N-propargylbenzylamine, a major metabolite of pargyline, is a potent inhibitor of monoamine oxidase type B in rats in vivo: a comparison with deprenyl.

In an effort to explore the contribution of the metabolites of pargyline towards the in vivo inhibition of monoamine oxidase (MAO), the effects of pargyline and its major metabolites on the production and metabolism of a number of biogenic amines were studied in rats. The administration of pargyline gave rise to three major ethyl acetate extractable metabolites: benzylamine, N-methylbenzylamine and N-propargylbenzylamine (NPB). Only NPB demonstrated in vivo monoamine oxidase inhibitory properties at an acute dose of 30 mg kg-1. The acute effects of pargyline, NPB, and deprenyl on urine and brain concentrations of a number of biogenic amines (phenylethylamine (PEA), m- and p-tyramine, noradrenaline (NA), dopamine, and 5-hydroxytryptamine (5-HT) and their metabolites were evaluated. Increased urine and brain concentrations of PEA were considered to represent in vivo inhibition of type B MAO while decreased concentrations of NA and 5-HT metabolites were regarded as indicators of an in vivo inhibition of MAO type A. NPB, like deprenyl and pargyline, significantly increased urine and brain PEA while only pargyline reduced 5-HT metabolism, suggesting that the metabolism of pargyline to NPB may contribute towards the MAO type B inhibitory effects of pargyline in vivo. Since the therapeutic benefits of MAO inhibitors in clinical practice usually require some period of chronic treatment, the chronic effects of repeated 14 daily doses of the above MAO inhibitors on central and peripheral biogenic amines were evaluated at the following times: during treatment, one day and five days after termination of treatment. The biochemical changes observed during the course of chronic NPB, pargyline and deprenyl treatments generally follow the expected in vitro characteristics of these drugs, but the detailed changes observed suggest clear differences. For example, the in vivo effect of pargyline on urine 5-hydroxyindoleacetic acid excretion was considerably weaker than its effect on the excretion of NA and dopamine metabolites. These changes are opposite to the in vitro effects of pargyline on 5-HT, dopamine and NA oxidative deamination. Inhibitions of the metabolism of all the amines studied were clearly observed during chronic MAOI treatments, but these effects were less evident five days after the end of treatment, suggesting an almost normal metabolism of biogenic amines. It is concluded that while MAO inhibitors may be the primary compound responsible for MAO inhibition, the effects of their metabolites in some cases may also play equally important roles in the regulation of monoamines both in the periphery and the brain. Thus, as demonstrated here, NPB was found to be as potent as pargyline and deprenyl with regard to its in vivo MAO type B inhibitory properties.