title: Monepantel allosterically activates DEG-3/DES-2 channels of the gastrointestinal nematode Haemonchus contortus.
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.
authors.affiliation: Institute of Cell Biology, University of Bern, Bühlstrasse 28, CH-3012 Bern, Switzerland.
authors.forename: Lucien
authors.initials: L
authors.lastname: Rufener
authors.forename: Roland
authors.initials: R
authors.lastname: Baur
authors.forename: Ronald
authors.initials: R
authors.lastname: Kaminsky
authors.forename: Pascal
authors.initials: P
authors.lastname: Mäser
authors.forename: Erwin
authors.initials: E
authors.lastname: Sigel
mesh_terms: D000494:Allosteric Regulation; D000607:Aminoacetonitrile / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000871:Anthelmintics / Q000737:chemistry / Q000494:pharmacology*; D002794:Choline / Q000494:pharmacology; D005260:Female; D006189:Haemonchus / Q000378:metabolism*; D018722:Nicotinic Agonists / Q000737:chemistry / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D021122:Protein Subunits / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D018079:Receptors, GABA / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D013237:Stereoisomerism; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D000871:Anthelmintics; D018722:Nicotinic Agonists; D021122:Protein Subunits; D018079:Receptors, GABA; D011978:Receptors, Nicotinic; D013450:Sulfones; C553923:monepantel sulfone; D000607:Aminoacetonitrile; C533978:monepantel; D002794:Choline