TY - JOUR T1 - Monepantel Irreversibly Binds to and Opens <em>Haemonchus contortus</em> MPTL-1 and <em>Caenorhabditis elegans</em> ACR-20 Receptors JF - Molecular Pharmacology JO - Mol Pharmacol SP - 96 LP - 102 DO - 10.1124/mol.114.095653 VL - 87 IS - 1 AU - Roland Baur AU - Robin Beech AU - Erwin Sigel AU - Lucien Rufener Y1 - 2015/01/01 UR - http://molpharm.aspetjournals.org/content/87/1/96.abstract N2 - 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) &gt;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. ER -