Synthesis, biological evaluation and quantitative structure activity relationship analysis of nuclear-substituted pargylines as competitive inhibitors of MAO-A and MAO-B.
A series of nuclear substituted derivatives of pargyline has been prepared and tested (under controlled conditions designed to measure the competitive component of the inhibition) as competitive inhibitors of MAO-A and -B. Adequate correlation of the biological data with the physiochemical constants of substituent groups was obtained only when the m- and p-substituted derivatives were considered separately. Due to the narrow range of activity displayed by the p-substituted derivates when inhibiting MAO-B, meaningful correlations were not found. However, the inhibition of MAO-B by the m-substituted derivatives required the inclusion of the Verloop L parameter for adequate correlation, suggesting that the inhibitor binding site of MAO-B is present within a cavity of more limited lateral dimensions than that present on the MAO-A surface. Inhibition of both MAO-A and -B demonstrated a parabolic relationship between inhibitory activity and pi. Whereas this parabolic relationship showed a maximal value for inhibition of MAO-A (mean pi o = 0.86), inhibition of MAO-B demonstrated a minimal value of pi (pi min = -0.5) i.e. the optimal value of pi for inhibition of MAO-B has not been achieved for this series of compounds but such would be greater than that demonstrated for MAO-A. The Hammett sigma function was important or significant only in the inhibition of MAO-A by the p-substituted derivatives.
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
A
A
Ali
J B
JB
Robinson
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D007700:Kinetics; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry*; D010293:Pargyline / Q000737:chemistry*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D008996:Monoamine Oxidase Inhibitors; D010293:Pargyline