J Appl Biomed 8:87-92, 2010 | DOI: 10.2478/v10136-009-0008-6

The effect of trimedoxime on acetylcholinesterase and on the cholinergic system of the rat bladder

Ondřej Soukup¹, Ondřej Holas³, Jiří Binder³, Kumar Killy⁴, Gunnar Tobin⁴, Daniel Jun^1,2, Josef Fusek¹, Kamil Kuča^1,2,5,*

¹ Department of Toxicology, Faculty of Military Health Sciences, University of Defence, Hradec Králové, Czech Republic

² Center of Advanced Studies, Faculty of Military Health Sciences, University of Defence, Hradec Králové, Czech Republic

³ Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic

⁴ Institute of Neuroscience and Physiology, Department of Pharmacology, the Sahlgrenska Academy at Goteborg University, Sweden

⁵ Department of Chemistry, Faculty of Sciences, J. E. Purkinje University, Ústí nad Labem, Czech Republic

Trimedoxime is a bisquaternary oxime that is widely used in the treatment of organophosphorous poisoning caused by tabun and paraoxon. We tested its affinity to acetylcholinesterase (AChE), its mechanism of interaction and effect on the cholinergic system of the rat bladder. The half maximal inhibitory concentration (IC₅₀) of trimedoxime to recombinant AChE was found to be 82.0 mM ± 30.1 mM. This represents a weak inhibition. Its interaction with AChE seems to be very similar to obidoxime - one aromatic nucleus interacts with the peripheral anionic site and the other with the residues TYR337 and TYR341 inside the cavity. Also the oxime moiety is moving towards the catalytic triade ready for the reactivation of the inhibited AChE. In the organ bath experiment no significant effect of trimedoxime was observed on the contraction of the detrusor caused by the muscarinic agonist metacholine.

Keywords: acetylcholinesterase; trimedoxime; antidote; muscarinic receptors; reactivation

Received: August 20, 2009; Published: July 31, 2010  Show citation