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Research ArticleArticle

Monepantel Allosterically Activates DEG-3/DES-2 Channels of the Gastrointestinal Nematode Haemonchus contortus

Lucien Rufener, Roland Baur, Ronald Kaminsky, Pascal Mäser and Erwin Sigel
Molecular Pharmacology November 2010, 78 (5) 895-902; DOI: https://doi.org/10.1124/mol.110.066498
Lucien Rufener
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Roland Baur
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Ronald Kaminsky
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Pascal Mäser
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Erwin Sigel
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Abstract

Monepantel is the first drug of a new family of anthelmintics, the amino acetonitrile derivatives (AAD), presently used to treat ruminants infected with gastrointestinal nematodes such as Haemonchus contortus. Monepantel shows an excellent tolerability in mammals and is active against multidrug-resistant parasites, indicating that its molecular target is absent or inaccessible in the host and is different from those of the classic anthelmintics. Genetic approaches with mutant nematodes have suggested acetylcholine receptors of the DEG-3 subfamily as the targets of AADs, an enigmatic clade of ligand-gated ion channels that is specific to nematodes and does not occur in mammals. Here we demonstrate direct interaction of monepantel, its major active metabolite monepantel sulfone, and other AADs with potential targets of the DEG-3 subfamily of acetylcholine receptors. H. contortus DEG-3/DES-2 receptors were functionally expressed in Xenopus laevis oocytes and were found to be preferentially activated by choline, to permeate monovalent cations, and to a smaller extent, calcium ions. Although monepantel and monepantel sulfone did not activate the channels by themselves, they substantially enhanced the late currents after activation of the channels with choline, indicating that these AADs are type II positive allosteric modulators of H. contortus DEG-3/DES-2 channels. It is noteworthy that the R-enantiomer of monepantel, which is inactive as an anthelmintic, inhibited the late currents after stimulation of H. contortus DEG-3/DES-2 receptors with choline. In summary, we present the first direct evidence for interaction of AADs with DEG-3-type acetylcholine receptors and discuss these findings in the context of anthelmintic action of AADs.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the Swiss National Science Foundation [Grant 3100A0-105272/2]; a Novartis PhD fellowship; and a research professorship grant from the Swiss National Science Foundation.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.066498.

  • ABBREVIATIONS:

    AAD
    amino-acetonitrile derivative
    nAChR
    nicotinic acetylcholine receptor
    PCR
    polymerase chain reaction
    DMSO
    dimethyl sulfoxide
    RACE-PCR
    rapid amplification of cDNA ends by polymerase chain reaction
    AAD-1566
    monepantel
    AAD-4670
    monepantel sulfone
    AAD-2224
    the optical R-enantiomer of monepantel
    Sandoz 202-791
    R(-)-R(-)-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridin-carboxylic acid isopropyl ester.

  • Received May 31, 2010.
  • Accepted August 2, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (5)
Molecular Pharmacology
Vol. 78, Issue 5
1 Nov 2010
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Research ArticleArticle

Monepantel Allosterically Activates DEG-3/DES-2 Channels of the Gastrointestinal Nematode Haemonchus contortus

Lucien Rufener, Roland Baur, Ronald Kaminsky, Pascal Mäser and Erwin Sigel
Molecular Pharmacology November 1, 2010, 78 (5) 895-902; DOI: https://doi.org/10.1124/mol.110.066498

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Research ArticleArticle

Monepantel Allosterically Activates DEG-3/DES-2 Channels of the Gastrointestinal Nematode Haemonchus contortus

Lucien Rufener, Roland Baur, Ronald Kaminsky, Pascal Mäser and Erwin Sigel
Molecular Pharmacology November 1, 2010, 78 (5) 895-902; DOI: https://doi.org/10.1124/mol.110.066498
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