Evidence for alternative binding modes in the interaction of benzylamine analogues with bovine liver monoamine oxidase B.

The interaction of purified bovine liver MAO B with the benzylamine analogues N,N-dimethylbenzylamine and alpha-methylbenzylamine has been investigated. Both classes of analogues are competitive inhibitors of benzylamine oxidase activity. The K(i) values were determined for nine different para-substituted N, N-dimethylbenzylamine analogues. Analysis of the binding affinities demonstrate the deprotonated forms of the tertiary amines are preferentially bound to MAO B and the affinity decreases with increasing van der Waals volume of the para-substituent. The correlation for this relation is:Log K(i)=-0.97+/-(0.28)sigma+(0. 75+/-0.11)(0.1xV(w))-4.24+/-(0.16)alpha-Methyl benzylamine analogues are also found to be competitive inhibitors of MAO B-catalyzed benzylamine oxidation. Similar K(i) values were determined using either the S or R stereoisomers. Analysis of the binding affinities of five para-substituted alpha-methylbenzylamine analogues to MAO B shows the deprotonated form also to be preferentially bound and the affinity is marginally increased with increasing van der Waals volume of the para-substituent:Log K(i)=-0.71sigma-(0.32)(0. 1xV(w))-3.50Comparison of these data with that previously published for para-substituted benzylamine binding to MAO B (Walker and Edmondson, Biochemistry 33 (1994) 7088-7098) demonstrates that these benzylamine analogues exhibit differing modes of binding to the active site of MAO B. The presence of an electronic substituent effect in the binding of these two classes of analogues compared with the lack of an observable electronic effect in the binding of benzylamine to MAO B is consistent with the proposal that orientation of the benzyl ring of the bound substrate is responsible for the absence of an electronic substituent effect on the rate of the reductive half reaction (Miller and Edmondson, Biochemistry 38 (1999) 13670-13683).