TRANSFORMATION OF MONOAMINE OXIDASE-B PRIMARY AMINE SUBSTRATES INTO TIME-DEPENDENT INHIBITORS - TERTIARY AMINE HOMOLOGS OF PRIMARY AMINE SUBSTRATES

A family of N-methylated and N,N-dimethylated alkyl and arylalkylamine s was prepared and more than half of the analogues were shown to be ti me-dependent pseudo-first-order inhibitors of monoamine oxidase-B. Som e of the time-dependent inactivators were reversible and others were i rreversible with respect to prolonged dialysis following inactivation. Partition ratios ranged from zero to 11 000. These results are ration alized in terms of a combination of an inductive effect and a stereoel ectronic effect as a result of hindered rotation of an active site cov alent adduct. A molecular mechanics calculation indicates that there i s at least 10 kcal/mol of torsional energy to be overcome in order for the enzyme adduct to be released. These findings show that tertiary a mine homologues of primary amine substrates of monoamine oxidase are t ime-dependent inhibitors, and this should be useful in the design of n ew inactivators of this enzyme.