engleski

Inhibition of acetylcholinesterase by three new pyridinium compounds and their effect on phosphonylation 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 (EC 3.1.1.7, AChE). All the three compounds inhibited AChE reversibly; their binding affinity for the enzyme was compared with their protective effect (PI) in AChE phoshonylation by soman and VX. Compound 1 was found to bind to both enzyme binding sites and the evaluated enzyme/ligand dissociation constants for the catalytic (Ka) and the allosteric (Ki) site were 6.9 microM and 27 microM respectively. Compound 2 was bound to the catalytic site with Ka = 59 microM and compound 3 to the allosteric site with Ki = 328 microM. PI was evaluated from phosphonylation measured in the absence and in presence of the compounds applied in concentration corresponding to their Ka or Ki value, and was also calculated from theoretical equations deduced from the reversible inhibition of the enzyme. 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. Compound 3 was found to be a weak reactivator of methylphosphonylated AChE.

mono-pyridinium compounds; acetylcholinesterase; reversible inhibition; Soman; VX; protection; reactivation

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