Oxidation Potentials of N-Modified Derivatives of the Analgesic Flupirtine Linked to Potassium KV7 Channel Opening Activity But Not Hepatocyte Toxicity
العنوان: | Oxidation Potentials of N-Modified Derivatives of the Analgesic Flupirtine Linked to Potassium KV7 Channel Opening Activity But Not Hepatocyte Toxicity |
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المؤلفون: | Anja Bodtke, Andreas Link, Christian J. Lemmerhirt, Patrick J. Bednarski, Mirko Rombach |
المصدر: | ChemMedChem. 10:368-379 |
بيانات النشر: | Wiley, 2014. |
سنة النشر: | 2014 |
مصطلحات موضوعية: | Cell Survival, Nitrogen, Potassium, Analgesic, Aminopyridines, chemistry.chemical_element, Mice, Transgenic, Pharmacology, Biochemistry, Cell Line, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Drug Discovery, medicine, Animals, Humans, General Pharmacology, Toxicology and Pharmaceutics, Cytotoxicity, Analgesics, KCNQ Potassium Channels, Retigabine, Organic Chemistry, Electrochemical Techniques, Transforming Growth Factor alpha, Potassium channel, Acetaminophen, HEK293 Cells, Mechanism of action, chemistry, Hepatocytes, Molecular Medicine, medicine.symptom, Flupirtine, Oxidation-Reduction, medicine.drug |
الوصف: | Openers of neuronal voltage-gated potassium channels (KV ) are of interest as therapeutic agents for treating pain (flupirtine) and epilepsy (retigabine). In an effort to better understand the mechanisms of action and toxicity of flupirtine, we synthesized nine novel analogues with varying redox behavior. Flupirtine can be oxidatively metabolized into azaquinone diimines; thus, the oxidation potentials of flupirtine and its analogues were measured by cyclic voltammetry. KV 7.2/3 (KCNQ2/3) opening activity was determined by an established assay with HEK293 cells overexpressing these channels. A link was found between the oxidation potentials of the compounds and their EC50 values for potassium channel opening activity. On the other hand, no correlation was observed between oxidation potentials and cytotoxicity in cultures of transgenic mouse hepatocytes (TAMH). These results support the idea that oxidative metabolites of flupirtine contribute to the mechanism of action, similar to what was recently proposed for acetaminophen (paracetamol), but not to hepatotoxicity. |
تدمد: | 1860-7179 |
الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d5a1db43422724f869881e1c59a45bc7Test https://doi.org/10.1002/cmdc.201402442Test |
حقوق: | CLOSED |
رقم الانضمام: | edsair.doi.dedup.....d5a1db43422724f869881e1c59a45bc7 |
قاعدة البيانات: | OpenAIRE |