title: Comparative studies of the effects of RS-8359 and safrazine on monoamine oxidase in-vitro and in-vivo in mouse brain.
abstract: The effect of RS-8359, pyrimidine on monoamine oxidase (MAO) has been compared with a hydrazinic MAO inhibitor, safrazine (beta-piperonylisopropylhydrazine hydrochloride,) which is a MAO inhibitor used clinically. In-vitro radiochemical determination of MAO activity showed that the IC50 of RS-8359 was 0.52 microM for the deamination of 5-hydroxytryptamine (5-HT) in the mouse brain mitochondrial preparation, while beta-phenylethylamine (PEA) deamination was inhibited by only 20% at 100 microM of the drug. 5-HT deamination in the brain homogenate prepared from mice killed 60 min after administration of RS-8359 was inhibited significantly by 14 and 48%, at 30 and 100 mg kg-1 (p.o.), respectively, while deamination of PEA was little affected at the same doses. On the other hand, safrazine strongly inhibited both 5-HT and PEA deaminations, but showed no selectivity toward the substrate used. The extent of MAO inhibition by RS-8359, measured fluorometrically with kynuramine as a substrate in the brain homogenate, was independent of preincubation up to 80 min. In contrast, the inhibitory potency of safrazine was strengthened by preincubation in a time-dependent manner. Oral administration of RS-8359 (3-30 mg kg-1) caused a dose-dependent increase in endogenous monoamines in mouse brain, which disappeared a few hours after its administration. Increase in monoamine content caused by safrazine lasted for at least 24 h. These results indicate that RS-8359 is a reversible and specific inhibitor of MAO-A, while safrazine is an irreversible and non-specific MAO inhibitor, in-vivo and in-vitro in mouse brain.
authors.affiliation: Biological Research Laboratories, Sankyo Co. Ltd., Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yokoyama
authors.forename: T
authors.initials: T
authors.lastname: Karube
authors.forename: N
authors.initials: N
authors.lastname: Iwata
mesh_terms: D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D004149:Dioxoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000201:enzymology; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013050:Spectrometry, Fluorescence; D013997:Time Factors
chemical_list: D015306:Biogenic Monoamines; D004149:Dioxoles; D008996:Monoamine Oxidase Inhibitors; D009570:Nitriles; D011743:Pyrimidines; C059590:RS 8359; C013242:safrazine