A new class of powerful inhibitors of monoamine oxidase A

Jin, Yuan-Zhen; Ramsay, Rona R.; Youngster, Stephen K.; Singer, Thomas P.

doi:10.1016/0006-291x(90)91596-k

Cited by 5 publications

(4 citation statements)

References 13 publications

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“…The inhibition of MAO B is therefore expressed as IC50 at 30 °C in the presence of 0.1 mM benzylamine in Table II. While 18 and 19 proved to be ineffective inhibitors of MAO B, as is true of most other MPP+ analogs (Youngster et al, 1989a;Jin et al, 1990), 17 was surprisingly potent with an IC50 value of 12 µ . This is in accord with the low Km value of 14, the parent tetra- hydropyridine for MAO B (Table I).…”

Section: Resultsmentioning

confidence: 98%

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Interaction of flexible analogs of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and of N-methyl-4-phenylpyridinium with highly purified monoamine oxidase A and B

Krueger¹,

Efange²,

Michelson³

et al. 1992

Biochemistry

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Sixteen analogs of N-methyl-1,2,3,6-tetrahydropyridine (MPTP) of varying degrees of flexibility have been studied as substrates of highly purified monoamine oxidases (MAO) A and B. The relative effectiveness of the various tetrahydropyridines as substrates of MAO A and B were evaluated in terms of the function turnover number/Km, as determined by initial rate measurements. The insertion of a methylene bridge between the phenyl and tetrahydropyridine moieties of MPTP to yield N-methyl-4-benzyl-1,2,3,6-tetrahydropyridine, rendering the molecule more flexible, greatly enhances reactivity with MAO B, but not with MAO A, as compared with MPTP itself, in accord with data in the literature (Youngster et al., 1989a). The ethylene-bridged MPTP analog, on the other hand, is a far better substrate of both forms of MAO than is MPTP itself. The effect of molecular flexibility on the rate of oxidation of these compounds is obscured by substituents on the aromatic ring. Branching and rigidity were detrimental to the activity as substrates of both forms of MAO. Those analogs of 1 which contain small electron-withdrawing substituents in the phenyl ring were found to be more selective for MAO B, while those substituted with bulky groups were selectively oxidized by MAO A. The substrate binding site of MAO A probably contains a lipophilic pocket larger than that found in a similar site in MAO B.

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Section: Resultsmentioning

confidence: 98%

“…do-irreversible inhibitors of MAO A and B, while their dihydropyridinium and pyridinium oxidation products proved to be potent reversible inhibitors of MAO A but not of MAO B (Salach et al, 1984;Singer et al, 1985Singer et al, ,1986Tipton et al, 1986;Krueger et al, 1990;Jin et al, 1990).…”

mentioning

confidence: 99%

Interaction of flexible analogs of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and of N-methyl-4-phenylpyridinium with highly purified monoamine oxidase A and B

Krueger¹,

Efange²,

Michelson³

et al. 1992

Biochemistry

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“…In an attempt to assess whether MAO-A regulates neuronal cell death, we first investigated changes in MAO-A activity and levels when mitochondrial dysfunction was induced by ETC inhibitors. Rotenone was used as the complex I inhibitor, because it is a pesticide that has been linked to the occurrence of PD (36); MPP ϩ could not be used because it has an inhibitory effect on MAO (37). Human SH-SY5Y neuroblastoma cells were used as the cellular model since they contain only MAO-A and have neuronal characteristics (3).…”

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confidence: 99%

Monoamine oxidase‐A knockdown in human neuroblastoma cells reveals protection against mitochondrial toxins

Fitzgerald

Ugun-Klusek²,

Allen

et al. 2013

FASEB j.

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The study examined how the mitochondrial enzyme monoamine oxidase-A (MAO-A), which produces hydrogen peroxide as a catalytic by-product, influences death and survival mechanisms. Targeted microRNA (miRNA) was used to stably knock down MAO-A mRNA, protein, and catalytic activity by 60-70% in SH-SY5Y human neuroblastoma cells. The effects of MAO-A knockdown (KD) on ATP, oxidative stress, electron transport chain, and survival following exposure to mitochondrial toxins were assessed. In control cells, complex I inhibition resulted in caspase-mediated cell death linked with ROS production and reduced ATP, followed by up-regulation of MAO-A mRNA, protein, and enzyme activity levels. Inhibition of complex III and IV resulted in a similar increase in MAO-A expression, while up-regulation of MAO-A was lower following complex II inhibition. MAO-A KD decreased basal reactive oxygen species levels by 50% and increased levels of ATP and reduced glutathione and Bcl-2. MAO-A KD specifically increased the activity of complex I but had no effect on complex II-IV activities. Furthermore, MAO-A KD protected against inhibitors of complex I, III, and IV. In summary, endogenous MAO-A levels influence mitochondrial function, notably complex I activity, and MAO-A may be a target for protection against neurodegenerative conditions that involve oxidative stress and mitochondrial dysfunction as underlying pathogenic factors.

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“…The order of MAO-A inhibition is MPDP + > MPP + > MPTP. SAR studies on MPP + analogues revealed that alkyl, alkoxy or halogen groups on the 2-or 3-or 4-positions on the C-4 phenyl ring of MPP + were more potent and selective MAO-A inhibitors than MPP + itself (235). That charged compounds such as MPDP + and MPP + are potent and selective MAO-A inhibitors indicates that MAO-A, but not MAO-B, may contain negatively charged residues for ion-pairing to the positively charged nitrogen in these compounds.…”

Section: H-indeno[12-c]pyridazinesmentioning

confidence: 99%

Interactions of Nitrogen-Containing Xenobiotics with Monoamine Oxidase (MAO) Isozymes A and B: SAR Studies on MAO Substrates and Inhibitors

Kalgutkar

Dalvie

Castagnoli

et al. 2001

Chem. Res. Toxicol.

197

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A new class of powerful inhibitors of monoamine oxidase A

Cited by 5 publications

References 13 publications

Interaction of flexible analogs of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and of N-methyl-4-phenylpyridinium with highly purified monoamine oxidase A and B

Interaction of flexible analogs of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and of N-methyl-4-phenylpyridinium with highly purified monoamine oxidase A and B

Monoamine oxidase‐A knockdown in human neuroblastoma cells reveals protection against mitochondrial toxins

Interactions of Nitrogen-Containing Xenobiotics with Monoamine Oxidase (MAO) Isozymes A and B: SAR Studies on MAO Substrates and Inhibitors

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