Inversion of selectivity of N-substituted propargylamine monoamine oxidaseinhibitors following structural modifications to quaternary salts

A number of N-substiluted-propargylamines are well known mechanism-based MA O inhibitors. Clorgyline and deprenyl in fact represent archetypal MAO-A an d MAO-B inhibitors respectively. In the present study several ring-substitu ted deprenyl structural analogues were synthesized and alterations of selec tivity and potency towards MAO-A and MAO-B activities were found. When depr enyl and its structural analogues were further modified to their correspond ing 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 substanti ally 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 in hibitor towards MAO. (C) 1999 Elsevier Science Ltd. All rights reserved.