Abstract

SKF 525-A and ten congeners were incubated with hepatic microsomes, and all were found to be N-dealkylated. The kinetics of the inhibition of the N-demethylation of ethylmorphine by the eleven compounds was studied and found to be competitive in all cases. These results strongly suggest that SKF 525-A type compounds produce their effects by combining with the active site of time N-demethylase, not by altering the permeability of the lipoid membrane of the microsomime or by uncoupling an oxidative mechanism as has been postulated by others. Kinetic data were presented which indicated that many of these compounds produce their inhibitory effects by serving as alternative substrates. Kinetic evidence is also presented to support the view that the activity of SKF 525-A may be due in part to one or more of its metabolites.