RS 8359
(Synonyms: 4-(7-羟基-6,7-二氢-5H-环戊烷并[D]嘧啶-4-基氨基)苯甲腈) 目录号 : GC31024RS8359是一种选择性的,可逆的MAO-A抑制剂,具有抗抑郁的功效。
Cas No.:105365-76-2
Sample solution is provided at 25 µL, 10mM.
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RS 8359 is a selective and reversible MAO-A inhibitor, with antidepressant activity.
RS 8359 shows relatively little effect upon blood pressure when administered together with tyramine. RS-8359 shows little affinity for the common central nervous system receptors and little anticholinergic effect[1].
[1]. Iwata N, et al. Pharmacology of the new reversible inhibitor of monoamine oxidase A, RS-8359. Int Clin Psychopharmacol. 1997 Sep;12 Suppl 5:S3-10.
Cas No. | 105365-76-2 | SDF | |
别名 | 4-(7-羟基-6,7-二氢-5H-环戊烷并[D]嘧啶-4-基氨基)苯甲腈 | ||
Canonical SMILES | OC1C2=NC=NC(NC3=CC=C(C#N)C=C3)=C2CC1 | ||
分子式 | C14H12N4O | 分子量 | 252.27 |
溶解度 | DMSO : 50 mg/mL (198.20 mM; ultrasonic and warming and heat to 80°C) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 3.964 mL | 19.82 mL | 39.6401 mL |
5 mM | 0.7928 mL | 3.964 mL | 7.928 mL |
10 mM | 0.3964 mL | 1.982 mL | 3.964 mL |
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RS 8359
Comparative studies of the effects of RS-8359 and safrazine on monoamine oxidase in-vitro and in-vivo in mouse brain
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.
Chiral inversion of RS-8359: a selective and reversible MAO-A inhibitor via oxido-reduction of keto-alcohol
RS-8359, (+/-)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]-pyrimidine is a selective and reversible MAO-A inhibitor. The (S)-enantiomer of RS-8359 has been demonstrated to be inverted to the (R)-enantiomer after oral administration to rats. In the current study, we investigated the chiral inversion mechanism and the properties of involved enzymes using rat liver subcellular fractions. The 7-hydroxy function of RS-8359 was oxidized at least by the two different enzymes. The cytosolic enzyme oxidized enantiospecifically the (S)-enantiomer with NADP as a cofactor. On the other hand, the microsomal enzyme catalyzed more preferentially the oxidation of the (S)-enantiomer than the (R)-enantiomer with NAD as a cofactor. With to product enantioselectivity of reduction of the 7-keto derivative, it was found that only the alcohol bearing (R)-configuration was formed by the cytosolic enzyme with NADPH and the microsomal enzyme with NADH at almost equal rate. The reduction rate was much larger than the oxidation rate of 7-hydroxy group. The results suggest that the chiral inversion might occur via an enantioselectivity of consecutive two opposing reactions, oxidation and reduction of keto-alcohol group. In this case, the direction of chiral inversion from the (S)-enantiomer to the (R)-enantiomer is governed by the enantiospecific reduction of intermediate 7-keto group to the alcohol with (R)-configuration. The enzyme responsible for the enantiospecific reduction of the 7-keto group was purified from rat liver cytosolic fractions and identified as 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) via database search of peptide mass data obtained by nano-LC/MS/MS.
Species differences in enantioselective 2-oxidations of RS-8359, a selective and reversible MAO-A inhibitor, and cinchona alkaloids by aldehyde oxidase
The 2-oxidation activity on the pyrimidine ring of RS-8359, a MAO-A inhibitor, is the major metabolic pathway catalysed by aldehyde oxidase. This study investigated the species differences in the 2-oxidation activity by using liver cytosolic fractions from rats, mice, guinea-pigs, rabbits, dogs, monkeys and humans. The Vmax/Km value for the (S)-enantiomer of RS-8359 was extremely high in monkeys and humans, moderate in guinea-pigs, and low in rats and mice. Dogs were deficient in 2-oxidation activity. The (R)-enantiomer was only oxidized at a very low rate in guinea-pigs, monkeys and humans, and not oxidized in rats, mice and rabbits. Thus, marked species differences and enantioselectivity were obvious for the 2-oxidation of the (S)-enantiomer of RS-8359. The in vitro results were in good accordance with previously reported in vivo excretion data of the 2-keto metabolite and the non-detectable plasma concentrations of the (S)-enantiomer in monkeys and humans after administration of racemic RS-8359. Enantioselectivity was also observed for the oxidation of cinchona alkaloids catalysed by aldehyde oxidase. Among the four cinchona alkaloids studied, the oxidation activity of cinchonidine, which has no substituents at the 6-hydroxy group but bears (8S,9R)-configurations, was highest. As opposed to the (S)-enantiomer, an extremely high catalytic activity of cinchonidine was confirmed in rabbits, but not in monkeys or humans. Rabbit liver aldehyde oxidase was suggested to have characteristic properties around the active site.
Stereospecific oxidation of the (S)-enantiomer of RS-8359, a selective and reversible monoamine oxidase A (MAO-A) inhibitor, by aldehyde oxidase
In a previous paper by the authors on RS-8359, a new selective and reversible monoamine oxidase A (MAO-A) inhibitor, it was reported that the (S)-enantiomer of RS-8359 is rapidly eliminated from rats, monkeys and humans as a result of the formation of a 2-oxidative metabolite. The present study investigates the properties of the enzyme responsible for the 2-oxidation of RS-8359. Subcellular localization, cofactor requirement and the inhibitory effects of typical compounds were studied using rat liver preparations. In addition, the enzyme was purified from rat liver cytosol for further characterization. The enzyme activity was localized in the cytosolic fraction without the need for any cofactor and was extensively inhibited by menadione, chlorpromazine and quinacrine. The purified enzyme was also a homodimer with a monomeric molecular weight of 140 kDa and it had an A280/A450 ratio of 5.1 in the absorption spectrum. The results suggest that the enzyme responsible for the biotransformation of RS-8359 to give the 2-keto derivative is aldehyde oxidase (EC 1.2.3.1). The reaction of aldehyde oxidase is highly stereoselective for the (S)-configuration of RS-8359 and the (9R)-configuration of cinchona alkaloids.