The antiparasitic bephenium is a potent agonist of Caenorhabditis elegans levamisole-sensitive nicotinic receptors

TURANI ORNELLA; HERNANDO GUILLERMINA; CORRADI JEREMÍAS ; BOUZAT CECILIA

Castellón

Congreso; 6th International Iberian Biophysics Congress. X Iberoamerican Congress of Biophysics.; 2018

Spanish Biophysical Society (SBE), the Portuguese Biophysical Society (SPBf) and the Latin American Federation of Biophysical Societies (LAFeBS)

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels involved in neuromus-cular transmission. In nematodes, muscle nAChRs are main targets of antiparasitic drugs. Ne-matode parasites contain three harmacological classes of muscle nAChRs, which are acti-vated by levamisole (L-type), nicotine (N-type) and bephenium (B-type). The free-living nematodeCaenorhabditis elegans is a model of parasitic nematodes, useful for drug discovery. Becausein C. elegans muscle only the N-AChR and L-AChR classes have been described, we explored thebehavioral (by paralysis assays) and molecular actions (by patch clamp recordings) of the an-tiparasitic bephenium. As in parasites, bephenium produced spastic paralysis. A mutant strainlacking the L-AChR showed full resistance to bephenium, indicating that this receptor is the drug target. Bephenium activated L-AChRs from isolated larvae muscle cells, eliciting channel activ-ity as that elicited by levamisole. The analysis revealed that it is a potent agonist of the L-AChRand an open-channel blocker at higher oncentrations. In contrast, we demonstrated that it is a very low efficacious agonist of the mammalian muscle nAChR. Molecular docking studiesproposed that bephenium can form key interactions required for activation in mammalian andnematode nAChRs, revealed differences with ACh binding, and provided explanations for theexperimental results.