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Molecular Pharmacology

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Research ArticleArticle

Monepantel Irreversibly Binds to and Opens Haemonchus contortus MPTL-1 and Caenorhabditis elegans ACR-20 Receptors

Roland Baur, Robin Beech, Erwin Sigel and Lucien Rufener
Molecular Pharmacology January 2015, 87 (1) 96-102; DOI: https://doi.org/10.1124/mol.114.095653
Roland Baur
Institute for Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland (R.Ba., E.S.); Institute of Parasitology, Macdonald College, McGill University, Ste Anne de Bellevue, Quebec, Canada (R.Be., L.R.); and Novartis Centre de Recherche Santé Animale, Saint-Aubin, Switzerland (L.R.)
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Robin Beech
Institute for Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland (R.Ba., E.S.); Institute of Parasitology, Macdonald College, McGill University, Ste Anne de Bellevue, Quebec, Canada (R.Be., L.R.); and Novartis Centre de Recherche Santé Animale, Saint-Aubin, Switzerland (L.R.)
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Erwin Sigel
Institute for Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland (R.Ba., E.S.); Institute of Parasitology, Macdonald College, McGill University, Ste Anne de Bellevue, Quebec, Canada (R.Be., L.R.); and Novartis Centre de Recherche Santé Animale, Saint-Aubin, Switzerland (L.R.)
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Lucien Rufener
Institute for Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland (R.Ba., E.S.); Institute of Parasitology, Macdonald College, McGill University, Ste Anne de Bellevue, Quebec, Canada (R.Be., L.R.); and Novartis Centre de Recherche Santé Animale, Saint-Aubin, Switzerland (L.R.)
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Abstract

Monepantel is a recently developed anthelmintic with a novel mode of action. Parasitic nematodes with reduced sensitivity to monepantel have led to the identification of MPTL-1, a ligand-gated ion-channel subunit of the parasitic nematode Haemonchus contortus, as a potential drug target. Homomeric MPTL-1 channels reconstituted in Xenopus oocytes are gated by µM concentrations of betaine and mM concentrations of choline. Measurement of reversal potentials indicated that the channel has a similar conductance for Na+ and K+ ions and does not permeate Ca2+. Concentrations of monepantel (amino-acetonitrile derivative [AAD]-2225) >0.1 μM, but not its inactive enantiomer AAD-2224, induced channel opening in an irreversible manner. Currents elicited by monepantel alone were larger than the maximal current amplitudes achieved with betaine or choline, making monepantel a superagonist. Currents elicited by betaine or choline were allosterically potentiated by nM concentrations of monepantel and to a much smaller degree by AAD-2224. We have also reconstituted the Caenorhabditis elegans homomeric ACR-20 receptor in Xenopus oocytes. The acr-20 sequence has higher similarity to mptl-1 than acr-23, the primary target for monepantel mode of action in C. elegans. The ACR-20 channel is gated similarly as MPTL-1. Monepantel, but not AAD-2224, was able to induce channel opening in an irreversible manner at similar concentrations as for MPTL-1. Interestingly, the allosteric potentiation measured in the presence of betaine was much smaller than in MPTL-1 receptors. Together, these results establish the mode of action of monepantel in H. contortus and contribute to our understanding of the mode of action of this anthelmintic.

Footnotes

    • Received August 30, 2014.
    • Accepted October 28, 2014.
  • L.R. and E.S. contributed equally to this work.

  • This work was supported in part by the Swiss National Foundation [Grant 31003A_132806/1] to R. Baur and E.S.; and by Novartis Animal Health as L.R. is a Novartis employee.

  • dx.doi.org/10.1124/mol.114.095653.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 87 (1)
Molecular Pharmacology
Vol. 87, Issue 1
1 Jan 2015
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Research ArticleArticle

Two Channels Irreversibly Opened by Monepantel

Roland Baur, Robin Beech, Erwin Sigel and Lucien Rufener
Molecular Pharmacology January 1, 2015, 87 (1) 96-102; DOI: https://doi.org/10.1124/mol.114.095653

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Research ArticleArticle

Two Channels Irreversibly Opened by Monepantel

Roland Baur, Robin Beech, Erwin Sigel and Lucien Rufener
Molecular Pharmacology January 1, 2015, 87 (1) 96-102; DOI: https://doi.org/10.1124/mol.114.095653
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