Activity of novel nicotinic anthelmintics in cut preparations of Caenorhabditis elegans

Abstract

The free-living nematode Caenorhabditis elegans is a useful model for studying the pharmacology of anthelmintics. Currently approved anthelmintics have various mechanisms of action, including activity at nematode nicotinic acetylcholine receptors (nAChRs). Classical anthelmintic agonists of these receptors (nicotine, levamisole, pyrantel and bephenium) caused intact specimens of C. elegans to undergo contracted paralysis. The nAChR antagonist mecamylamine paralysed intact worms and blocked the actions of the agonists. The time to onset of effects of these drugs was enhanced when worms bisected between the mid- and anterior-portions were tested. The novel anthelmintic nAChR antagonist derquantel (2-desoxoparaherquamide, 2-DOPH) was weakly active in intact specimens of C. elegans at concentrations of 50 μM over several days. No antagonism of the nAChR agonists was observed with this drug in intact worms. However, derquantel had direct and marked effects on motility in cut worms and blocked the effects of nAChR agonists in this preparation. A representative of the new amino-acetonitrile derivative (AAD) class of nAChR agonists was not antagonised by derquantel in cut C. elegans, suggesting that these two anthelmintics may not demonstrate unfavourable drug-drug interactions at the receptor level if used to treat livestock infected with parasitic nematodes. The permeability properties of the C. elegans cuticle may be more restrictive than those of adult parasites, calling into question primary anthelmintic screening strategies that rely on this model organism.