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Vers de nouveaux antalgiques : optimisation de molécules activatrices des canaux potassiques TREK-1

Abstract : Morphine remains the analgesic of reference for the treatment of pain (nociception), but it is also responsible for serious adverse effects. Research studies have shown that animals deprived of potassium channels TREK-1 (TWIK-related K+ channels) were over-sensitive to pain. More recently, it has been demonstrated that the TREK-1 potassium channel is a crucial contributor of morphine-induced analgesia in mice, while it is not involved in morphine-induced constipation, respiratory depression and dependence. These results suggest that the TREK-1 channels constitute targets of interest for the design of novel analgesics without opioid-like adverse effects. Previous studies within our consortium led to the identification of four lead structures as TREK-1 activators exhibiting analgesic activity in vivo.Since the 3D structure of TREK-1 was not available at the time, we decided to perform hit optimization by conventional structure-activity relationship (SAR) studies. Thirty six analogs were synthesized via Knoevenagel condensation and evaluated for their analgesic effect (writhing test, hot plate assay) and their ability to activate TREK-1 channel (electrophysiology). It turned out that the possibility to form hydrogen bonding interaction (aryl moiety) and the volume of substituents of the amide or ester has a crucial influence on activity. Promising results emerged from this SAR study: 5 molecules display a very good analgesic activity (> 50% inhibition of pain, hot plate assay) as well as a good activation of TREK-1 channels (R ≥ 2 at 10μM or R ≥ 4 above 20μM).
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Submitted on : Thursday, June 11, 2015 - 9:24:38 AM
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  • HAL Id : tel-01162628, version 1


Delphine Vivier. Vers de nouveaux antalgiques : optimisation de molécules activatrices des canaux potassiques TREK-1. Autre. Université Blaise Pascal - Clermont-Ferrand II, 2014. Français. ⟨NNT : 2014CLF22518⟩. ⟨tel-01162628⟩



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