Aliphatic propargylamines, a new series of potent selective, irreversible non-amphetamine-like MAO-B inhibitors. Their structures, function and pharmacological implications.
1-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.(ABSTRACT TRUNCATED AT 250 WORDS)
Yu
P H
PH
Department of Psychiatry, University of Saskatchewan, Saskatoon, Canada.
Davis
B A
BA
Boulton
A A
AA
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors; D000661:Amphetamine; D000818:Animals; D051379:Mice; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010293:Pargyline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011437:Propylamines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D008996:Monoamine Oxidase Inhibitors; D011437:Propylamines; C082737:N-methyl-N-(2-pentyl)propargylamine; C094098:N-2-hexyl-N-methylpropargylamine; D010293:Pargyline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000661:Amphetamine