Inversion of selectivity of N-substituted propargylamine monoamine oxidase inhibitors following structural modifications to quaternary salts.
A number of N-substituted-propargylamines are well known mechanism-based MAO inhibitors. Clorgyline and deprenyl in fact represent archetypal MAO-A and MAO-B inhibitors respectively. In the present study several ring-substituted deprenyl structural analogues were synthesized and alterations of selectivity and potency towards MAO-A and MAO-B activities were found. When deprenyl and its structural analogues were further modified to their corresponding quaternary ammonium salts. i.e. by attaching either an extra propargyl or a methyl group to the nitrogen atom, the potency of inhibition of MAO-B activity was drastically reduced and inhibition of MAO-A activity substantially increased. Such a complete inversion of selectivity may be related to a hydrophilic and electrophilic region seemingly present only in the MAO-A but not in the MAO-B molecule. The results also suggest that at least three sites are required for the selectivity and mechanism-based action of an inhibitor towards MAO.
Yu
P H
PH
Department of Psychiatry, University of Saskatchewan, Saskatoon, Canada. yup@sask.usask.ca
Davis
B A
BA
D000595:Amino Acid Sequence; D000818:Animals; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D007700:Kinetics; D008930:Mitochondria, Liver / Q000201:enzymology*; D008969:Molecular Sequence Data; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D010293:Pargyline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D011437:Propylamines / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D011437:Propylamines; C009054:propargylamine; D010293:Pargyline; D008995:Monoamine Oxidase