Mechanism of inactivation of monoamine oxidase-B by the anticonvulsant agent milacemide (2-(n-pentylamino)acetamide)

Silverman, Richard B.; Nishimura, Kuniko; Lu, Xincheng

doi:10.1021/ja00065a001

Cited by 16 publications

(11 citation statements)

References 2 publications

(2 reference statements)

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“…These results were consistent with reports from earlier studies that showed stereospecific conversion of only the S-(-2 H)-deuteroamines (Belleau et al, 1960;Belleau and Moran, 1963;Battersby et al, 1979;Yu and Davis, 1988). Mechanistic studies on MAO catalyzed deamination suggest C-H bond cleavage to be a requisite and rate determining step in the oxidation process (Belleau et al, 1960;Yu et al, 1986;Yu and Davis, 1988;Ottoboni et al, 1989;Silverman et al, 1993;Edmondson et al, 2004;Edmondson et al, 2007;Orru et al, 2013). While three mechanisms for C-H bond cleavage have been proposed (Edmondson et al, 2007;Edmondson et al, 2009;Vianello et al, 2012), the exact mechanism for oxidation of RP101075 is unknown.…”

Section: Discussionsupporting

confidence: 91%

Investigation into MAO B–Mediated Formation of CC112273, a Major Circulating Metabolite of Ozanimod, in Humans and Preclinical Species: Stereospecific Oxidative Deamination of (S)-Enantiomer of Indaneamine (RP101075) by MAO B

et al. 2021

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Ozanimod, recently approved for treating relapsing MS, produced a disproportionate, active, MAO B-catalyzed metabolite (CC112273) that showed remarkable interspecies differences and led to challenges in safety testing. This study explored the kinetics of CC112273 formation from its precursor RP101075. Incubations with human liver mitochondrial fractions revealed K Mapp , V max and Cl int for CC112273 formation to be 4.8 M, 50.3 pmol/min/mg protein and 12 l/min/mg, respectively, while K M with human recombinant MAO B was 1.1 M. Studies with liver mitochondrial fractions from preclinical species led to K Mapp , V max and Cl int estimates of 3.0, 35 and 33 M, 80.6, 114, 37.3 pmol/min/mg and 27.2, 3.25 and 1.14 l/min/mg in monkey, rat and mouse, respectively, and revealed marked differences between rodents and primates, primarily attributable to differences in the K M . Comparison of Cl int estimates revealed monkey to be ~two-fold more efficient and the mouse and rat to be 11 and 4-fold less efficient than humans in CC112273 formation. The influence of stereochemistry on MAO B-mediated oxidation was also investigated using the R-isomer of RP101075 (RP101074). This showed marked selectivity towards catalysis of the S-isomer (RP101075) only. Docking into MAO B crystal structure suggested that even though both the isomers occupied its active site, only the orientation of RP101075 presented the C-H on the -carbon that was ideal for the C-H bond cleavage, which is a requisite for oxidative deamination. These studies explain the basis for the observed interspecies differences in the metabolism of ozanimod as well as the substrate stereospecificity for formation of CC112273.

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Section: Discussionsupporting

confidence: 91%

Investigation into MAO B–Mediated Formation of CC112273, a Major Circulating Metabolite of Ozanimod, in Humans and Preclinical Species: Stereospecific Oxidative Deamination of (S)-Enantiomer of Indaneamine (RP101075) by MAO B

et al. 2021

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“…Results of this study show that most of the synthesized compounds are potent and selective inhibitors of MAO-A rather than of MAO-B. [6][7][8][9]34] For the QSAR study to target MAO enzyme selection of series is based on IC 50 value. The ratio of Maximum and minimum IC50 value should be ≥ 1000.…”

Section: -Phenoxyacetamidementioning

confidence: 99%

A QSAR study of some Phenoxyacetamide derivatives as a MAO-A inhibitor

Bais¹,

Yadav²,

Mafidar³

et al. 2018

IJRDPL

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Available online on:15.01.2018@http://ijrdpl.com http://dx.doi.org/10.21276/IJRDPL. 2278-0238.2018.7(1).2931-2940 ABSTRACT: Antidepressants are the most prescribed therapy for depression. The prevailing theory is that antidepressants increase the concentration of one or more brain chemicals (neurotransmitters) that nerves in the brain use to communicate with one another.The neurotransmitters affected by antidepressants are norepinephrine, serotonin, and dopamine. In order to address the need for new MAO inhibitors with less side effects, we can aim compounds previously discovered for their potential as MAOIs. Among them, safinamide was reported to be a potent anti-MAO B agent, and milacemide, which was found to be a potent MAO inhibitor and a prodrug for glycine. The present work deals with the aim because Currentely available MAO inhibitors {Isocarboxazid (Marplan), Phenelzine (Nardil), Selegiline (Emsam), Tranylcypromine (Parnate) etc} develop side effects because they do not selectively for MAO-A and MAO-B. So, the present study is focused to develop potent selective MAO-A inhibitors, to treat depression, that may be of better pharmacological activity with less adverse effect.

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“…In order to address the need for new MAO inhibitors with fewer side effects, our group evaluated compounds previously discovered for their potential as MAOIs. Among them, we found safinamide, which was reported to be a potent anti-MAO B agent, and milacemide, which was found to be a potent MAO inhibitor and a prodrug for glycine [9,10]. Of note, both compounds possess an acetamide group (Figure 1), prompting us to hypothesize that acetamide might play an important role in inhibition of MAO activities.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of 2-Phenoxyacetamide Analogues, a Novel Class of Potent and Selective Monoamine Oxidase Inhibitors

Shen

Zhang

et al. 2014

Molecules

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Monoamine oxidases (EC 1.4.3.4; MAOs), a family of FAD-containing enzymes, is an important target for antidepressant drugs. In this paper, a series of 2-phenoxyacetamide analogues were synthesized, and their inhibitory potency towards monoamine oxidases A (MAO-A) and B (MAO-B) were evaluated using enzyme and cancer cell lysate. 2-(4-Methoxyphenoxy)acetamide (compound 12) (SI = 245) and (2-(4-((prop-2-ynylimino)methyl)phenoxy)acetamide (compound 21) (IC50MAO-A = 0.018 μM, IC50MAO-B = 0.07 μM) were successfully identified as the most specific MAO-A inhibitor, and the most potent MAO-A/-B inhibitor, respectively. The inhibitory activities of these two compounds in living cells were also further evaluated utilizing HepG2 and SHSY-5Y cell lysates.

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Mechanism of inactivation of monoamine oxidase-B by the anticonvulsant agent milacemide (2-(n-pentylamino)acetamide)

Cited by 16 publications

References 2 publications

Investigation into MAO B–Mediated Formation of CC112273, a Major Circulating Metabolite of Ozanimod, in Humans and Preclinical Species: Stereospecific Oxidative Deamination of (S)-Enantiomer of Indaneamine (RP101075) by MAO B

Investigation into MAO B–Mediated Formation of CC112273, a Major Circulating Metabolite of Ozanimod, in Humans and Preclinical Species: Stereospecific Oxidative Deamination of (S)-Enantiomer of Indaneamine (RP101075) by MAO B

A QSAR study of some Phenoxyacetamide derivatives as a MAO-A inhibitor

Synthesis and Biological Evaluation of 2-Phenoxyacetamide Analogues, a Novel Class of Potent and Selective Monoamine Oxidase Inhibitors

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