title: The effect of oxime reactivators on muscarinic receptors: functional and binding examinations.
abstract: The antidotal treatment of organophosphorus poisoning is still a problematic issue since no versatile antidote has been developed yet. In our study, we focused on an interesting property, which does not relate to the reactivation of inhibited acetylcholinesterase (AChE) of some oximes, but refers to their anti-muscarinic effects which may contribute considerably to their treatment efficacy. One standard reactivator (HI-6) and two new compounds (K027 and K203) have been investigated for their antimuscarinic properties. Anti-muscarinic effects were studies by means of an in vitro stimulated atrium preparation (functional test), the [(3)H]-QNB binding assay and G-protein coupled receptor assay (GPCR, beta-Arrestin Assay). Based on the functional data HI-6 demonstrates the highest anti-muscarinic effect. However, only when comparing [(3)H]-QNB binding results and GPCR data, K203 shows a very promising compound with regard to anti-muscarinic potency. The therapeutic impact of these findings has been discussed.
authors.affiliation: Department of Toxicology, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, Hradec Kralove 50001, Czech Republic. soukup.ondrej@seznam.cz
authors.forename: O
authors.initials: O
authors.lastname: Soukup
authors.forename: U K
authors.initials: UK
authors.lastname: Kumar
authors.forename: J
authors.initials: J
authors.lastname: Proska
authors.forename: L
authors.initials: L
authors.lastname: Bratova
authors.forename: A
authors.initials: A
authors.lastname: Adem
authors.forename: D
authors.initials: D
authors.lastname: Jun
authors.forename: J
authors.initials: J
authors.lastname: Fusek
authors.forename: K
authors.initials: K
authors.lastname: Kuca
authors.forename: G
authors.initials: G
authors.lastname: Tobin
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D002801:Cholinesterase Reactivators / Q000378:metabolism / Q000494:pharmacology*; D004558:Electric Stimulation; D006339:Heart Rate / Q000187:drug effects; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010091:Oximes / Q000378:metabolism / Q000494:pharmacology*; D010095:Oxotremorine / Q000031:analogs & derivatives / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000378:metabolism / Q000494:pharmacology; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects*
chemical_list: D002801:Cholinesterase Reactivators; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D010091:Oximes; D011726:Pyridinium Compounds; D043562:Receptors, G-Protein-Coupled; D011976:Receptors, Muscarinic; D010095:Oxotremorine; C042743:oxotremorine M; D011813:Quinuclidinyl Benzilate; D000110:Acetylcholinesterase; C022870:asoxime chloride