N-methylated tetrahydroisoquinolines as dopaminergic neurotoxins.
N-Methylation of dopamine-derived 6,7-dihydroxyisoquinolines produces compounds whose chemical structures are similar to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). N-Methylation of 1,2,3,4-tetrahydroisoquinoline was proved by in vitro experiments using human brain homogenate as an enzyme source. By in vivo microdialysis in rat brains, N-methylation of 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines (salsolinols) was also demonstrated. Among the brain regions examined, the activity of N-methylation was the highest in the substantia nigra. N-methyl-1,2,3,4-tetrahydroisoquinoline was oxidized to produce N-methyl-isoquinolinium ion by type A and type B monoamine oxidase prepared from human brain synaptosomal mitochondria. The structure of the oxidized isoquinoline is similar to that of 1-methyl-4-phenylpyridinium ion, a potent dopaminergic neurotoxin. These results indicate that these isoquinolines produced in or around dopamine neurons are N-methylated especially in substantia nigra and may be further oxidized by monoamine oxidase to produce ions. This biosynthesis pathway is quite similar to the oxidative synthesis of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. N-Methylation and oxidation of isoquinolines or other endogenous compounds may be involved in the pathogenesis of Parkinson's disease.
Naoi
M
M
Department of Biosciences, Nagoya Institute of Technology, Japan.
Dostert
P
P
Yoshida
M
M
Nagatsu
T
T
D000818:Animals; D001921:Brain / Q000201:enzymology*; D016923:Cell Death / Q000502:physiology; D046508:Culture Techniques; D004298:Dopamine / Q000502:physiology*; D006801:Humans; D007546:Isoquinolines / Q000493:pharmacokinetics*; D008745:Methylation; D008780:Methyltransferases / Q000502:physiology; D008995:Monoamine Oxidase / Q000502:physiology; D009410:Nerve Degeneration / Q000502:physiology; D010300:Parkinson Disease / Q000503:physiopathology; D051381:Rats; D011954:Receptors, Dopamine / Q000502:physiology; D013378:Substantia Nigra / Q000502:physiology; D044005:Tetrahydroisoquinolines
D007546:Isoquinolines; D011954:Receptors, Dopamine; D044005:Tetrahydroisoquinolines; C050386:1-methyl-1,2,3,4-tetrahydroisoquinoline; C014843:1,2,3,4-tetrahydroisoquinoline; C036617:salsolinol; D008995:Monoamine Oxidase; D008780:Methyltransferases; D004298:Dopamine