The effects of 3-methylclonazepam on Schistosoma mansoni musculature are not mediated by benzodiazepine receptors

Schistosomiasis is one of the most prevalent infectious diseases worldwide and classified as a neglected disease for which there is an urgent need for searching new drug candidates. According to TDR/WHO, existing leads with proven schistosomicidal activity, like meclonazepam, might be the objects of further exploration. Here, we decided to investigate if the benzodiazepine binding sites that we recently characterized in adult Schistosoma mansoni could represent the molecular target of meclonazepam for its effect on worm motility and morphological appearance. The EC50 of meclonazepam for its contracturant effect is 10–20 times lower than its IC50 for binding to the worm benzodiazepine binding sites. On the contrary, benzodiazepines like flunitrazepam and diazepam have affinities at least 50 times higher than meclonazepam for these binding sites but did not induce contraction of the worms. We also confirmed the existence of a great similarity between the appearance, kinetics, Emax and external calcium dependency of the contractile effect of praziquantel and meclonazepam. Based on computer-aided molecular modeling calculations, we verified that a certain structural similarity exists between the active enantiomers of both drugs. We further proposed the hypothesis of common pharmacophoric elements including amide and imine subunits and the asymmetric carbons of S-(+)-meclozepam and R-(−)-praziquantel. As a whole, the present data indicate that the contracturant effect of meclonazepam is not a result of its binding to the worm benzodiazepine binding sites but that it shares some basic transduction pathway with praziquantel, even if not through identical molecular targets or binding sites.