Deuterium Isotope Effects in Relation to the Chemical Mechanism of Monoamine Oxidase*

Belleau, B.; Moran, Joseph

doi:10.1111/j.1749-6632.1963.tb13326.x

Cited by 90 publications

(8 citation statements)

References 38 publications

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“…2). A CYD bond is more difficult to cleave than a CYH bond so that the rate of a reaction that involves breaking a specific CYH bond in the rate limiting step will be reduced [42]. This is called the deuterium isotope effect.…”

Section: Imaging Maomentioning

confidence: 99%

Translational Neuroimaging: Positron Emission Tomography Studies of Monoamine Oxidase

et al. 2005

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Positron emission tomography (PET) using radiotracers with high molecular specificity is an important scientific tool in studies of monoamine oxidase (MAO), an important enzyme in the regulation of the neurotransmitters dopamine, norepinephrine, and serotonin as well as the dietary amine, tyramine. MAO occurs in two different subtypes, MAO A and MAO B, which have different substrate and inhibitor specificity and which are different gene products. The highly variable subtype distribution with different species makes human studies of special value. MAO A and B can be imaged in the human brain and certain peripheral organs using PET and carbon-11 (half-life 20.4 minutes) labeled mechanism-based irreversible inhibitors, clorgyline and L -deprenyl, respectively. In this article we introduce MAO and describe the development of these radiotracers and their translation from preclinical studies to the investigation of variables affecting MAO in the human brain and peripheral organs.

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Section: Imaging Maomentioning

confidence: 99%

Translational Neuroimaging: Positron Emission Tomography Studies of Monoamine Oxidase

et al. 2005

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“…The magnitude of this primary isotope effect was found to be in the range of 2, indicating that the rate of oxidative deamination of dopamine by MAO is twice as slow when the α-carbon is deuteriated. Secondary isotope effects in the MAO catalyzed reaction were also observed following substitution of the second hydrogen at the α-carbon in the dopamine molecule (Yu et al, 1986) and following β-substitutions in the kynuramine molecule (Belleau and Moran, 1963). The conversion of dopamine to noradrenaline involves the cleavage of a C-H bond and the introduction of a hydroxyl group at the β-carbon, a reaction catalyzed by the enzyme dopamine β-hydroxylase (DβH) (see Figure 6).…”

Section: In Vitro Isotope Effects On Dopamine Metabolism and Conversimentioning

confidence: 99%

Deuterium substitutions in the L-DOPA molecule improve its anti-akinetic potency without increasing dyskinesias

Malmlöf

Rylander

Alken³

et al. 2010

Experimental Neurology

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“…One is the formation of the lactam, M12 (Erickson et al, 2007). Initial oxidation by MAO leads to the formation of an imine (Belleau and Moran, 1963); the enzyme responsible for further oxidation to the lactam has not been delineated. The other main pathway is oxidation of the methyl group, via M2, to the …”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, Disposition, and Metabolism of Bicifadine in the Mouse, Rat, and Monkey

Musick¹,

Gohdes²,

Duffy³

et al. 2008

Drug Metabolism and Disposition

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ABSTRACT:Bicifadine [DOV 220,075; (؎)-1-(4-methylphenyl)-3-azabicyclo[3.1.0]-hexane HCl)] is a non-narcotic analgesic that is effective in animal models of acute and chronic pain. In this study, the pharmacokinetics, disposition, and metabolism of bicifadine were determined in male and female mice, rats, and cynomolgus monkeys following single oral and i.v. doses. [ 14 C]Bicifadine was well absorbed in all three species. The oral bioavailability of bicifadine in mice and rats was 50 to 63% and 79 to 85%, respectively, and slightly lower in monkeys (33-42%). Based on the values of the area under the concentration-time curves, unchanged bicifadine comprised 7 to 12% of the plasma radioactivity after the oral dose and 14 to 26% after the i.v. dose in all three species. The major plasma metabolites were the lactam (M12), the lactam acid (M9), and the acid (M3) plus its glucuronide conjugate. At 0.5 h after the oral dose to rats, 63 to 64% of the radioactivity in the rat brain was bicifadine, and the remainder was the lactam. Most of the radioactivity after oral and i.v. dosing to the three species was recovered in the urine. The lactam acid was the major urinary metabolite in all species; bicifadine and the lactam were either not detected or were minor components in urine. Fecal radioactivity was due to the acid and lactam acid in the three species. Rat bile contained mainly the lactam acid and the acid plus its acyl glucuronide. Plasma protein binding of [ 14 C]bicifadine was moderate in the mouse (80-86%) and higher in the rat and monkey (95-97%). In summary, bicifadine was well absorbed, extensively metabolized, and excreted via the urine and feces as metabolites.Bicifadine (Fig. 1) is an inhibitor of norepinephrine and serotonin uptake that is being developed for the treatment of acute and chronic pain. The compound is a non-narcotic analgesic (Epstein et al., 1982) that is active in preclinical models of neuropathic pain. In animals, bicifadine has been shown to inhibit dopamine uptake, thus making it a functional triple reuptake inhibitor with antinociceptive and antiallodynic activity in acute, persistent, and chronic pain models (Basile et al., 2007). Clinically, it has been shown to be effective in the treatment of acute dental (Stern et al., 2005) and bunionectomy pain (Riff et al., 2006).The metabolites of bicifadine formed by mouse, rat, monkey, and human hepatocytes and microsomes were reported previously (Erickson et al., 2007). The two main metabolic pathways in all four species were formation of a lactam and the oxidation of the tolylmethyl group. When tested in human in vitro systems, MAO-B was the principal enzyme that formed the lactam, whereas CYP2D6 was responsible for the initial hydroxylation of the tolylmethyl group. The present studies were performed to determine the pharmacokinetics, metabolism, and disposition of bicifadine in the mouse, rat, and monkey, the species used in toxicological and carcinogenicity studies. Materials and MethodsChemicals and Reagents. [ Animal Studies. All experim...

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Deuterium Isotope Effects in Relation to the Chemical Mechanism of Monoamine Oxidase*

Cited by 90 publications

References 38 publications

Translational Neuroimaging: Positron Emission Tomography Studies of Monoamine Oxidase

Translational Neuroimaging: Positron Emission Tomography Studies of Monoamine Oxidase

Deuterium substitutions in the L-DOPA molecule improve its anti-akinetic potency without increasing dyskinesias

Pharmacokinetics, Disposition, and Metabolism of Bicifadine in the Mouse, Rat, and Monkey

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