Inhibitors of Monoamine Oxidase VI: Effects of Substitution on Inhibitory Activity of 6(or 8)-Substituted β-Carbolines

Abstract

A number of 6(or 8)-substituted aromatic β-carbolines were synthesized, and their inhibitory activities toward monoamine oxidase were compared with their tetrahydro congeners. A considerable difference in the effects of 6(or 8)-substitution on the inhibitory activities existed between these aromatic and tetrahydro-β-carbolines. Influence of 9-methyl substitution on activities was greater with the tetrahydro than the aromatic series; as a result, 9-methyltetrahydro-β-carbolines were generally much better inhibitors of the enzyme than the corresponding 9-hydrogen-tetrahydro-β-carbolines. An amino group at C1 of β-carboline caused a fivefold decrease in inhibitory activity. This decrease was likely due to the steric hindrance by the bulk of the amino group. Aromatic β-carbolines were prepared by the palladium-on-charcoal catalyzed dehydrogenation of the corresponding tetrahydro-β-carbolines. Methylation of the N9 of aromatic β-carboline was carried out with methyl iodide in the presence of sodium hydride. Nitration of β-carboline gave a mixture of two isomeric products, 6- and 8-nitro-β-carbolines, which were separated with hot chloroform. Catalytic reduction converted the nitro compounds to 6- and 8-amino-β-carbolines, respectively. The positions of the amino group was confirmed by NMR spectrometry.