Neurotoxicity studies with the monoamine oxidase B substrate 1-methyl-3-phenyl-3-pyrroline

Ogunrombi, Modupe; Malan, Sarel F.; Terre’Blanche, Gisella; Castagnoli, Kay; Castagnoli, Neal; Bergh, Jacobus J.; Petzer, Jacobus P.

doi:10.1016/j.lfs.2007.06.014

Cited by 7 publications

(3 citation statements)

References 34 publications

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“…The low levels and detectability of MPTP only at early time points are in agreement with the findings of other investigators (Hammock et al 1989; Giovanni et al 1991; Giuseppe et al 2003; Ogunrombi et al 2007). In fact, only one other investigator was able to measure MPTP after 30 min (Ogunrombi et al 2007), and reported peak concentrations of MPTP occurred at 10 min following injection, falling to nearly undetectable levels at 30 min. Therefore, it is reasonable to assume that the inability to measure MPTP at later time points in the present study is due to its rapid metabolism.…”

Section: Discussionsupporting

confidence: 92%

Liquid chromatographic–electrospray mass spectrometric determination of 1-methyl-4-phenylpyridine (MPP⁺) in discrete regions of murine brain

Lehner

Johnson

Simkins

et al. 2010

Toxicology Mechanisms and Methods

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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is widely used as a neurotoxin in several models of Parkinson’s disease in mice. MPTP is metabolized to 1-methyl-4-phenylpyridinium (MPP+), which is a mitochondrial toxicant of central dopamine (DA) neurons. There are species, strain, and age differences in sensitivity to MPTP. Simultaneous measurement of the MPTP active metabolite MPP+ and dopamine (DA) in the brain would be helpful in mechanistic studies of this neurotoxin. The objective of this study was to develop a liquid chromatography–mass spectrometry (LC/MS) method for analysis of MPTP and MPP+ in brain tissue and correlate these in the same sample with changes in DA measured via HPLC coupled with electrochemical detection. Twenty-five C57BL/6J7 8-week old female mice were used in the study. Mice were given a single subcutaneous injection of MPTP (20 mg/kg) and were sacrificed 1, 2, 4, or 8 h later. Zero time control mice received an injection of 0.9% normal saline (10 ml/kg) and were killed 1 h later. Brains were rapidly harvested and quickly frozen, and microdissected brain regions were placed in 0.1 M phosphate-citric acid buffer containing 20% methanol (pH 2.5). A new LC/MS method was successfully developed that utilized selected reaction monitoring (SRM) of MPP+ m/z 170→127, 170→128, and 170→154 fragmentation for quantitation and area ratios (m/z 127)/(m/z 128) and (m/z 154)/(128) for identity confirmation. A similar SRM strategy from m/z 174 was unable to detect any significant levels of MPTP down to 0.4 ppb. According to this method, MPP+ was detected in the nucleus accumbens (NA) and the striatum (ST), with the levels in the NA being 3-times higher than those in the ST. The advantage of this approach is that the tissue buffer used in this procedure allowed concurrent measurement of striatal DA, thus enabling direct correlation between accumulation of tissue MPP+ and depletion of DA concentrations in discrete regions of the brain.

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Section: Discussionsupporting

confidence: 92%

Liquid chromatographic–electrospray mass spectrometric determination of 1-methyl-4-phenylpyridine (MPP⁺) in discrete regions of murine brain

Lehner

Johnson

Simkins

et al. 2010

Toxicology Mechanisms and Methods

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“…1), a metabolite of melatonin, 15 is a substrate for both MAO-A and B and used in in vitro MAO assays. 16 The substrate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 17 is converted into a neurotoxin by MAO-B 18 and has been explored as a scaffold for the synthesis of other MAO-substrates including 1-methyl-3-phenyl-2,5-dihydro-1Hpyrrole, 19,20 2-methylisoindolines, 19 4-(1-methyl-1H-pyrrol-2-yl)-1-(prop-2-yn-1-yl)piperidine, 21 3,4-cyclopropyl analogs of MPTP 22 as well as 1-methyl-3-phenylpyrrolidine and the 3,4-cyclopropyl analogs hereof 23 (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Profiling substrate specificity of two series of phenethylamine analogs at monoamine oxidase A and B

Heuson¹,

Storgaard²,

Huynh³

et al. 2014

Org. Biomol. Chem.

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The membrane bound enzyme monoamine oxidase exist in two splice variants designated A and B (MAO-A and MAO-B) and are key players in the oxidative metabolism of monoamines in mammalians. Despite their importance and being a prevalent target for the development of inhibitors as drugs, no systematic study of substrate specificity has been reported. In this study we present a systematic study of the MAO-A and MAO-B substrate specificity profile by probing two series of phenethylamine analogs. Km and kcat values were determined for four N-alkyl analogs 2-5 and four aryl halide analogs 6-9 at MAO-A and MAO-B. A following in silico study disclosed a new adjacent compartment to the MAO-B substrate pocket defined by amino acids Tyr188, Tyr435, Tyr398, Thr399, Cys172 and Gly434. This new insight is important for the understanding of the substrate specificity of the MAO-B enzyme and will be relevant for future drug design within the field of monoamines.

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“…16 Moreover, the corresponding 3-arylpyrroles act as reversible competitive inhibitors of monoamine oxidase B. 17 Besides the aforementioned HBrpromoted rearrangement of 2-aryl-2-vinylaziridines, 13c ring-closing metathesis (RCM), 18 Suzuki coupling reactions, 19 ring contraction of 4-aryl-1,2,5,6-tetrahydropyridines, 20 and dehydration of 3-aryl-3-pyrrolidinols, 16d,21 have also been reported as alternative methods for the preparation of 3-aryl-3-pyrrolines.…”

mentioning

confidence: 99%

Synthesis of 3-Aryl-3-pyrrolines and 3-Arylpyrroles via Spontaneous Rearrangement of N-Sulfinyl 2-Aryl-2-vinylaziridines

Leemans¹,

Colpaert²,

Mangelinckx³

et al. 2011

Synlett

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Addition of vinylmagnesium bromide across chiral achloro N-tert-butanesulfinyl ketimines afforded 3-aryl-1-(tert-butanesulfinyl)-3-pyrrolines in high yield (65-91%) after purification by means of recrystallization from diethyl ether. The synthesis of these 3-aryl-3-pyrrolines is explained by initial formation of 2-aryl-2-vinylaziridines which spontaneously rearrange via carbon-nitrogen bond cleavage to form stabilized 1,3-dipolar intermediates which in turn ring closed to 3-pyrrolines.

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Neurotoxicity studies with the monoamine oxidase B substrate 1-methyl-3-phenyl-3-pyrroline

Cited by 7 publications

References 34 publications

Liquid chromatographic–electrospray mass spectrometric determination of 1-methyl-4-phenylpyridine (MPP⁺) in discrete regions of murine brain

Liquid chromatographic–electrospray mass spectrometric determination of 1-methyl-4-phenylpyridine (MPP⁺) in discrete regions of murine brain

Profiling substrate specificity of two series of phenethylamine analogs at monoamine oxidase A and B

Synthesis of 3-Aryl-3-pyrrolines and 3-Arylpyrroles via Spontaneous Rearrangement of N-Sulfinyl 2-Aryl-2-vinylaziridines

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Neurotoxicity studies with the monoamine oxidase B substrate 1-methyl-3-phenyl-3-pyrroline

Cited by 7 publications

References 34 publications

Liquid chromatographic–electrospray mass spectrometric determination of 1-methyl-4-phenylpyridine (MPP+) in discrete regions of murine brain

Liquid chromatographic–electrospray mass spectrometric determination of 1-methyl-4-phenylpyridine (MPP+) in discrete regions of murine brain

Profiling substrate specificity of two series of phenethylamine analogs at monoamine oxidase A and B

Synthesis of 3-Aryl-3-pyrrolines and 3-Arylpyrroles via Spontaneous Rearrangement of N-Sulfinyl 2-Aryl-2-vinylaziridines

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Liquid chromatographic–electrospray mass spectrometric determination of 1-methyl-4-phenylpyridine (MPP⁺) in discrete regions of murine brain

Liquid chromatographic–electrospray mass spectrometric determination of 1-methyl-4-phenylpyridine (MPP⁺) in discrete regions of murine brain