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Oxidation Potentials of N‐Modified Derivatives of the Analgesic Flupirtine Linked to Potassium K V 7 Channel Opening Activity But Not Hepatocyte Toxicity
Author(s) -
Lemmerhirt Christian J.,
Rombach Mirko,
Bodtke Anja,
Bednarski Patrick J.,
Link Andreas
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402442
Subject(s) - chemistry , acetaminophen , potassium channel , cyclic voltammetry , neurotoxicity , analgesic , potassium , pharmacology , mechanism of action , redox , toxicity , biochemistry , biophysics , electrochemistry , in vitro , organic chemistry , electrode , medicine , biology
Openers of neuronal voltage‐gated potassium channels (K V ) 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. K V 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 EC 50 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.