Aliphatic Propargylamines, a New Series of Potent Selective, Irreversible Non-Amphetamine-Like MAO-B Inhibitors

Their Structures, Function and Pharmacological Implications
  • Peter H. Yu
  • Bruce A. Davis
  • Alan A. Boulton
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 363)


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.


Aliphatic Amine Carbon Chain Length Terminal Carbon Parkinson Study Group High Acute Dose 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 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
  2. 2.
    Lieberman A. and Fazzini E. 1991 Experience with selegiline and levodopa in advanced Parkinson’s disease. Acta Neurol. Scand. 84Suppl. 136: 66–69.CrossRefGoogle Scholar
  3. 3.
    The Parkinson Study Group. (1989) Effect of deprenyl on the progression of disability in early Parkinson’s disease. New Engl. J. Med. 321: 1364–1371.CrossRefGoogle Scholar
  4. 4.
    he Parkinson Study Group (1993) Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. New Engl. J. Med. 328: 176–183.CrossRefGoogle Scholar
  5. 5.
    Tetrud J. W. and Langston J. W. (1989) The effect of deprenyl (selegiline) on the natural history of Parkinson’s disease. Science 245: 519–522.PubMedCrossRefGoogle Scholar
  6. 6.
    Allain H., Cougnard J., Neukirch H.C., the FMST members. (1991) Selegiline in de novo parkinsonian patients: The French selegiline multicenter trial (FSMT).Acta Neurol. Scand. 84 (Suppl.) 136: 73–78.CrossRefGoogle Scholar
  7. 7.
    Mangoni A., Grassi M. P., Frattola L., Piolti R., Brassi S., Motta A., Marcone A. and Smirne S. (1991) Effects of a MAO-B inhibitor in the treatment of Alzheimer disease. Eur. Neurol. 31: 100–107.PubMedCrossRefGoogle Scholar
  8. 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
  9. 9.
    Quitkin FM, Liebowitz MR, Stewart JW, McGrath P. J., Harrison W., Rabkin J. G., Markowitz J. and Davies S. O. (1984) l-Deprenyl in atypical depressives. Arch. Gen. Psychiatry41: 777–781.PubMedCrossRefGoogle Scholar
  10. 10.
    Knoll J., Dallo J. and Yen T. T. (1989) Striatal dopamine, sexual activity and lifespan longevity of rats treated with (-)-deprenyl. Life Sciences 45: 525–531.PubMedCrossRefGoogle Scholar
  11. 11.
    Birkmayer W., Knoll J., Riederer P., Hars V. and Marton J. (1985) Increased life expectancy resulting from addition of 1-deprenyl to Madopar treatment in Parkinson’s disease: A long term study. J. Neural Transm. 64: 113–127.PubMedCrossRefGoogle Scholar
  12. 12.
    Heikkila R. E., Hess A. and Duvoisin R. C. (1984) Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine in mice. Science 224: 1451–1453.PubMedCrossRefGoogle Scholar
  13. 13.
    Finnegan K. T., Skratt J. S., Irwin I., DeLanney L. E. and Langston J. W. (1990) Protection against DSP-4-induced neurotoxicity by deprenyl is not related to its inhibition of MAO-B. Eur. J. Pharmacol. 184: 119–126.PubMedCrossRefGoogle Scholar
  14. 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
  15. 15.
    Tatton W. G. and Greenwood C. E. (1991) Rescue of dying neurons: a new action for deprenyl in MPTP Parkinsonism. J. Neurosc. Res. 30: 666–672.CrossRefGoogle Scholar
  16. 16.
    Langston J. W., Ballard P. A., Tetrud J. W. and Irwin I. (1983) Chronic parkinsonism in human due to product of meperidine-analog synthesis. Science 219: 979–980.PubMedCrossRefGoogle Scholar
  17. 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
  18. 18.
    Langston J. W., Forno L. S., Rebert C. S. and Irwin I (1984) Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine in the squirrel monkey. Brain Res. 292: 390–394.PubMedCrossRefGoogle Scholar
  19. 19.
    Davis G. C., Williams A. C., Markey S. P., Evert M. H., Caine E. D., Reichert C. M. and Kopin I. J. (1979) Chronic Parkinsonism secondary to intravenos injection of meperidine analogues. Psychiat. Res. 1: 249–254.CrossRefGoogle Scholar
  20. 20.
    Chiba K., Trevor A. and Catagnoli N. Jr. (1984) Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem. Biophys. Res. Comm. 120: 574–578.PubMedCrossRefGoogle Scholar
  21. 21.
    Snyder S. H. and D’Amato R. J. (1986) MPTP: a neurotoxin relevant to the pathophysiology of Parkinson’s diasease. Neurology 36: 250–258.PubMedCrossRefGoogle Scholar
  22. 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. 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. 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
  25. 25.
    Li X. M., Juorio A. V., Paterson I. A., Zhu M. Y. and Boulton A. A. (1992) Specific irreversible monoamine oxidase B inhibitors stimulate gene expression of aromatic 1-amino acid decarboxylase in PC 12 cells. J. Neurochem. 59: 2324–2327.PubMedCrossRefGoogle Scholar
  26. 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
  27. 27.
    De Varebeke P. J., Cavalier R., David-Remacle M. and Youdim M. B. H. (1988) Fonnation of the neurotransmitter glycine from the anticonvulsant milacemide is mediated by brain monoamine oxidase-B. J. Neurochem. 50: 1011–1016.CrossRefGoogle Scholar
  28. 28.
    van Dorsser W., Barris D., Cordi A. and Roba J. (1983) Anticonvulsant activity of milacemide. Arch. Int. Pharmacodyn. 266, 239–249.PubMedGoogle Scholar
  29. 29.
    Handelmann G. E., Nevins M. E., Mueller L. L., Arnolde S. M. and Cordi A. A. (1989) Milacemide, a glycine prodrug, enhances performance of learning tasks in normal and amnestic rodents. Pharmacol. Biochem. Behav. 34, 823–828.PubMedCrossRefGoogle Scholar
  30. 30.
    Yu, P. H. and Davis, B. A. 2-Propyl-1-aminopentane, its deamination by monoamine oxidase and semicarbazide-sensitive amine oxidase, conversion to valproic acid and behavioral effects. Neuropharmacology 30 (1991) 507–515.PubMedCrossRefGoogle Scholar
  31. 31.
    Yu, P. H. and Davis, B. A. Simultaneous delivery of valproic acid and glycine to the brain; deamination of 2-propylpentylglycinamide by monoamine oxidase B. Mol. Chem. Neuropathol. 15 (1991) 37–49.CrossRefGoogle Scholar
  32. 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. 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
  34. 34.
    Langston J. W. (1990) Selegiline as neuroprotective therapy in Parkinson’s disease: concepts and controversies. Neurology 40 (Suppl.): 61–66.PubMedGoogle Scholar
  35. 35.
    Yu P. H., Davis B. A. and Boulton A. A. (1992) Aliphatic propargylamines: potent selective irreversible monoamine oxidase B inhibitors. J. Med. Chem. 35: 3705–3713.PubMedCrossRefGoogle Scholar
  36. 36.
    Robinson B. J. (1985) Stereoselectivity and isozyme selectivity of monoamine oxidase inhibitors: enantiomers of amphetamine, N-methylamphetamine and deprenyl. Biochem. Phannacol. 34: 4105–4108.CrossRefGoogle Scholar
  37. 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. 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

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • Peter H. Yu
    • 1
  • Bruce A. Davis
    • 1
  • Alan A. Boulton
    • 1
  1. 1.Neuropsychiatric Research Unit Department of PsychiatryUniversity of SaskatchewanSaskatoonCanada

Personalised recommendations