Pharmacological profile of CEB-1957 and atropine toward brain muscarinic receptors and comparative study of their efficacy against sarin poisoning.
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.
Trovero
F
F
Psypharm S.A. BP 5, La Brûlatte, France.
Brochet
D
D
Breton
P
P
Tambuté
A
A
Bégos
A
A
Bizot
J C
JC
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*
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