Neurochemical and neuroprotective effects of some aliphatic propargylamines: new selective nonamphetamine-like monoamine oxidase B inhibitors.

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 that l-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 l-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 l-deprenyl and M-2-PP causes selective inhibition of MAO-B activity and increases dopamine levels in mouse caudate. M-2-PP, like l-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 l-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.

Involvement of brain trace amines in the behavioural effects of phenelzine.

The MAO inhibitor phenelzine (PLZ) at a dose of 25 mg/kg does not affect the behavior of rats. In contrast, the equivalent dose of a deuterated analog (alpha, alpha, beta, beta-tetradeutero-PLZ, d4PLZ) elicits a biphasic behavioral syndrome in rats. In an attempt to correlate changes in cerebral monoamines with behavior, the concentration of various amines were measured at various times after the administration of either d4PLZ or PLZ (25 mg/kg). In general, PLZ and d4PLZ caused elevations in brain amine levels, particularly in the time period 2-12 hours after drug administration. Furthermore, d4PLZ increased the concentrations of serotonin (5-HT), phenylethylamine (PE), tryptamine (T), meta-tyramine (mTA), and 3-methoxytyramine (3-MT) to a greater extent than PLZ. Since the time course of behavioral excitation closely parallels the elevations in T and PE levels in the brain and since the percentage increases in PE and T levels following d4PLZ compared to PLZ treatment were substantially greater than those of the other amines, it was postulated that PE and T are involved in d4PLZ-induced behaviors.

Changes in brain catecholamine levels following DL-dopa are not potentiated by deuterium substitution.

Adult male Wistar rats were treated with either DL-dopa, D3-DL-dopa or vehicle and sacrificed at various time intervals after treatment. Brain dopamine and noradrenaline concentrations were measured using quantitative mass spectrometric analysis. After treatment with DL-dopa or D3-DL-dopa, total dopamine levels increased above control values; however, no differences were observed between the two drug treatments. Total noradrenaline levels were not significantly altered by treatment with either DL-dopa or D3-DL-dopa. Deuterium substitution did not appear to affect catecholamine deamination or beta-hydroxylation in vivo.

Identification and distribution of phenylacetic acid in the brain of the rat.

Phenylacetic acid, the major metabolite of phenylethylamine, has been identified and quantitated in rat brain regions by capillary column high-resolution gas chromatography mass spectrometry. Its distribution is heterogeneous and correlates with that of phenylethylamine. The values obtained were (ng/g +/- SEM): whole brain, 31.2 +/- 2.7; caudate nucleus, 64.6 +/- 6.5; hypothalamus, 60.1 +/- 7.4; cerebellum, 31.3 +/- 2.9; brainstem, 33.1 +/- 3.3, and the "rest," 27.6 +/- 3.0.

Identification and distribution of m- and p-hydroxyphenylacetic acids in the brain of the rat.

The m and p isomers of hydroxyphenylacetic acid have been identified and quantitated in whole rat brain and in several regions using a capillary column high resolution gas chromatography - mass spectrometry procedure. Their concentrations were: for m-hydroxyphenylacetic acid (mean +/- S.E., number of determinations in parentheses)-whole brain, 2.3 +/- 0.3 ng/g (7); hypothalamus, 1.2 +/- 0.3 ng/g (5); caudate nucleus, 5.5 +/- 0.6 ng/g (5); brain stem, 1.8 +/- 0.1 ng/g (5); cerebellum, 1.2 +/- 0.1 ng/g (5) and the "rest," 1.7 +/- 0.1 ng/g (5); and for p-hydroxyphenylacetic acid-whole brain, 10.6 +/- 0.7 ng/g (7); hypothalamus, 4.5 +/- 0.1 ng/g (4); caudate nucleus, 28.3 +/- 1.6 ng/g (5); brain stem, 8.6 +/- 0.6 ng/g (5); cerebellum, 8.1 +/- 0.4 ng/g (5), and the "rest," 5.3 +/- 0.5 ng/g (5). This heterogeneous distribution parallels closely that exhibited by their respective precursor amines, m- and p-tyramine.