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In the human brain, monoamine-derived 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines and 1,2,3,4-tetrahydroisoquinolines have been identified and their enzymatic methylation into N(2)-methylisoquinolines has been also confirmed. N-methylated 6,7-dihydroxyisoquinolines were found to be oxidized into 6,7-dihydroxy-N-methylisoquinolinium ions. The effects of the isoquinolinium ions on type A and B monoamine oxidase were examined, using enzyme samples isolated from human brain synaptosomal mitochondria. 1,2-Dimethyl-6,7-dihydroxyisoquinolinium ion (N-methylsalsolinium ion) and 2-methyl-6,7-dihydroxyisoquinolinium ion (N-methylnorsalsolinium ion), were found to be potent inhibitors of type A monoamine oxidase. The inhibition was competitive to the substrate, while the isoquinolinium ions were much weaker inhibitors of type B and the inhibition was non-competitive to the substrate. Isoquinolinium ions without catechol structure, N(2)-methylisoquinolinium ion and 1,2-dimethylisoquinolinium ion also inhibited both type A and B monoamine oxidase. 1,2-Dimethylisoquinolinium was the most potent inhibitor among examined isoquinolines, followed by the N-methylsalsolinium ion. The activity-structure relationship of the isoquinolines with and without catechol structure was examined in terms of potency and selectivity of inhibition to type A and B monoamine oxidase. Catechol structure was found to increase the selectivity of inhibition to type A, as shown by comparison of N-methylsalsolinium ion with 1,2-dimethylisoquinolinium ion. N-Methylsalsolinium ion inhibited type A MAO more selectively than 1,2-dimethylisoquinolinium ion, which inhibited type A and type B with almost the sam values of the inhibitor constant.(ABSTRACT TRUNCATED AT 250 WORDS)
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