engleski

Inhibition of acetylcholinesterase by three new pyridinium compounds and their effect on phosphylation of the enzyme

Three new compounds of the benzoyl-pyridinium type were prepared: 1-phenacyl-2-methylpyridinium chloride (1), 1-benzoylethyl-pyridinium chloride (2) and 1-benzoylethylpyridinium-4-aldoxime chloride (3) and assayed in vitro for their inhibitory effect on human blood acetylcholinesterase (AChE). All the three compounds inhibited AChE reversibly ; compound 1 was found to bind to both enzyme binding sites, compound 2 was bound to the catalytic site and compound 3 to the allosteric site. The binding affinity of the compounds for the enzyme was compared with their protective effect (PI) in AChE phoshonylation by soman and VX. PI was evaluated from phosphonylation measured in the absence and in presence of the compounds, which were applied in concentrations corresponding to the values of their enzyme/inhibitor dissociation constants for binding of the inhibitor to the catalytic and/or allosteric binding sites on the enzyme. PI was also calculated from theoretical equations deduced from the reversible inhibition of the enzyme. The compounds 1 and 3 protected the enzyme from phosphonylation by soman and VX, whereas no protection was observed in the presence of compound 2 under the same conditions. Irrespective of the binding sites to AChE, PI for compounds 1 and 3 evaluated from phosphonylation agreed with PI calculated from reversible inhibition. The oxime compound 3 was found to be a weak reactivator of methylphosphonylated AChE.

benzoyl-pyridinium compounds; mono-pyridinium compounds; acetylcholinesterase; reversible inhibition; soman; VX; protection; reactivation

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