INHIBITION OF MONOAMINE-OXIDASE BY THE R-ENANTIOMER AND S-ENANTIOMER OF N[3-(2,4-DICHLOROPHENOXY)PROPYL]-N-METHYL-3-BUTYN-2-AMINE

The chemical synthesis of the R-(+)- and S-(-)-enantiomers of N[3-(2,4-dichlorophenoxy)propyl]-N-methyl-3-butyn-2-amine is described. These compounds are derivatives of the mechanism-based irreversible monoamine oxidase inhibitor clorgyline in which a methyl group is substituted for a hydrogen atom on the propargyl methylene carbon. The enantiomeric clorgyline derivatives were both found to be reversible, linearly-competitive inhibitors of monoamine oxidase-A and -B. Thus the methyl-substitution does not prevent non-covalent binding of the inhibitors to the active sites, but it does prevent these compounds from reacting within that complex to form covalent adducts with the enzymes. The substitution of the methyl group resulted in a decreased affinity, as compared to clorgyline, for non-covalent binding to monoamine oxidase-A, with the S-enantiomer having the lower affinity. In contrast, the S-enantiomer showed increased affinity for monoamine oxidase-B. These effects resulted in the high selectivity of the parent compound, clorgyline, towards monoamine oxidase-A being lost. The R-enantiomer showed a small degree of selectivity towards the A-form of the enzyme, whereas the S-enantiomer had a higher affinity for the B-form. These results are discussed in terms of the chemical mechanisms proposed for the interactions of the monoamine oxidases with substrates and inhibitors.