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Neurochemical and Neuroprotective Effects of Some Aliphatic Propargylamines: New Selective Nonamphetamine‐Like Monoamine Oxidase B Inhibitors

Abstract: Aliphatic N‐propargylamines have recently been discovered to be highly potent, selective, and irreversible monoamine oxidase B (MAO‐B) inhibitors. N‐Methyl‐N‐(2‐pentyl)propargylamine (M‐2‐PP) and N‐methyl‐N‐(2‐hexyl) propargylamine (2‐HxMP), for example, are approximately fivefold more potent than I‐deprenyl at inhibiting mouse brain MAO‐B activity following oral administration. These inhibitors are nonaromatic compounds and are chemically quite different from other known MAO‐B inhibitors. Some of their neurochemical and neuroprotective properties have been evaluated and compared with those of I‐deprenyl. We have confirmed that these new inhibitors selectively inhibit MAO‐B activity both in vitro and in vivo. 2‐Phenylethylamine levels were substantially increased following administration of M‐2‐PP, but the levels of dopamine, 3,4‐dihydroxyphenylacetic acid, homovanillic acid, 5‐hydroxytryptamine, and 5‐hydroxyindoleacetic acid were not affected except at high, nonselective doses. Chronic oral administration of I‐deprenyl and M‐2‐PP causes selective inhibition of MAO‐B activity and increases dopamine levels in mouse caudate. M‐2‐PP, like I‐deprenyl, has been shown to be potent in protecting against MPTP‐induced damage in the mouse. N‐(2‐Chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (DSP‐4), a noradrenaline neurotoxin, is not an MAO substrate. Its noradrenaline‐depleting effects were substantially mitigated by I‐deprenyl as well as by M‐2‐PP and 2‐HxMP in the mouse hippocampus. Administration of 2‐phenylethylamine, however, failed to reverse the effect of DSP‐4. The neuroprotective effect of M‐2‐PP and 2‐HxMP is apparently unrelated to the uptake of DSP‐4.