Dopamine uptake inhibitory capacities of β-carboline and 3,4-dihydro-β-carboline analogs of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) oxidation products

Drucker, George E.; Raikoff, Kiril; Neafsey, Edward J.; Collins, Michael A.

doi:10.1016/0006-8993(90)90318-6

Cited by 76 publications

(38 citation statements)

References 22 publications

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“…The 2-MeDH3Cs and 2-Mef3Cs other than 2-methylharmine (all in Fig. 1) were synthesized as iodide salts from the desmethyl compounds as described (10). The iodide salt of 2,9-Me2Nh was from L. Meyerson of Shaman Pharmaceuticals (San Carlos, CA) and also was synthesized in our laboratory by K. Matsubara by sequential reaction of norharman with methyl iodide.…”

Section: Methodsmentioning

confidence: 99%

“…Intrigued by the structural overlap between MPP+ and indole-derived p-carboline (,8C) compounds that are methylated (quaternized) on the 2-nitrogen (2-Mef3Cs), we and others (5-9) have hypothesized possible neurotoxic roles for 2-MeBCs in Parkinson disease. Endogenous biosynthetic pathways can be envisioned for 2-MepC formation from indoleamines or even tryptophan (10).…”

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confidence: 99%

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Mitochondrial respiratory inhibition by N-methylated beta-carboline derivatives structurally resembling N-methyl-4-phenylpyridine.

Albores

Neafsey

Drucker

et al. 1990

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

111

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Mitochondrial accumulation and respiratory inhibition are critical steps in the actions of N-methyl-4-phenylpyridinium ion (MPP+), the toxic metabolite of the parkinsonism-inducing agent, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We examined the respiratory characteristics of 2-methylated fi-carbolines (2-MejBCs) and 2-methylated 3,4-dihydro-f3-carbolines (2-MeDHIBCs), which encompass the MPP+ structure. As indoleamine derivatives, they could have endogenous roles in idiopathic parkinsonism. With rat liver mitochondria, the order for inhibition of NAD'-linked 02 consumption (6-min preincubations) was as follows: MPP+ = 2-methylharmine > 2-methylharmol = 2-methylharmaline >> 2-methylharmalol > 2-methylnorharman > 6-OH-2-methyiharmalan >> 2-methylharman. Similar to MPP+, 2-MeDHI3C/2-MePC inhibition was potentiated by tetraphenylboron and reversed by dinitrophenol, consistent with the involvement of cationic forms. However, the participation of neutral forms was indicated by the 2-MeDHfiC/2-MeBC inhibitory time courses, which were unlike MPP+. The neutral forms probably arise via indolic nitrogen deprotonation because the characteristics of a cationic .-carboline that cannot N-deprotonate, 2,9-dimethylnorharman, mirrored MPP+ rather than 2-MeCs. Succinate-supported respiration was also significantly blocked by 2-MeDHI3Cs/2-MefiCs, but results with tetraphenylboron and 2,9-dimethylnorharman indicated that cationic forms were less important than in the inhibition of NAD+-linked respiration. We suggest that the relatively potent inhibition by certain 2-MeDHI3Cs/2-MeIJCs involves neutral forms for passive mitochondrial entry and cationic as well as neutral forms that act at several respiratory sites. Respiratory inhibition could reasonably underlie the reported neurotoxicity of 2-MefiCs.Interest in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a street drug contaminant that selectively destroys nigrostriatal cells, has stimulated investigations of environmental or endogenous toxins that might be associated with idiopathic parkinsonism (1, 2). An oxidation product of MPTP, N-methyl-4-phenylpyridine (MPP+), is believed to be the species that exerts neurotoxicity by inhibiting the mitochondrial respiratory chain at site I (NADH dehydrogenase) (3,4). Intrigued by the structural overlap between MPP+ and indole-derived p-carboline (,8C) compounds that are methylated (quaternized) on the 2-nitrogen (2-Mef3Cs), we and others (5-9) have hypothesized possible neurotoxic roles for 2-MeBCs in Parkinson disease. Endogenous biosynthetic pathways can be envisioned for 2-MepC formation from indoleamines or even tryptophan (10).Although ,BCs and their hydrogenated derivatives (3,4-dihyro-,BCs; DHPCs) have been studied extensively (see Discussion), little is known about the toxic capabilities of their N-methylated analogs. Hoppel et al. (8) noted that the ,BC, 2-methylharmine, was an effective mitochondrial respiratory inhibitor, and we now present results showing that several 2-MeDHfC/2-Mef3C isomers with 7-oxygenat...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Mitochondrial respiratory inhibition by N-methylated beta-carboline derivatives structurally resembling N-methyl-4-phenylpyridine.

Albores

Neafsey

Drucker

et al. 1990

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

111

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“…It was proposed that environmental or endogenously generated toxins could account for this, and several candidate toxins were considered (28,44,47,73,77,86,89,104). No potential toxic agent, though, seemed able to generate sustained enthusiasm.…”

Section: Swerdlowmentioning

confidence: 99%

Does Mitochondrial DNA Play a Role in Parkinson's Disease? A Review of Cybrid and Other Supportive Evidence

Swerdlow

2012

Antioxidants & Redox Signaling

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Significance: Mitochondria are currently believed to play an important role in the neurodysfunction and neurodegeneration that underlie Parkinson's disease (PD). Recent Advances: While it increasingly appears that mitochondrial dysfunction in PD can have different causes, it has been proposed that mitochondrial DNA (mtDNA) may account for or drive mitochondrial dysfunction in the majority of the cases. If correct, the responsible mtDNA signatures could represent acquired mutations, inherited mutations, or population-distributed polymorphisms. Critical Issues and Future Directions: This review discusses the case for mtDNA as a key mediator of PD, and especially focuses on data from studies of PD cytoplasmic hybrid (cybrid) cell lines. Antioxid. Redox Signal. 16, 950-964.

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“…14.6 ~nlnol) in DMF (20 mL) and under an argon atmosphere. (Caution: various 3,4-dihydro-P-carbolines and 3,4-dihydro-2-methyl-P-carbolinium salts have recently been implicated in provoking the neuronal degeneration underlying idiopathic Parkinson's disease (27).) The mixture was stirred for 30 nmin and then cooled to -60°C at which time p-toluenesulfonyl chloride (3.15 g. 16.5 mmol) was added.…”

Section: (I's)-3-[1'-0-(s-mtpa)etl~yl]-4-rr1etlr~lpyridi1ze (9)mentioning

confidence: 99%

Total synthesis and establishment of the absolute stereochemistry of (+)-mostueine. Addition of chiral nucleophiles to 3,4-dihydro-2-methyl-9-(p-toluenesulfonyl)-β-carbolinium iodide

Rey¹,

Szarek²,

MacLean³

1992

Can. J. Chem.

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A highly convergent synthesis of the pentacyclic indole alkaloid (+)-mostueine (1) is described. The key step involved the coupling of the dianion derived from (1′S)-3-(1′-hydroxyethyl)-4-methylpyridine (4) with the iminium salt 3,4-dihydro-2-methyl-9-(p-toluenesulfonyl)-β-carbolinium iodide (3). Low asymmetric induction (15% de) at the C-1 position of the β-carboline ring system (C-3 of mostueine) was obtained. The nonfermenting baker's yeast-mediated reduction of 3-acetyl-4-methylpyridine provided the hydroxyethylpyridine component in acceptable yield (67%) and high optical purity (99.0% ee). This synthesis of 1 has established that the absolute stereochemistry of mostueine is (3S, 19R).

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Dopamine uptake inhibitory capacities of β-carboline and 3,4-dihydro-β-carboline analogs of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) oxidation products

Cited by 76 publications

References 22 publications

Mitochondrial respiratory inhibition by N-methylated beta-carboline derivatives structurally resembling N-methyl-4-phenylpyridine.

Mitochondrial respiratory inhibition by N-methylated beta-carboline derivatives structurally resembling N-methyl-4-phenylpyridine.

Does Mitochondrial DNA Play a Role in Parkinson's Disease? A Review of Cybrid and Other Supportive Evidence

Total synthesis and establishment of the absolute stereochemistry of (+)-mostueine. Addition of chiral nucleophiles to 3,4-dihydro-2-methyl-9-(p-toluenesulfonyl)-β-carbolinium iodide

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