Stereoisomers of allenic amines as inactivators of monoamine oxidase type B. Stereochemical probes of the active site.
The kinetics of inactivation of mitochondrial monoamine oxidase type B (MAO-B) by a series of 18 stereoisomers of tertiary alpha-allenic amines have been investigated in detail. The chirality of the allene group in N-methyl-N-aralkylpenta-2,3-dienamines was found to have a profound effect on the inactivation rate, with the (R)-allenes being up to 200-fold more potent than their (S)-allenic counterparts. The ability of (S)-allenes to inactivate MAO was severely compromised by the presence of N-phenethyl or N-alpha-substituted-aralkyl substituents. The opposing chiralities in both the allene and aralkyl groups of (R,R)- and (S,S)-N-methyl-N-(1,2,3,4-tetrahydro-1-naphthyl)-penta-2,3-dienamine+ ++ resulted in a difference of more than 3 orders of magnitude in inactivation rates. The stereoselectivity of MAO-B was examined further with a series of reversible aralkylamine inhibitors; thus (R)-1,2,3,4-tetrahydro-1-naphthylamine was determined to be 150-fold more potent than its enantiomer.
Smith
R A
RA
Syntex Research, Canada, Mississauga, Ontario.
White
R L
RL
Krantz
A
A
D000475:Alkenes / Q000138:chemical synthesis / Q000494:pharmacology; D000588:Amines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D055598:Chemical Phenomena; D002621:Chemistry; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000475:Alkenes; D000588:Amines; D008996:Monoamine Oxidase Inhibitors