A contribution to the mechanism of action of SAD-128.
SAD-128 was found to be an effective protector of acetylcholinesterase against inhibition by soman, due to its ability to function as a reversible inhibitor and allosteric modifier of the AChE active site. It also attenuated aging of the soman-inhibited enzyme. In order to study the connection between some of these effects of SAD-128 and structural changes in acetylcholinesterase and/or the membrane to which the enzyme is bound, the influences of SAD-128 on the EPR spectra of the spin labelled enzyme and of the membrane were studied under various conditions and the results correlated with the kinetic parameters. SAD-128 increases the fluidity of human erythrocyte membranes but not that of the Torpedo marmorata electric organ. Similarly, the binding properties of membrane acetylcholinesterase for SAD-128, expressed in terms of the Hill coefficient, differ for the two preparations. Some structural changes in the enzyme active site were also observed in the presence of SAD-128. The high protective effect of SAD-128 against AChE inhibition was confirmed by the EPR method regardless of the organophosphorus inhibitor tested. On the other hand, the effect of SAD-128 on the retardation of irreversible inhibition of the enzyme essentially depends on the inhibitor used. From present results it can be concluded that the protective effects of SAD-128 against inhibition of m-AChE are related to the structural changes of the active site and can be additionally moderated by the microviscosity changes of the membrane.
Stalc
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Institute of Pathophysiology, Medical Faculty, E. Kardelj University of Ljubljana, Yugoslavia.
Sentjurc
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D000818:Animals; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004557:Electric Organ; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D008560:Membrane Fluidity / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000037:antagonists & inhibitors; D011726:Pyridinium Compounds / Q000494:pharmacology*
D002800:Cholinesterase Inhibitors; D009943:Organophosphorus Compounds; D011726:Pyridinium Compounds; C016845:SAD-128