; Swedish Governmental Agency for Innovation SystemsVinnova; Eurostars-2 Joint Programme [E! 113377]; European UnionEuropean Commission

Available from: 2022-02-01 Created: 2022-02-01 Last updated: 2024-10-23Bibliographically approved
Wallgren, J., Vikingsson, S., Rautio, T., Nasr, E., Åstrand, A., Watanabe, S., . . . Konradsson, P. (2020). Structure elucidation of urinary metabolites of fentanyl and five fentanyl analogues using LC-QTOF-MS, hepatocyte incubations and synthesized reference standards. Journal of Analytical Toxicology, 44(9)
Open this publication in new window or tab >>Structure elucidation of urinary metabolites of fentanyl and five fentanyl analogues using LC-QTOF-MS, hepatocyte incubations and synthesized reference standards
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2020 (English)In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 44, no 9Article in journal (Refereed) Published
Abstract [en]

Fentanyl analogues constitute a particularly dangerous group of new psychoactive compounds responsible for many deaths around the world. Little is known about their metabolism and studies utilizing LC-QTOF-MS analysis of hepatocyte incubations and/or authentic urine samples does not allow for determination of the exact metabolite structures, especially when it comes to hydroxylated metabolites. In this study seven motifs (2-, 3-, 4- and β-OH as well as 3,4-diOH, 4-OH-3-OMe and 3-OH-4-OMe) of fentanyl and five fentanyl analogues, acetylfentanyl, acrylfentanyl, cyclopropylfentanyl, isobutyrylfentanyl and 4F-isobutyrylfentanyl were synthesized. The reference standards were analyzed by LC-QTOF-MS, which enabled identification of the major metabolites formed in hepatocyte incubations of the studied fentanyls. By comparison with our previous data sets, major urinary metabolites could tentatively be identified. For all analogues, β-OH, 4-OH and 4-OH-3-OMe were identified after hepatocyte incubation. β-OH was the major hydroxylated metabolite for all studied fentanyls, except for acetylfentanyl where 4-OH was more abundant. However, the ratio 4-OH/β-OH was higher in urine samples than in hepatocyte incubations for all studied fentanyls. Also, 3-OH-4-OMe was not detected in any hepatocyte samples, indicating a clear preference for the 4-OH-3-OMe, which was also found to be more abundant in urine compared to hepatocytes. The patterns appear to be consistent across all studied fentanyls and could serve as a starting point in the development of methods and synthesis of reference standards of novel fentanyl analogues where nothing is known about the metabolism.

Place, publisher, year, edition, pages
Oxford University Press, 2020
Keywords
Fentanyl analogue, human hepatocytes, metabolism, new psychoactive substances, reference standards
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:liu:diva-169944 (URN)10.1093/jat/bkaa021 (DOI)000634883300014 ()32104892 (PubMedID)
Note

Funding agencies: Strategiomradet Forensiska Vetenskaper (Strategic Research Area Forensic Sciences) at Linkoping University; Swedish Governmental Agency for Innovation SystemsVinnova; Eurostars-2 Joint Programme; European UnionEuropean Commission [E!10628]

Available from: 2020-09-25 Created: 2020-09-25 Last updated: 2024-10-23Bibliographically approved
Silverå Ejneby, M., Wu, X., Ottosson, N., Münger, E. P., Lundström, I., Konradsson, P. & Elinder, F. (2018). Atom-by-atom tuning of the electrostatic potassium-channel modulator dehydroabietic acid. The Journal of General Physiology, 150(5), 731-750
Open this publication in new window or tab >>Atom-by-atom tuning of the electrostatic potassium-channel modulator dehydroabietic acid
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2018 (English)In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 150, no 5, p. 731-750Article in journal (Refereed) Published
Abstract [en]

Dehydroabietic acid (DHAA) is a naturally occurring component of pine resin that was recently shown to open voltage-gated potassium (KV) channels. The hydrophobic part of DHAA anchors the compound near the channel’s positively charged voltage sensor in a pocket between the channel and the lipid membrane. The negatively charged carboxyl group exerts an electrostatic effect on the channel’s voltage sensor, leading to the channel opening. In this study, we show that the channel-opening effect increases as the length of the carboxyl-group stalk is extended until a critical length of three atoms is reached. Longer stalks render the compounds noneffective. This critical distance is consistent with a simple electrostatic model in which the charge location depends on the stalk length. By combining an effective anchor with the optimal stalk length, we create a compound that opens the human KV7.2/7.3 (M type) potassium channel at a concentration of 1 µM. These results suggest that a stalk between the anchor and the effector group is a powerful way of increasing the potency of a channel-opening drug.

Place, publisher, year, edition, pages
New York, United States: Rockefeller Institute for Medical Research, 2018
National Category
Physiology and Anatomy
Identifiers
urn:nbn:se:liu:diva-147837 (URN)10.1085/jgp.201711965 (DOI)000434417800008 ()2-s2.0-85046705149 (Scopus ID)
Note

Funding agencies: Swedish Research Council [2016-02615]; Swedish Heart-Lung Foundation [20150672]; Swedish Brain Foundation [2016-0326]

Available from: 2018-05-15 Created: 2018-05-15 Last updated: 2025-02-10Bibliographically approved
Zhang, J., Wang, J., Sandberg, A., Wu, X., Nyström, S., LeVine, H. I., . . . Lindgren, M. (2018). Intramolecular Proton and Charge Transfer of Pyrene-based trans-Stilbene Salicylic Acids Applied to Detection of Aggregated Proteins.. ChemPhysChem, 19(22), 3001-3009
Open this publication in new window or tab >>Intramolecular Proton and Charge Transfer of Pyrene-based trans-Stilbene Salicylic Acids Applied to Detection of Aggregated Proteins.
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2018 (English)In: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 19, no 22, p. 3001-3009Article in journal (Refereed) Published
Abstract [en]

Two analogues to the fluorescent amyloid probe 2,5-bis(4'-hydroxy-3'-carboxy-styryl)benzene (X-34) were synthesized based on the trans-stilbene pyrene scaffold (Py1SA and Py2SA). The compounds show strikingly different emission spectra when bound to preformed Aβ1-42 fibrils. This remarkable emission difference is retained when bound to amyloid fibrils of four distinct proteins, suggesting a common binding configuration for each molecule. Density functional theory calculations show that Py1SA is twisted, while Py2SA is more planar. Still, an analysis of the highest occupied molecular orbitals (HOMOs) and lowest unoccupied molecular orbitals (LUMOs) of the two compounds indicates that the degree of electronic coupling between the pyrene and salicylic acid (SA) moieties is larger in Py1SA than in Py2SA. Excited state intramolecular proton transfer (ESIPT) coupled-charge transfer (ICT) was observed for the anionic form in polar solvents. We conclude that ICT properties of trans-stilbene derivatives can be utilized for amyloid probe design with large changes in emission spectra and decay times from analogous chemical structures depending on the detailed physical nature of the binding site.less thanbr /greater than (© 2018 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim.)

Place, publisher, year, edition, pages
Weinheim, Germany: Wiley-VCH Verlag, 2018
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:liu:diva-152767 (URN)10.1002/cphc.201800823 (DOI)000450672100006 ()30183138 (PubMedID)
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2019-11-08
Elgland, M., Nordeman, P., Fyrner, T., Antoni, G., Nilsson, P. & Konradsson, P. (2017). beta-Configured clickable [F-18] FDGs as novel F-18-fluoroglycosylation tools for PET. New Journal of Chemistry, 41(18), 10231-10236
Open this publication in new window or tab >>beta-Configured clickable [F-18] FDGs as novel F-18-fluoroglycosylation tools for PET
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2017 (English)In: New Journal of Chemistry, ISSN 1144-0546, E-ISSN 1369-9261, Vol. 41, no 18, p. 10231-10236Article in journal (Refereed) Published
Abstract [en]

In oncology and neurology the F-18-radiolabeled glucose analogue 2-deoxy-2-[F-18]fluoro-D-glucose ([F-18]FDG) is by far the most commonly employed metabolic imaging agent for positron emission tomography (PET). Herein, we report a novel synthetic route to beta-configured mannopyranoside precursors and a chemoselective F-18-fluoroglycosylation method that employ two b-configured [F-18]FDG derivatives equipped with either a terminal azide or alkyne aglycon respectively, for use as a CuAAC clickable tool set for PET. The b-configured precursors provided the corresponding [F-18]FDGs in a radiochemical yield of 77-88%. Further, the clickability of these [F-18]FDGs was investigated by click coupling to the suitably functionalized Fmoc-protected amino acids, Fmoc-N-(propargyl)-glycine and Fmoc-3-azido-L-alanine, which provided the F-18-fluoroglycosylated amino acid conjugates in radiochemical yields of 75-83%. The F-18-fluoroglycosylated amino acids presented herein constitute a new and interesting class of metabolic PET radiotracers.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2017
National Category
Organic Chemistry
Identifiers
urn:nbn:se:liu:diva-141934 (URN)10.1039/c7nj00716g (DOI)000411767400073 ()
Note

Funding Agencies|Swedish Foundation for Strategic Research; Swedish Research Council

Available from: 2017-10-13 Created: 2017-10-13 Last updated: 2018-02-21
Zhang, J., Sandberg, A., Wu, X., Nyström, S., Lindgren, M., Konradsson, P. & Hammarström, P. (2017). trans-Stilbenoids with Extended Fluorescence Lifetimes for the Characterization of Amyloid Fibrils. ACS Omega, 2(8), 4693-4704
Open this publication in new window or tab >>trans-Stilbenoids with Extended Fluorescence Lifetimes for the Characterization of Amyloid Fibrils
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2017 (English)In: ACS Omega, E-ISSN 2470-1343, Vol. 2, no 8, p. 4693-4704Article in journal (Refereed) Published
Abstract [en]

It was previously reported that two naphthyl-based trans-stilbene probes, (E)-4-(2-(naphthalen-1-yl)vinyl)benzene-1,2-diol (1) and (E)-4-(2-(naphthalen-2-yl)vinyl)benzene-1,2-diol (3), can bind to both native transthyretin (TTR) and misfolded protofibrillar TTR at physiological concentrations, displaying distinct emission maxima bound to the different conformational states (>100 nm difference). To further explore this amyloid probe scaffold to obtain extended fluorescence lifetimes, two new analogues with expanded aromatic ring systems (anthracene and pyrene), (E)-4-(2-(anthracen-2-yl)vinyl)benzene-1,2-diol (4) and (E)-4-(2-(pyren-2-yl)vinyl)benzene-1,2-diol (5), were synthesized employing the palladium-catalyzed Mizoroki–Heck reaction. (E)-4-Styrylbenzene-1,2-diol (2), 3, 4, and 5 were investigated with respect to their photophysical properties in methanol and when bound to insulin, lysozyme, and Aβ1-42 fibrils, including time-resolved fluorescence measurements. In conclusion, 4 and 5 can bind to both native and fibrillar TTR, becoming highly fluorescent. Compounds 2–5 bind specifically to insulin, lysozyme, and Aβ1-42 fibrils with an apparent fluorescence intensity increase and moderate binding affinities. The average fluorescence lifetimes of the probes bound to Aβ1-42 fibrils are 1.3 ns (2), 1.5 ns (3), 5.7 ns (4), and 29.8 ns (5). In summary, the variable aromatic moieties of the para-positioned trans-stilbenoid vinyl-benzene-1,2-diol with benzene, naphthalene, anthracene, and pyrene showed that the extended conjugated systems retained the amyloid targeting properties of the probes. Furthermore, both the anthracene and pyrene moieties extensively enhanced the fluorescence intensity and prolonged lifetimes. These attractive probe properties should improve amyloid detection and characterization by fluorescence-based techniques.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017
Keywords
Fluorescence; Glycoproteins; Molecular association; Molecular recognition; Optical materials; Quantum transition; Spectra
National Category
Organic Chemistry
Identifiers
urn:nbn:se:liu:diva-151658 (URN)10.1021/acsomega.7b00535 (DOI)000409924000069 ()
Available from: 2018-09-28 Created: 2018-09-28 Last updated: 2020-12-15Bibliographically approved
Campos Melo, R. I., Wu, X., Elgland, M., Konradsson, P. & Hammarström, P. (2016). Novel Trans-Stilbene-based Fluorophores as Probes for Spectral Discrimination of Native and Protofibrillar Transthyretin. ACS Chemical Neuroscience, 7(7), 924-940
Open this publication in new window or tab >>Novel Trans-Stilbene-based Fluorophores as Probes for Spectral Discrimination of Native and Protofibrillar Transthyretin
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2016 (English)In: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 7, no 7, p. 924-940Article in journal (Refereed) Published
Abstract [en]

Accumulation of misfolded transthyretin (TTR) as amyloid fibrils causes various human disorders. Native transthyretin is a neurotrophic protein and is a putative extracellular molecular chaperone. Several fluorophores have been shown in vitro to bind selectively to native TTR. Other compounds, such as thioflavin T, bind TTR amyloid fibrils. The probe 1-anilinonaphthalene-8-sulfonate (ANS) binds to both native and fibrillar TTR, becoming highly fluorescent, but with indistinguishable emission spectra for native and fibrillar TTR. Herein we report our efforts to develop a fluorescent small molecule capable of binding both native and misfolded protofibrillar TTR, providing distinguishable emission spectra. We used microwave synthesis for efficient production of a small library of trans-stilbenes and fluorescence spectral screening of their binding properties. We synthesized and tested 22 trans-stilbenes displaying a variety of functional groups. We successfully developed two naphthyl-based trans-stilbenes probes that detect both TTR states at physiological concentrations. The compounds bound with nanomolar to micromolar affinities and displayed distinct emission maxima upon binding native or misfolded protofibrillar TTR (>100 nm difference). The probes were mainly responsive to environment polarity providing evidence for the divergent hydrophobic structure of the binding sites of these protein conformational states. Furthermore, we were able to successfully use one of these probes to quantify the relative amounts of native and protofibrillar TTR in a dynamic equilibrium. In conclusion, we identified two trans-stilbene-based fluorescent probes, (E)-4-(2-(naphthalen-1-yl)vinyl)benzene-1,2-diol (11) and (E)-4-(2-(naphthalen-2-yl)vinyl)benzene-1,2-diol (14), that bind native and protofibrillar TTR, providing a wide difference in emission maxima allowing conformational discrimination by fluorescence spectroscopy. We expect these novel molecules to serve as important chemical biology research tools in studies of TTR folding and misfolding.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016
Keywords
transthyretin, amyloid, stilbene, fluorescence, probe, spectrum
National Category
Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-122842 (URN)10.1021/acschemneuro.6b00062 (DOI)000380297500009 ()27144293 (PubMedID)
Note

At the time for thesis presentation publication was in status: Manuscript

Funding agencies:The work was supported by Goran Gustafsson's Foundation (PH), The Swedish Research Council (PH), The Linkoping center for systemic neuroscience, LiU-Neuro, (XW), and Sven and Lilly Lawski's foundation (ME).

Available from: 2015-11-26 Created: 2015-11-26 Last updated: 2023-08-28Bibliographically approved
Ottosson, N., Wu, X., Nolting, A., Karlsson, U., Lund, P.-E., Ruda, K., . . . Elinder, F. (2015). Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability. Scientific Reports, 5(13278)
Open this publication in new window or tab >>Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability
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2015 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 5, no 13278Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Nature Publishing Group: Open Access Journals - Option C / Nature Publishing Group, 2015
National Category
Clinical Medicine Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-121307 (URN)10.1038/srep13278 (DOI)000359905300001 ()26299574 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Brain Foundation; Swedish Heart-Lung Foundation; ALF; County Council of Ostergotland

Available from: 2015-09-16 Created: 2015-09-14 Last updated: 2022-09-15Bibliographically approved
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