4-(O-benzylphenoxy)-N-methylbutylamine (bifemelane) and other 4-(O-benzylphenoxy)-N-methylalkylamines as new inhibitors of type A and B monoamine oxidase.
4-(O-Benzylphenoxy)-N-methylbutylamine (Bifemelane, BP-N-methylbutylamine), a new psychotropic drug, was found to inhibit monoamine oxidase (MAO) in human brain synaptosomes. It inhibited type A MAO (MAO-A) competitively and type B (MAO-B) noncompetitively. BP-N-methylbutylamine had a much higher affinity to MAO-A than an amine substrate, kynuramine, and it was a more potent inhibitor of MAO-A than of MAO-B. The Ki values of MAO-A and -B were determined to be 4.20 and 46.0 microM, respectively, while the Km values of MAO-A and -B with kynuramine were 44.1 and 90.0 microM, respectively. The inhibition of MAO-A and -B by BP-N-methylbutylamine was found to be reversible by dialysis of the incubation mixture. MAO-A in human placental and liver mitochondria and in a rat clonal pheochromocytoma cell line, PC12h, was inhibited competitively by BP-N-methylbutylamine, while MAO-B in human liver mitochondria was inhibited noncompetitively, as in human brain synaptosomes. BP-N-methylbutylamine was not oxidized by MAO-A and -B. The effects of other BP-N-methylalkylamines, such as BP-N-methylethylamine, -propylamine, and -pentanylamine, on MAO activity were examined. BP-N-methylbutylamine was the most potent inhibitor of MAO-A, and BP-N-methylethylamine and -propylamine inhibited MAO-B competitively, whereas BP-N-methylbutylamine and -pentanylamine inhibited it noncompetitively. Inhibition of these BP-N-methylalkylamines on MAO-A and -B is discussed in relation to their chemical structure.
Naoi
M
M
Department of Biochemistry, Nagoya University School of Medicine, Japan.
Nomura
Y
Y
Ishiki
R
R
Suzuki
H
H
Nagatsu
T
T
D000310:Adrenal Gland Neoplasms / Q000201:enzymology; D000818:Animals; D000928:Antidepressive Agents; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001667:Binding, Competitive; D001921:Brain / Q000201:enzymology; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D006801:Humans; D007735:Kynuramine / Q000378:metabolism; D008930:Mitochondria, Liver / Q000201:enzymology; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010673:Pheochromocytoma / Q000201:enzymology; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D051381:Rats; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000201:enzymology; D014407:Tumor Cells, Cultured
D000928:Antidepressive Agents; D001559:Benzhydryl Compounds; D008996:Monoamine Oxidase Inhibitors; D007735:Kynuramine; D008995:Monoamine Oxidase; C031906:bifemelane