Acetylcholinesterase Inhibition and Protection by Dizocilpine (MK−801) Enantiomers

Abstract

Abstract The optical isomers of the N-methyl-d-aspartate (NMDA) receptor ion-channel blocker dizocilpine (MK−801) were shown to interact with electric eel and rat brain acetylcholinesterase (AChE) in a mixed competitive-noncompetitive way. The (-) form, pharmacologically less active, was the most potent of the two isomers as an AChE inhibitor (K1 for electric eel and rat brain AChE being 6ṁ2 and 17ṁ9μM, respectively, compared with 200 and 450 μM, respectively, of the (+) form). Both enantiomers premixed with AChE preparations, dose-dependently protected the enzyme from inactivation by diisopropylfluorophosphate (DFP). The maximal protective effects against 40 and 10 μM DFP were in the ranges 10ṁ7−23ṁ8 and 19ṁ5−31ṁ4% of control enzymic activity for the (+) and (-) forms of dizocilpine, respectively. The extent of the protective effect against DFP was increased up to 80ṁ1% of control enzymic activity for (-)-dizocilpine and to 38ṁ4% for (+)-dizocilpine by diluting the enzymic mixtures 1000 times after treatment with the organophosphate agent. The two enantiomers added to AChE 15 min after DFP, failed to reactivate the enzyme. Finally, it was shown that (+)- and (-)-dizocilpine dose-dependently and competitively decreased the DFP bimolecular reaction constant, Ki. We conclude that dizocilpine exerts a protective action towards AChE against irreversible DFP inhibition, but the molecular mechanism of such an action is at present unclear.