Effect of structural modification of alkyl N-propargylamines on the selective inhibition of monoamine oxidase B activity.

A series of alkyl N-methyl-propargylamine derivatives has been discovered recently to be very potent selective irreversible monoamine oxidase B inhibitors (MAO-B). In the present study, we used a simple compound in this series, namely N-2-butyl-N-methylpropargylamine.HCl (2-BuMP), as the basic structure to investigate the effect of structural modification on the effectiveness and selectivity of the inhibition of MAO activities. When the N-methyl group was replaced by a hydrogen atom, an ethyl group or a propargyl group, MAO inhibitory activity was abolished. The modification of the propargyl group, e.g. to 3-butynyl, N-cyanomethyl or to allyl groups, also destroyed the inhibitory activity. The potency of the inhibitors was related to the carbon chain length of the alkyl group as well as to the substitution of the alpha or the terminal carbon atoms. Substitution of hydroxyl, carboxyl or carboethoxyl groups on the terminal carbon of the alkyl chain drastically reduced the inhibitory activity. More potent MAO inhibitory activity was observed for molecules with a single methyl group substitution on the alpha carbon in comparison with those substituted with two hydrogen or two methyl groups. Other branched alkyl N-methylpropargylamines, e.g. N-methyl-N-(3-pentyl)propargylamine, appeared to be slightly less selective in the inhibition of MAO-B activity. Some of these alkyl propargylamine MAO-B inhibitors, which do not possess the amphetamine-like moiety of L-deprenyl, may have significant neuropsychopharmacological implications.