• Philippe Favreau, Evelyne Benoit, Henry G Hocking, Ludovic Carlier, Dieter D' hoedt, Enrico Leipold, René Markgraf, Sébastien Schlumberger, Marco A Córdova, Hubert Gaertner, Marianne Paolini-Bertrand, Oliver Hartley, Jan Tytgat, Stefan H Heinemann, Daniel Bertrand, Rolf Boelens, Reto Stöcklin, and Jordi Molgó.
• Atheris Laboratories, Bernex-Geneva, Switzerland.
• Br. J. Pharmacol. 2012 Jul 1; 166 (5): 1654-68.

Background And PurposeThe µ-conopeptide family is defined by its ability to block voltage-gated sodium channels (VGSCs), a property that can be used for the development of myorelaxants and analgesics. We characterized the pharmacology of a new µ-conopeptide (µ-CnIIIC) on a range of preparations and molecular targets to assess its potential as a myorelaxant.Experimental Approachµ-CnIIIC was sequenced, synthesized and characterized by its direct block of elicited twitch tension in mouse skeletal muscle and action potentials in mouse sciatic and pike olfactory nerves. µ-CnIIIC was also studied on HEK-293 cells expressing various rodent VGSCs and also on voltage-gated potassium channels and nicotinic acetylcholine receptors (nAChRs) to assess cross-interactions. Nuclear magnetic resonance (NMR) experiments were carried out for structural data.Key ResultsSynthetic µ-CnIIIC decreased twitch tension in mouse hemidiaphragms (IC(50) = 150 nM), and displayed a higher blocking effect in mouse extensor digitorum longus muscles (IC = 46 nM), compared with µ-SIIIA, µ-SmIIIA and µ-PIIIA. µ-CnIIIC blocked Na(V)1.4 (IC(50) = 1.3 nM) and Na(V)1.2 channels in a long-lasting manner. Cardiac Na(V)1.5 and DRG-specific Na(V)1.8 channels were not blocked at 1 µM. µ-CnIIIC also blocked the α3β2 nAChR subtype (IC(50) = 450 nM) and, to a lesser extent, on the α7 and α4β2 subtypes. Structure determination of µ-CnIIIC revealed some similarities to α-conotoxins acting on nAChRs.Conclusion And Implicationsµ-CnIIIC potently blocked VGSCs in skeletal muscle and nerve, and hence is applicable to myorelaxation. Its atypical pharmacological profile suggests some common structural features between VGSCs and nAChR channels.© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

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