Monoamine Oxidase Inhibitory Properties of Some Methoxylated and Alkylthio Amphetamine Derivatives

Scorza, Ma.Cecilia; Carrau, Cecilia; Silveira, Ricardo dos Reis; Zapata‐Torres, Gerald; Cassels, Bruce K.; Reyes‐Parada, Miguel

doi:10.1016/s0006-2952(97)00405-x

Cited by 86 publications

(95 citation statements)

References 34 publications

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“…The uptake of methamphetamine into dopaminergic neurons is facilitated by DAT (30). Once inside monoaminergic neurons, methamphetamine inhibits monoamine oxidase (31), promotes flux reversal of DAT, and induces DA efflux from vesicles into the cytosol and then the extracellular compartment (32,33). All these changes lead to a rapid increase in extracellular DA (34).…”

Section: Discussionmentioning

confidence: 99%

The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway

Cui

Aras

Christian

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

185

170

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Toxic organic cations can damage nigrostriatal dopaminergic pathways as seen in most parkinsonian syndromes and in some cases of illicit drug exposure. Here, we show that the organic cation transporter 3 (Oct3) is expressed in nondopaminergic cells adjacent to both the soma and terminals of midbrain dopaminergic neurons. We hypothesized that Oct3 contributes to the dopaminergic damage by bidirectionally regulating the local bioavailability of toxic species. Consistent with this view, Oct3 deletion and pharmacological inhibition hampers the release of the toxic organic cation 1-methyl-4-phenylpyridinium from astrocytes and protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration in mice. Furthermore, Oct3 deletion impairs the removal of the excess extracellular dopamine induced by methamphetamine and enhances striatal dopaminergic terminal damage caused by this psychostimulant. These results may have far-reaching implications for our understanding of the mechanism of cell death in a wide range of neurodegenerative diseases and may open new avenues for neuroprotective intervention.astrocytes ͉ Parkinson's disease ͉ extraneuronal monoamine transporter ͉ dopamine ͉ methamphetamine

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Section: Discussionmentioning

confidence: 99%

The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway

Cui

Aras

Christian

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

185

170

View full text Add to dashboard Cite

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“…Inside dopaminergic neurons, methamphetamine induces dopamine release from the synaptic vesicles into the cytosol (Sulzer et al 1995) where it is reversely transported by the dopamine transporter into the synaptic cleft (Sulzer et al 1993). Through these actions, in combination with blocking dopamine degradation by monoamine oxidase (Scorza et al 1997), methamphetamine induces dramatic release of dopamine into extracellular space. In vivo microdialysis experiments demonstrate that this release peaks within 1 h after systemic injection (Clausing and Bowyer 1999;Kita et al 2000;Cui et al 2009), leading to acute behavioral changes such as increased locomotor activity (Ricaurte et al 1994;Segal and Kuczenski 1994).…”

Section: Amphetaminesmentioning

confidence: 99%

A Guide to Neurotoxic Animal Models of Parkinson's Disease

Tieu¹

2011

Cold Spring Harbor Perspectives in Medicine

400

299

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Parkinson's disease (PD) is a neurological movement disorder primarily resulting from damage to the nigrostriatal dopaminergic pathway. To elucidate the pathogenesis, mechanisms of cell death, and to evaluate therapeutic strategies for PD, numerous animal models have been developed. Understanding the strengths and limitations of these models can significantly impact the choice of model, experimental design, and data interpretation. The primary objectives of this article are twofold: First, to assist new investigators who are contemplating embarking on PD research to navigate through the available animal models. Emphasis will be placed on common neurotoxic murine models in which toxic molecules are used to lesion the nigrostriatal dopaminergic system. And second, to provide an overview of basic technical requirements for assessing the pathology, structure, and function of the nigrostriatal pathway.

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“…9-11 Structure-activity relationship (SAR) studies, including quantitative analyses (QSAR), [10][11][12] have shown that the presence of electron-donating, unbranched, alkylthio substituents at the para position of the aromatic ring of the amphetamine scaffold generate potent and selective MAO-A inhibitors. In addition, a few studies have shown that the (S)-isomers of substituted amphetamines (which are always dextrorotatory) are the eutomers.…”

Section: Introductionmentioning

confidence: 99%

Human and rat monoamine oxidase-A are differentially inhibited by (S)-4-alkylthioamphetamine derivatives: Insights from molecular modeling studies

Fierro

Osorio

Cassels

et al. 2007

Bioorganic & Medicinal Chemistry

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Four enantiomerically pure (S)-4-alkylthioamphetamine derivatives were evaluated as monoamine oxidase (MAO) inhibitors using the human and rat isoforms of the enzyme. Molecular dockings were performed in order to gain insights regarding the binding mode of these inhibitors. All compounds were potent and selective MAO-A inhibitors although different rank orders of potencies were observed against the enzymes from different species. This behavior can be rationalized on the basis of different binding modes to each enzyme, as determined in silico. These findings further support the concept that MAO inhibitory activity of novel compounds, determined with enzymes from diverse mammalian species, should be considered with caution if human MAO is the final target to be addressed.

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Monoamine Oxidase Inhibitory Properties of Some Methoxylated and Alkylthio Amphetamine Derivatives

Cited by 86 publications

References 34 publications

The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway

The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway

A Guide to Neurotoxic Animal Models of Parkinson's Disease

Human and rat monoamine oxidase-A are differentially inhibited by (S)-4-alkylthioamphetamine derivatives: Insights from molecular modeling studies

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