1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine analogs. Inactivation of monoamine oxidase by conformationally rigid analogs of N,N-dimethylcinnamylamine

• Published in: Journal of medicinal chemistry 1988-08, Vol.31 (8), p.1566-1570
• Main Authors: Hiebert, Charles K, Silverman, Richard B
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Chemical Phenomena; Chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; In Vitro Techniques; Kinetics; Liver - drug effects; Liver - enzymology; Monoamine Oxidase Inhibitors - chemical synthesis; N,N-dimethylcinnamylamine; Organic chemistry; Preparations and properties; Propylamines - chemical synthesis; Propylamines - pharmacology; Pyridines - chemical synthesis; Pyridines - pharmacology; Rats
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00403a013

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent neurotoxin and also an inactivator of monoamine oxidase (MAO). Since MPTP is a conformationally rigid analogue of N,N-dimethylcinnamylamine, other conformationally rigid analogues of N,N-dimethylcinnamylamine were synthesized and tested as inhibitors and inactivators of MAO. (E)-2-(Phenylmethylene)cyclohexanamine (5a), (E)-N,N-dimethyl-2-(phenylmethylene)cyclohexanamine (5b), 3-phenyl-2-cyclohexen-1-amine (6a), N,N-dimethyl-3-phenyl-2-cyclohexen-1-amine (6b), and (E)- and (Z)-N-methyl-3-(phenylmethylene)piperidine (7 and 8) are all inhibitors and time-dependent inactivators of MAO B, but none is as potent as MPTP. alpha-Methylation and methylation of the amino group in all cases increases the Ki value relative to that for the parent compound. Compounds 5a, 5b, 6a and 6b are highly cytotoxic, but cytotoxicity is not prevented by pretreatment of the cells with pargyline. There does not appear to be a correlation between the configuration of the N,N-dimethylcinnamylamine analogue and its potency as a MAO inactivator.