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 analogu es N,N-dimethylbenzylamine and alpha-methylbenzylamine has been investigate d. Both classes of analogues are competitive inhibitors of benzylamine oxid ase activity. The K-i values were determined for nine different para-substi tuted N,N-dimethylbenzylamine analogues. Analysis of the binding affinities demonstrate the deprotonated forms of the tertiary amines are preferential ly 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)(0.1 x V-w)-4.24 +/- (0.16 ) alpha-Methyl benzylamine analogues are also found to be competitive inhibit ors of MAO B-catalyzed benzylamine oxidation. Similar K-i values were deter mined using either the S or R stereoisomers. Analysis of the binding affini ties of five para-substituted alpha-methylbenzylamine analogues to MAO B sh ows the deprotonated form also to be preferentially bound and the affinity is marginally increased with increasing van der Waals volume of the para-su bstituent: Log K-i = -0.71 sigma-(0.32)(0.1 x V-w)-3.50 Comparison of these data with that previously published for para-substitute d benzylamine binding to MAO B (Walker and Edmondson, Biochemistry 33 (1994 ) 7088-7098) demonstrates that these benzylamine analogues exhibit differin g modes of binding to the active site of MAO B. The presence of an electron ic substituent effect in the binding of these two classes of analogues comp ared with the lack of an observable electronic effect in the binding of ben zylamine to MAO B is consistent with the proposal that orientation of the b enzyl ring of the bound substrate is responsible for the absence of an elec tronic substituent effect on the rate of the reductive half reaction (Mille r and Edmondson, Biochemistry 38 (1999) 13670-13683). (C) 2000 Elsevier Sci ence B.V. All rights reserved.