Oxidation potentials of N-modified derivatives of the analgesic flupirtine linked to potassium KV 7 channel opening activity but not hepatocyte toxicity.
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.
Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Ernst Moritz Arndt University, Friedrich-Ludwig-Jahn-Str. 17, 17487 Greifswald (Germany).
Christian J
CJ
Lemmerhirt
Mirko
M
Rombach
Anja
A
Bodtke
Patrick J
PJ
Bednarski
Andreas
A
Link
D000631:Aminopyridines / Q000032:analysis / Q000737:chemistry* / Q000633:toxicity; D000700:Analgesics / Q000032:analysis / Q000737:chemistry* / Q000633:toxicity; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D055664:Electrochemical Techniques; D057809:HEK293 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051656:KCNQ Potassium Channels / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009584:Nitrogen / Q000737:chemistry; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism
D000631:Aminopyridines; D000700:Analgesics; D051656:KCNQ Potassium Channels; D016211:Transforming Growth Factor alpha; C034161:flupirtine; D009584:Nitrogen
KCNQ; KV7; alkylation; cyclic voltammetry; flupirtine