Stereochemical studies on the novel monoamine oxidase B substrates (1R,6S)- and (1S,6R)-3-methyl-6-phenyl-3-aza-bicyclo[4.1.0]heptane

Bissel, Philippe; Khalil, Ashraf; Rimoldi, John M.; Igarashi, Kazuo; Edmondson, Dale E.; Miller, Anthony G.; Castagnoli, Neal

doi:10.1016/j.bmc.2008.02.014

Cited by 6 publications

(3 citation statements)

References 33 publications

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“…The main supporting evidence for the hemolytic one-electron mechanism is the observation that MAO A or MAO B is inactivated by cyclopropylamine analogues with subsequent ring opening, a reaction characteristic of radical reactions. Recent studies of the MAO B-catalyzed oxidation of “Rimoldi’s Amine”, which consists of a cyclopropyl group fused to an N -methylpyridinium ring, show the cyclic imine formation to occur without opening of the cyclopropyl ring (Scheme ) which would be expected if the reaction were to involve radical intermediates. In the aggregate, these studies do not support the concept that the mechanism of amine oxidation in MAO is initiated by a hemolytic single-electron transfer step.…”

Section: Mechanistic Studies On Mao Catalysismentioning

confidence: 99%

“…hemolytic one-electron mechanism is the observation that MAO A or MAO B is inactivated by cyclopropylamine analogues with subsequent ring opening, a reaction characteristic of radical reactions. Recent studies of the MAO B-catalyzed oxidation of "Rimoldi's Amine", which consists of a cyclopropyl group fused to an N-methylpyridinium ring, show the cyclic imine formation to occur without opening of the cyclopropyl ring (Scheme 5)(71) …”

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confidence: 99%

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Molecular and Mechanistic Properties of the Membrane-Bound Mitochondrial Monoamine Oxidases

et al. 2009

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The last decade has brought major advances in our knowledge of the structures and mechanisms of MAO A and MAO B, which are pharmacological targets for specific inhibitors. In both enzymes, crystallographic and biochemical data show their respective C-terminal transmembrane helices anchor the enzymes to the outer mitochondrial membrane. Pulsed EPR data show both enzymes are dimeric in their membrane-bound forms with agreement between distances measured in their crystalline forms. Distances measure between active-site directed spin labels in membrane preparations show excellent agreement with those estimated from crystallographic data. Our knowledge of requirements for development of specific reversible MAO B inhibitors is in a fairly mature status. Less is known regarding the structural requirements for highly specific reversible MAO A inhibitors. In spite of their 70% sequence identity and similarities of Cα-folds, the two enzymes exhibit significant functional and structural differences that can be exploited in the ultimate goal of the development of highly specific inhibitors. This review summarizes the current structural and mechanistic information available that can be utilized in the development of future highly specific neuroprotectants and cardioprotectants.

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Section: Mechanistic Studies On Mao Catalysismentioning

confidence: 99%

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confidence: 99%

Molecular and Mechanistic Properties of the Membrane-Bound Mitochondrial Monoamine Oxidases

et al. 2009

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“…39,40 It is closely related to paroxetine as the azabicycloheptane derivatives have been recently designed as potent and selective triple reuptake inhibitors, 41,42 and the same heterocyclic moiety has been described as important in monoamine oxidase substrates. 43 The cyclodehydration pathway 5 → 9 couples the elimination of water to the formation of an azetidine ring system (Scheme 2). The dehydration reaction with azetidine ring closure occurs in a number of pharmaceuticals based on aminoalcohol substructures, [44][45][46] including the tropanederived paroxetine analogs, 47 which supports the proposal that a similar mechanism can be expected in the paroxetine metabolite III.…”

Section: Cyclodehydration Reactions Ofmentioning

confidence: 99%

The chemical fate of paroxetine metabolites. Dehydration of radicals derived from 4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine

et al. 2013

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Quantum chemical calculations have been used to model reactions which are important for understanding the chemical fate of paroxetine-derived radicals in the environment. In order to explain the experimental observation that the loss of water occurs along the ( photo)degradation pathway, four different mechanisms of radical-induced dehydrations have been considered. The elimination of water from the Ncentered radical cation, which results in the formation of an imine intermediate, has been calculated as the most feasible process. The predicted energy barrier (ΔG # 298 = 98.5 kJ mol −1 ) is within the barrier limits set by experimental measurements. All reaction intermediates and transition state structures have been calculated using the G3(MP2)-RAD composite procedure, and solvent effects have been determined using a mixed (cluster/continuum) solvation model. Several new products, which comply with the available experimental data, have been proposed. These structures could be relevant for the chemical fate of antidepressant paroxetine, but also for biologically and environmentally related substrates.

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Humane Enzyme für die organische Synthese

et al. 2018

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Humane Enzyme wurden im Rahmen vieler Disziplinen untersucht. Die Anzahl an Reaktionen, die im menschlichen Körper stattfinden, ist enorm, ebenso wie die Anzahl möglicher Katalysatoren für eine Anwendung in der organischen Synthese. Dieser Aufsatz befasst sich mit chemischen Reaktionen humaner Enzyme, die eine Rolle im Metabolismus von Wirkstoffen oder Xenobiotika spielen. Einige dieser Reaktionen wurden im präparativen Maßstab untersucht. Der größte Teil an Anwendungen von humanen Enzymen stammt aus dem Bereich der Wirkstoffentwicklung, wo sie zur Synthese von Wirkstoffmetaboliten eingesetzt werden.

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Stereochemical studies on the novel monoamine oxidase B substrates (1R,6S)- and (1S,6R)-3-methyl-6-phenyl-3-aza-bicyclo[4.1.0]heptane

Cited by 6 publications

References 33 publications

Molecular and Mechanistic Properties of the Membrane-Bound Mitochondrial Monoamine Oxidases

Molecular and Mechanistic Properties of the Membrane-Bound Mitochondrial Monoamine Oxidases

The chemical fate of paroxetine metabolites. Dehydration of radicals derived from 4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine

Humane Enzyme für die organische Synthese

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