title: In vitro inactivation of rat brain acetylcholinesterase by DSP-4 and its derivatives OS-21 and OS-23 and protective activity of tacrine (9-amino-1,2,3,4-tetrahydroacridine).
abstract: Tertiary N-haloethylamines are able to cyclize to the corresponding aziridinium ions. The inhibitory activity of the DSP-4 (N-(o-brombenzyl)-N-ethyl-2-chlorethylamine) and its two derivatives OS-21 (N-benzyl-N-ethyl-2-chloroethylamine) and OS-23 (N-fenylethyl-N-ethyl-2-chloroethylamine) was studied toward rat brain acetylcholinesterase (AChE) in vitro. The influence of the THA (tacrine; 9-amino-1,2,3,4-tetrahydroacridine) on AChE inhibition by these substances was also evaluated. The results demonstrated that all of three aziridinium compounds formed in solution caused a time- and concentration-dependent irreversible enzyme inhibition. The association of aziridinium compounds with the AChE was a relatively slow second-order reaction. DSP-4 showed the fastest rate of AChE alkylation, OS-21 had a lowered rate and OS-23 displayed the lowest rate. Pretreatment of the enzyme by THA decreased the rate of alkylation by all three aziridinium compounds by allosteric mechanism.
authors.affiliation: University of Defence, Faculty of Military Health Sciences, Department of Toxicology, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Patockal
authors.forename: Daniel
authors.initials: D
authors.lastname: Jun
authors.forename: Kamil
authors.initials: K
authors.lastname: Kucal
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology*; D001921:Brain / Q000201:enzymology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D005021:Ethylamines / Q000494:pharmacology*; D066298:In Vitro Techniques; D051381:Rats; D013619:Tacrine / Q000494:pharmacology*
chemical_list: D001596:Benzylamines; D002800:Cholinesterase Inhibitors; D005021:Ethylamines; C510850:N-benzyl-N-ethyl-2-chloroethylamine; C510851:N-phenylethyl-N-ethyl-2-chloroethylamine; D013619:Tacrine; D000110:Acetylcholinesterase; C012102:DSP 4