Novel acetylcholinesterase reactivator K112 and its cholinergic properties.
The oxime reactivator K112 is a member of the new group of xylene linker-containing AChE reactivators. Its cholinergic properties could be of importance at OP poisoning and are not related to the AChE reactivation that has been studied. It has been found that, despite of reactivating potency, this compound has additional effects. These cholinergic effects include a weak inhibition of AChE (IC(50)=43.8 ± 4.88 μM), inhibition of binding to the porcine muscarinic M2 receptor (IC(50)=4.36 μM) and finally, the inhibition of HACU (68.4 ± 9.9%), a key regulatory step in the synthesis of ACh. The inhibition of the binding of (3H)-HC-3 (64.7 ± 4.7%) and the influence on the membrane fluidity have also been observed. Blocking properties of K112 on the muscarinic receptors have been revealed in the in vitro experiment (rat urinary bladder) and in the in vivo experiment (rat heart BPM) as well. All these cholinergic properties could significantly contribute to the antidotal effect of K112 at the poisoning by the organophosphates.
Soukup
O
O
Department of Toxicology, Faculty of Military Health Sciences, University of Defence, Trebesska 1575 Hradec Kralove, 500 01, Czech Republic. soukup.ondrej@seznam.cz
Kristofikova
Z
Z
Proska
J
J
Tobin
G
G
Patocka
J
J
Marek
J
J
Jun
D
D
Fusek
J
J
Ripova
D
D
Kuca
K
K
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002801:Cholinesterase Reactivators / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D066298:In Vitro Techniques; D008560:Membrane Fluidity / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000201:enzymology; D062025:Organophosphate Poisoning; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D011041:Poisoning / Q000188:drug therapy / Q000201:enzymology; D011485:Protein Binding; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043585:Receptor, Muscarinic M2 / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013552:Swine; D013574:Synaptosomes / Q000187:drug effects / Q000201:enzymology; D001743:Urinary Bladder / Q000187:drug effects / Q000201:enzymology
C555713:4,4'-bis(hydroxyiminomethyl)-1,10-(1,2-phenylenedimethyl)bispyridinium; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010091:Oximes; D011726:Pyridinium Compounds; D043585:Receptor, Muscarinic M2; D011994:Recombinant Proteins; D000110:Acetylcholinesterase