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.

Functional Analysis of Aldehyde Oxidase Using Expressed Chimeric Enzyme between Monkey and Rat

“…14-18) The compound is a reversible and selective monoamine oxidase (MAO)-A inhibitor 19,20) and has been developed as an anti-depressant. 21,22) As to species differences, monkeys showed the highest activity followed by humans.…”

“…Similar to those reports, we observed remarkable species differences, rat strain differences, and polymorphism-based individual differences in Donryu strain rat in the AO-catalyzed 2-oxidation activity of the (S)-enantiomer of RS-8359, [(Ϯ)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]-pyrimidine]. [14][15][16][17][18] The compound is a reversible and selective monoamine oxidase (MAO)-A inhibitor 19,20) and has been developed as an anti-depressant. 21,22) As to species differences, monkeys showed the highest activity followed by humans.…”

Genetic Polymorphism of Aldehyde Oxidase in Donryu Rats

“…RS-8359 is a reversible and selective monoamine oxidase type A (MAO-A) inhibitor (Yokoyama et al, 1989;Miura et al, 1993), which has been developed as an antidepressant Puchler et al, 1997). One of the major metabolic pathways of RS-8359 is aldehyde oxidase-catalyzed 2-oxidation on the pyrimidine ring to give the 2-keto metabolite, which is preferential in rats, monkeys, and humans .…”

Novel Monoamine Oxidase Inhibitors, 3-(2-Aminoethoxy)-1,2-benzisoxazole Derivatives, and Their Differential Reversibility

“…Male ddY mice weighing 30 -35 g from SLC (Shizuoka) were used to obtain brain mitochondria, following our previously reported method (6,7). Animals were housed in our temperature-and humidity-controlled animal quarters with free access to food and water for more than 1 week before use.…”