The comparative effects of single and multiple doses of RS-8359, moclobemide and placebo on psychomotor function in healthy subjects

Puechler, K.; Schaffler, K.; Wauschkuhn, C H; Plenker, A.

doi:10.1016/0924-977x(96)83010-0

Cited by 4 publications

(5 citation statements)

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“…RS-8359 is a racemic compound with a reversible and selective inhibitory activity against MAO-A [1-4] and has been developed as an antidepressant [5,6]. Previous metabolic studies on RS-8359 revealed that one of the major metabolic pathways is the stereoselective 2-oxidation of the (S)-enantiomer of RS-8359 catalysed by aldehyde oxidase [7,9].…”

Section: Discussionmentioning

confidence: 99%

“…RS-8359, [ðAEÞ-4-(4-cyanoanilino)-5,6-dihydro-7hydroxy-7H-cyclopenta[d]-pyrimidine], is a reversible MAO-A inhibitor with a weak inhibitory effect of about one two-thousandth against MAO-B [1][2][3][4], and has been developed as an antidepressant [5,6]. MAO-A inhibitory activity is reported to exist mainly in the (R)-enantiomer of that compound [4].…”

Section: Introductionmentioning

confidence: 99%

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Rat strain differences in stereospecific 2‐oxidation of RS‐8359, a reversible and selective MAO‐A inhibitor, by aldehyde oxidase

Sasaki

Masubuchi

Yamamura

et al. 2006

Biopharm & Drug Disp

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Aldehyde oxidase catalysed 2-oxidation activity of the (S)-enantiomer of RS-8359, a selective and reversible monoamine oxidase A (MAO-A) inhibitor, was investigated in liver cytosolic fractions from ten rat strains. Remarkably large strain differences were observed with approximately a 230 variation between the highest activity in the Wistar-Imamichi strain and the lowest activity in the Slc:Wistar strain. The activities of Crj:SD and Slc:SD strain rats were considerably low, and that of the F344/DuCrj strain was very low. Among six Wistar strains, Crj:Wistar, Slc:Wistar, WKY/Izm, WKAH/Hkm, Jcl:Wistar and Wistar-Imamichi, the Slc:Wistar strain rats showed exceptionally low 2-oxidation activity that was comparable to that of the F344/DuCrj strain. The rat strain differences in the catalytic activity of aldehyde oxidase could correlate in part with the expressed levels of protein based on the mRNA of aldehyde oxidase. However, no small discrepancy existed in the almost negligible catalytic activity and the fairly high expression levels of protein and mRNA in the F344/DuCrj and Slc:Wistar strain rats. Some genetic factors might possibly be one of reasons for the discrepancy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rat strain differences in stereospecific 2‐oxidation of RS‐8359, a reversible and selective MAO‐A inhibitor, by aldehyde oxidase

Sasaki

Masubuchi

Yamamura

et al. 2006

Biopharm & Drug Disp

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show abstract

“…RS-8359, [(AE)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]-pyrimidine], is a reversible, selective MAO-A inhibitor (Miura et al 1993;Yokoyama et al 1989) and has been developed as an antidepressant Puchler et al 1997). One of the major metabolic pathways of RS-8359 is the AO-catalyzed 2-oxidation on the pyrimidine ring to give the 2-keto metabolite .…”

Section: Introductionmentioning

confidence: 99%

Lack of dimer formation ability in rat strains with low aldehyde oxidase activity

et al. 2007

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Aldehyde oxidase (AO) is a homodimer with a molecular weight of 300 kDa. To clarify the reasons for the well-known differences in rat strains, we set out to study the relationship between AO activity and the expression levels of its dimer. AO-catalyzed 2-oxidation activity of (S)-RS-8359 was measured in liver cytosols from ten rat strains. The expression levels of AO dimeric protein were evaluated by the native-PAGE/Western blot. Rat strains with low AO activity showed only a monomer, whereas strains with high activity overwhelmingly exhibited a dimer. Exceptionally, one strain in the high AO activity group displayed complex mixed expression patterns of low and high AO activity groups. However, there was a good relationship between AO activity and the expression levels of a dimer, but not of a monomer. The results suggest that rat strains with low AO activity lack the ability to produce a dimer necessary for catalytic activity, and AO differences in rat strains should be discussed in terms of the expression levels of the dimer itself.

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“…Clinical studies showed that RS-8359 might improve cognitive performance that is often impaired in major depressive disorders. 8 Further, the drug did not result in an elevation of blood pressure when given with tyramine-rich food, the so-called ''cheese'' effect associated with nonselective inhibition of both monoamine oxidase subtypes. 9 The main metabolic pathways of RS-8359 were proposed from structure analyses of NMR and MS spectra of the isolated urinary metabolites (Fig.…”

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confidence: 99%

Stereoselective pharmacokinetics of RS‐8359, a selective and reversible MAO‐A inhibitor, by species‐dependent drug‐metabolizing enzymes

et al. 2005

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RS-8359, (+/-)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]pyrimidine selectively and reversibly inhibits monoamine oxidase A (MAO-A). After oral administration of rac-RS-8359 to rats, mice, dogs, monkeys, and humans, plasma concentrations of the (R)-enantiomer were greatly higher than were those of the (S)-enantiomer in all species studied. The AUC((R)) to AUC((S)) ratios were 2.6 in rats, 3.8 in mice, 31 in dogs, and 238 in monkeys, and the (S)-enantiomer was almost negligible in human plasma. After intravenous administration of RS-8359 enantiomers to rats, the pharmacokinetic parameters showed that the (S)-enantiomer had a 2.7-fold greater total clearance (CL(t)) and a 70% shorter half-life (t(1/2)) than those for the (R)-enantiomer but had no difference in distribution volume (V(d)). No significant difference in the intestinal absorption rate was observed. The principal metabolites were the 2-keto form, possibly produced by aldehyde oxidase, the cis-diol form, and the 2-keto-cis-diol form produced by cytochrome P450 in rats, the cis-diol form in mice, RS-8359 glucuronide in dogs, and the 2-keto form in monkeys and humans. Thus, the rapid disappearance of the (S)-enantiomer from the plasma was thought to be due to the rapid metabolism of the (S)-enantiomer by different drug-metabolizing enzymes, depending on species.

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The comparative effects of single and multiple doses of RS-8359, moclobemide and placebo on psychomotor function in healthy subjects

Cited by 4 publications

References 0 publications

Rat strain differences in stereospecific 2‐oxidation of RS‐8359, a reversible and selective MAO‐A inhibitor, by aldehyde oxidase

Rat strain differences in stereospecific 2‐oxidation of RS‐8359, a reversible and selective MAO‐A inhibitor, by aldehyde oxidase

Lack of dimer formation ability in rat strains with low aldehyde oxidase activity

Stereoselective pharmacokinetics of RS‐8359, a selective and reversible MAO‐A inhibitor, by species‐dependent drug‐metabolizing enzymes

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