Interaction of a bisquaternary ammonium compound with the peripheral organophosphorus (POP) site on acetylcholinesterase

O-ethyl-S (2 diisopropylaminoethyl) methyl phosphorothiolate (MPT) is an active site-directed inhibitor of acetylcholinesterase (AChE). The inhibition of mouse muscle AChE by MPT as well as the inhibition of its individual molecular forms do not proceed as simple irreversible bimolecular reactions. The insolubilization of AChE into a semisolid matrix allows to characterize, after dialysis of all unbound ligand, a partially reversible phase of the inhibition by MPT. These results can be explained in terms of two different modes of inhibition by MPT: the classical irreversible phosphorylation of the active site and an inhibition phase involving the reversible binding of MPT at a site peripheral to the active site, the peripheral organophosphorus site (POP-site). We now find that BW 284 C 51, a reversible specific inhibitor of AChE which protects the active site against irreversible inhibition by low MPT concentrations, can prevent the occurrence of the partially reversible inhibition phase. Hence, BW may bind to a peripheral site that either overlaps or is linked to the POP-site.