Abstract:Newly synthesized compounds have been found to inhibit mitochondrial monoamine oxidase (MAO) in mouse brain and rat liver. A series of 2‐acylamino‐3‐tert‐aminopropiophenones acted preferentially against MAO type B (2‐phenylethylamine as substrate), apparently irreversibly. 2‐Decanoylamino‐3‐morpholinopropiophenone acted similarly in vivo toward the cerebral MAO, producing a dose‐related inhibition. At high dose levels, MAO type A was also severely inhibited. The effects were produced rapidly and restoration of enzyme activity also appeared rapidly. The half‐life for MAO type A could be estimated from the rate of enzyme reappearance to be 13 h. It is suggested that the amino ketones undergo a β‐elimination reaction at the enzyme's active site, forming a reactive species (an α,β‐unsaturated ketone), which reacts covalently with a nucleophilic group of the enzyme by a Michael addition. Some other related compounds, derivatives of phenylpropane, also showed inhibitory activity against MAO, particularly against type A (serotonin as substrate). The morpholino compound might have promise as a quickly effective, short‐acting inhibitor of MAO type B.