SELECTIVE ACETYLENIC ‘SUICIDE’ AND REVERSIBLE INHIBITORS OF MONOAMINE OXIDASE TYPES A AND B

1 A number of aromatic‐ N ‐propargyl (acetylenic) compounds and indoleamines were tested for their inhibitory action on monoamine oxidase (MAO) type A and type B using the substrates 5‐hydroxytryptamine (5‐HT), β‐phenylethylamine (PEA) and dopamine. 2 Structure activity studies with aromatic‐ N ‐propragyl (acetylenic) derivatives have shown that MAO inhibitory potency is least dependent on the aromatic portion of the compounds. N ‐methylated propargyl derivatives are the most active and replacement of the methyl group with a higher alkyl or aromatic group results in significant reduction of activity. The triple bond in the N ‐propargyl portion is absolutely essential for activity and must be β‐to the nitrogen. It is the acetylenic group that gives these compounds their irreversible MAO inhibitory property. 3 The present study has indicated that since the acetylenic compounds resemble the enzyme substrates the distance between the aromatic ring and the N ‐propargyl terminal is crucial in designating the type A or type B MAO inhibitory property. For MAO type A inhibition, a distance equivalent to at least three carbon units is required, while for the inhibition of the B type enzyme this distance can be 1 or 2 carbon units. 4 The compounds AGN‐1133 and AGN‐1135 show most promise in Parkinson's disease or as anti‐depressants because of their irreversible selective type B MAO inhibition in vitro and in vivo . 5 A number of indoleamine derivatives were found to be reversible selective type A inhibitors.