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 discove red recently to be very potent selective irreversible monoamine oxidas e B inhibitors (MAO-B). In the present study, we used a simple compoun d in this series, namely N-2-butyl-N-methylpropargylamine . HCl (2-BuM P), as the basic structure to investigate the effect of structural mod ification on the effectiveness and selectivity of the inhibition of MA O activities. When the N-methyl group was replaced by a hydrogen atom, an ethyl group or a propargyl group, MAO inhibitory activity was abol ished. The modification of the propargyl group, e.g. to 3-butynyl, N-c yanomethyl 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 carboetho xyl groups on the terminal carbon of the alkyl chain drastically reduc ed the inhibitory activity. More potent MAO inhibitory activity was ob served for molecules with a single methyl group substitution on the al pha carbon in comparison with those substituted with two hydrogen or t wo methyl groups. Other branched alkyl N-methylpropargylamines, e.g. N -methyl-N-(3-pentyl)propargylamine, appeared to be slightly less selec tive in the inhibition of MAO-B activity. Some of these alkyl propargy lamine MAO-B inhibitors, which do not possess the amphetamine-like moi ety of L-deprenyl, may have significant neuropsychopharmacological imp lications.