Aliphatic Propargylamines, a New Series of Potent Selective, Irreversible Non-Amphetamine-Like MAO-B Inhibitors
l-Deprenyl, a selective irreversible MAO-B inhibitor, has been shown to prolong the onset of disability in Parkinson’s patients and to improve cognitive behavior in Alzheimer’s disease. It has been claimed that 1-deprenyl exhibits neuroprotective and neurorescue effects in several animal models. The precise mechanism of these effects is unknown. It is yet to be established whether or not the effects are unique to 1-deprenyl; a drug which possesses, in addition to inhibition of MAO-B activity, an amphetamine moiety. Based on the fact that several N-methylpropargylamine derivatives have been shown to be MAO inhibitors and that aliphatic amines are typical MAO-B substrates with a high affinity for the enzyme, we have synthesized a series of aliphatic propargylamines which have turned out to be highly potent, selective and irreversible MAO-B inhibitors, structurally unrelated to amphetamine. The potency of these inhibitors is related to their chain length and the substitution of a hydrogen on the terminal carbon of the aliphatic chain. MAO-I activity, as assessed in vitro, increased as the aliphatic carbon chain length increased; substitution of the hydrogen at the aliphatic chain terminal by hydroxyl, carboxyl or carboethoxyl groups or replacement of the methyl group on the nitrogen atom by an ethyl group considerably reduced their inhibitory activity. Stereospecific effects were observed with the R-(-)-enantiomer being 20-fold more active than the S-(+)-enantiomer. Inhibitors with relatively short carbon chain lengths (i.e. four to six carbons) were found to be more potent at inhibiting brain MAO-B activity in vivo especially after oral administration. M-2-PP [N-methyl-N-(2-pentyl)-propargylamine] and 2-HxMP [N-(2-hexyl)-N-methyl-propargylamine], for example, are approximately 5 fold more potent and selective inhibitors of mouse brain MAO-B activity than 1-deprenyl after oral administration. Like 1-deprenyl, chronic low dose administration of the aliphatic propargylamines caused a slight cumulative inhibition of MAO-A activity in the mouse brain. These new inhibitors selectively inhibited MAO-B activity in vivo, i.e. they increased 2-phenylethylamine levels substantially, but did not affect the levels of dopamine, DOPAC, HVA, 5-HT and 5-HIAA. Both 2-HxMP and M-2-PP have been shown to be capable of protecting against MPTP-induced nigrostriatal dopamine depletion and against DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] induced noradrenaline depletion in the hippocampus of the mouse. These new aliphatic MAO-B inhibitors seem to be nontoxic and may be useful in the treatment of certain neuropsychiatric disorders.
KeywordsDopamine Noradrenaline Neurol Levodopa Lamines
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- 1.Birkmayer W, Knoll J, Riederer P and Youdim MBH (1983) (-)-Deprenyl leads to prolongation of 1-Dopa efficacy in Parkinson’s disease. Mod. Pbl. Pharmacopsychiatr.19: 170–176.Google Scholar
- 8.Tariot P. N., Cohen R. M., Sunderland T., Newhouse P. A., Yount D., Mellow A. M., Weingartner H., Mueller E. A. and Murphy D. L. (1987) L-Deprenyl in Alzheimer’s disease-preliminary evidence for behavioral change with monoamine oxidase B inhibition. Arch. Gen. Psychiatry 44: 427–433.PubMedCrossRefGoogle Scholar
- 14.Salo P. T. and Tatton W. G. (1991) Deprenyl reduces the death of motoneurons caused by axotomy. J. Neurosci. Res. 31: 394400.Google Scholar
- 17.Burn R. S., Chiueh C. C., Markey S. P., Ebert M. H., Jacobowitz D. M. and Kopin I. J. (1983) A primate model of Parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine. Proc. Natl. Acad. Sci. USA 80: 4546–4550.CrossRefGoogle Scholar
- 22.Ohta S., Kohno M., Makino Y., Tachikawa O. and Hirobe, M. (1987) Tetrahydroisoquinoline and 1-methyltetrahydroisoquinoline are present in the human brain: relation to parkinson’s disease. Biomed. Res. 8: 453–456.Google Scholar
- 23.John G, and Spina M. B. (1989) Deprenyl suppresses the oxidant stress associated with increased dopamine turnover. Amer. Neurol. Assoc. 26: 689–690.Google Scholar
- 24.Skibo G., Ahmed I., Yu P. H., Boulton A. A. and Fedoroff S. (1992) l-Deprenyl, a monoamine oxidase-B (MAO-B) inhibitor, acts on the astroglia cell cycle at the G1/G0 boundary. Am. Soc. Cell Biology.Google Scholar
- 26.Li X. M., Qi J., Juorio A. V. and Boulton A. A. Reduction in GFAP mRNA abundance induced by (-)-deprenyl and other MAO-B inhibitors in C6 glioma cells. J. Neurochem. (in press).Google Scholar
- 32.Yu, P. H. (1989) Deamination of aliphatic amines of different chain lengths by rat liver monoamine oxidase A and B. J. Pharm. Pharmacol. 41, 205–208.Google Scholar
- 33.Heinonen E. H., Myllyla V., Sotaniemi, K., Lammintausta, R., Salonen, J. S., Anttila, M., Savijarvi, M. and Rinne, U. K. (1989) Pharmacokinetics and metabolism of selegiline. Acta Neurol. Scand., 126: 93–99.Google Scholar
- 37.Yu P. H., Davis B. A and Boulton A. A. Effect of structural modification of alkyl N-propargylamines on the selective inhibition of monoamine oxidase B activity. Biochem. Phannacol. (in press).Google Scholar
- 38.Yu P. H., Davis B. A. and Boulton A. A. Neurochemical and neuroprotective effects of some aliphatic propargylamine MAO-B inhibitors. J. Neurochem. (in press).Google Scholar