title: Characterization of two classes of benzodiazepine binding sites in Schistosoma mansoni.
abstract: As we have recently shown that GABA should be considered a putative neurotransmitter in Schistosoma mansoni, the present work aimed to search for GABAA receptors in adult worms using [3H]-flunitrazepam to label the allosteric benzodiazepine binding site which is classically present on GABAA receptor complexes. We detected a large population (Bmax=8.25+/-1.1 pmol x mg protein(-1)) of high affinity (Kd=33.6+/-1.5 nM) binding sites for flunitrazepam. These sites harboured a singular pharmacological modulation that does not fit well with a mammalian central benzodiazepine receptor, mainly due to a very high affinity for Ro5-4864 and a very low affinity for clonazepam. We also detected a second population of benzodiazepine binding sites labelled with high affinity (IC50=85 nM) by [3H]-PK11195, a selective ligand of the mammalian peripheral benzodiazepine receptor. In conclusion, this work describes the pharmacological properties of a large population of central-like benzodiazepine receptors supporting their study as putative new targets for the development of anti-parasitic agents. We also describe, for the first time, the presence of peripheral benzodiazepine receptors in this parasite.
authors.affiliation: Departamento de Farmacologia Básica e Clínica, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, 21941-590, Rio de Janeiro, Brasil. fnoel@pharma.ufrj.br
authors.forename: F
authors.initials: F
authors.lastname: Noël
authors.forename: D L
authors.initials: DL
authors.lastname: Mendonça-Silva
authors.forename: J-P B
authors.initials: JP
authors.lastname: Thibaut
authors.forename: D V S
authors.initials: DV
authors.lastname: Lopes
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism*; D001570:Benzodiazepinones / Q000378:metabolism; D001665:Binding Sites; D002998:Clonazepam / Q000378:metabolism / Q000494:pharmacology; D003975:Diazepam / Q000378:metabolism / Q000494:pharmacology; D005445:Flunitrazepam / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000378:metabolism; D008024:Ligands; D008297:Male; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D012550:Schistosoma mansoni / Q000187:drug effects / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism; D013696:Temperature; D013997:Time Factors; D014316:Tritium / Q000032:analysis; D000077334:Zolpidem
chemical_list: D001570:Benzodiazepinones; D018755:GABA Agonists; D018757:GABA Modulators; D007546:Isoquinolines; D008024:Ligands; D011725:Pyridines; D011963:Receptors, GABA-A; D014316:Tritium; D001569:Benzodiazepines; C028513:4'-chlorodiazepam; D002998:Clonazepam; D005445:Flunitrazepam; D000077334:Zolpidem; D003975:Diazepam; C037850:PK 11195