Analgesics used today date from the 19th century. Morphine remains the analgesic of reference for the treatment of pain (nociception), but it is also responsible for serious adverse effects. Research studies have showed that animals deprived of potassium channels (TREK-1) were over-sensitive to pain[1]?. More recently, it has been demonstrated that the TREK-1 K+ channel is a crucial contributor of morphine-induced analgesia in mice, while it is not involved in morphine-induced constipation, respiratory depression and dependence[2]. 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 different families of TREK-1 activators exhibiting analgesic activity in vivo[3] ,[4]. We present here the synthesis and pharmacological evaluation of the third generation of analogues to confirm their therapeutic interest.[1]A. Alloui, K. Zimmermann, J. Mamet, F. Duprat, J. Noel, J. Chemin, N. Guy, N. Blondeau, N. Voilley, C. Rubat-Coudert, M. Borsotto, G. Romey, C. Heurteaux, P. Reeh, A. Eschalier, M. Lazdunski, EMBO J., 2006,  25(11), 2368-2376.[2]M. Devilliers, J. Busserolles, S. Lolignier, E. Deval, V. Pereira, A. Alloui, M. Christin, B. Mazet, P. Delmas, J. Noel, M. Ladzunski, A. Eschalier, Nat. Commun., 2013 , doi:10.1038/ncomms3941[3]S. Ducki, K. Bennis, A. Eschalier, J. Busserolles, F. Lesage, N. Rodrigues, D. Vivier, 2013 , WO 2013098416/A2[4]N. Rodrigues, K. Bennis, D. Vivier, V. Pereira, F. Chatelain, E. Chapuy, H. Deokar, J. Busserolles, F. Lesage, A. Eschalier, and S. Ducki, Eur. J. Med. Chem., 2014 , accepted for publication

Synthesis, optimization, and pharmacological evaluation of TREK-1 activators as novel analgesics

248th National Meeting (2014)

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