title: Pharmacological profile of CEB-1957 and atropine toward brain muscarinic receptors and comparative study of their efficacy against sarin poisoning.
abstract: This study consists of two parts, first to compare the pharmacological profile of atropine and CEB-1957 substance toward muscarinic receptor subtypes. In various rat brain structures, binding properties were determined by competition experiments of [3H]pirenzepine, [3H]AF-DX 384, and [3H]4-DAMP in quantitative autoradiography of M1, M2, and M3 muscarinic receptor subtypes, respectively. Competition curves have shown that atropine presents similar nanomolar inhibition constants toward each subtype, while CEB-1957 has distinct affinities (Ki from 0.26 to 73 nM) with the following range order: M3 > or = M2 > M1. The second part is to compare atropine and CEB-1957 (in combination with pralidoxime) for their ability to protect against the lethality induced by 2 x LD50 of the acetylcholinesterase inhibitor sarin. CEB-1957 reduced the mortality at doses 10 times lower than atropine. Finally, from these results, it is proposed that a selective blockade of M2 and M3 receptor subtypes could play a pivotal role in the protective effect against sarin poisoning.
authors.affiliation: Psypharm S.A. BP 5, La Brûlatte, France.
authors.forename: F
authors.initials: F
authors.lastname: Trovero
authors.forename: D
authors.initials: D
authors.lastname: Brochet
authors.forename: P
authors.initials: P
authors.lastname: Breton
authors.forename: A
authors.initials: A
authors.lastname: Tambuté
authors.forename: A
authors.initials: A
authors.lastname: Bégos
authors.forename: J C
authors.initials: JC
authors.lastname: Bizot
mesh_terms: D000818:Animals; D001285:Atropine / Q000378:metabolism / Q000494:pharmacology*; D001345:Autoradiography; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000506:poisoning*; D008297:Male; D018727:Muscarinic Antagonists / Q000378:metabolism / Q000494:pharmacology*; D010276:Parasympatholytics / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D011041:Poisoning / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D012524:Sarin / Q000506:poisoning*; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D010276:Parasympatholytics; D010880:Piperidines; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D013876:Thiophenes; C065959:AFDX 384; D010890:Pirenzepine; C113456:CEB 1957; D001285:Atropine; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; D012524:Sarin