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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)

Abstract

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.

Keywords

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.

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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

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