The importance of the ‘4–5’ double bond for neurotoxicity in primates of the pyridine derivative MPTP

Langston, J. William; Irwin, Ian; Langston, Elizabeth B.; Forno, Lysia S.

doi:10.1016/0304-3940(84)90501-9

Cited by 50 publications

(15 citation statements)

References 12 publications

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“…The primary product of this oxidation is the resonance-stabilized cation MPDP + which is rapidly oxidized to the stable MPP + [39,40]. In contrast to MPTP, 1-methyl-4-phenylpiperidine, the product of the partial hydrogenation of MPTP, is a poor substrate of MAO [41]. This contrast suggests that the allylic double bond greatly accelerates substrate oxidation.…”

Section: Discussionmentioning

confidence: 68%

Molecular determinants in the bioactivation of the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Efange

Boudreau

1991

J Computer-Aided Mol Des

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Nineteen analogs of the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have been used as probes to study the structural parameters that influence MAO-catalyzed oxidation. In this study, the efficiency of enzyme-catalyzed substrate oxidation was found to be unrelated to parameters such as the ionization potential, dipole moment, net atomic charge at C5 and the dihedral angle between the phenyl ring and the tetrahydropyridine moiety. Conformational analysis revealed that substitution at the C2' position of MPTP yields atropisomers. It is suggested that one of these atropisomers would be either inactive or substantially less active than the other. Therefore, the relative oxidative efficiency and toxicity of these compounds reported earlier may have been significantly underestimated. Based on the conformational analysis and other data, a rudimentary model of the MAO substrate site has been developed which partially explains the substrate specificities of MAO A and MAO B. Each substrate binding site can be divided into two regions, (a) an amine-binding pocket (for the tetrahydropyridine moiety), and (b) a 'bulky substituent' region (for the phenyl group and its substituents). The length of the substrate binding site (measured along the long axis of MPTP) is approximately 8.5 A, and the width of the 'amine-binding' pocket is approximately 2.5 A (from C3 to C5). The 'bulky substituent' region contains a central area for binding the phenyl group of MPTP. This central area is flanked by two hydrophobic pockets, P2' and P3'. In MAO A, the pocket P2'-A is oriented 45-135 degrees relative to the plane of the tetrahydropyridine moiety, with a radius of 3.1 A from C2' of the phenyl ring. The radius of a similar but smaller pocket, P2'-B, in MAO B, is approximately 2.7 A. In MAO B, the pocket P3'-B (radius 2.36 A from C3') is larger than a similar pocket P3'-A (radius 1.70 A from C3') in MAO A. The foregoing characterization suggests that differences in the size and topography of both of the substituent pockets play an important role in determining the substrate specificities of these two isozymes.

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Section: Discussionmentioning

confidence: 68%

Molecular determinants in the bioactivation of the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Efange

Boudreau

1991

J Computer-Aided Mol Des

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“…1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is converted by monoamine oxidase B (MOA-B) to form the active neurotoxic metabolite MPP + (Langston et al, 1984) which is then taken up into the dopaminergic neurons via the dopamine transporter (Javitch et al, 1985). MPP + accumulates in the mitochondria of the neuronal cells (Ramsay et al, 1986(Ramsay et al, , 1991.…”

Section: Introductionmentioning

confidence: 99%

Acetylsalicylic acid and acetaminophen protect against MPP+-induced mitochondrial damage and superoxide anion generation

Maharaj

Daya

2006

Life Sciences

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“…It has been s eculated that ,311 understanding of the understanding of the etiological factors in Parkinsonism (Irwin and Langston, 1985;Kopin and Markey, 1988;Langston et al, 1983, 1!386). In this regard, the neurotoxic effects of MPTP are dependent upon its oxidation to 1-methyl-4-phenyl pyridinium ion (MPP+) by monoamine oxidase-B (MAO-B) (Castagnoli et al, 1985;Chiba et al, 1984;Langston et al, 1984b;1984d;Markey et al, 1984). A second critical step in the neurotoxic actions of MPTP is the uptake of MPP' into dopaminergic neurons (Javitch and Snyder, 1984).…”

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confidence: 99%

1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine‐Induced neurotoxicity in the rat: Characterization and age‐dependent effects

Jarvis

Wagner

1990

Synapse

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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent dopaminergic toxin that has been found to produce Parkinson's disease-like symptoms in humans and monkeys. The neurotoxic effects of MPTP appear to be reduced in rodents where multiple dosing procedures are required to demonstrate long-lasting neuronal deficits. In the present study, the neurotoxic effects of MPTP were further characterized in the rat. Following the repeated administration of MPTP, pronounced (60-80%) and dose-dependent depletions of striatal dopamine and serotonin concentrations were found in the rat brain. Time-course studies revealed that while striatal dopamine concentrations remained consistently reduced for at least 8 weeks following MPTP treatment, striatal serotonin depletions as well as MPTP-induced monoamine depletions in other brain regions were transient in nature. Pretreatment with the MAO-B inhibitor pargyline afforded a selective and complete protection of striatal dopamine levels without significantly affecting MPTP-induced striatal serotonin depletions. Similarly, treatment with ascorbic acid was found to selectively attenuate MPTP-induced dopamine depletions in rats. The neurotoxic effects of MPTP were also found to increase in the developing rat. No significant brain monoamine depletions were observed in neonatal rats following the repeated administration of MPTP. However, MPTP-induced neurotoxicity progressively increased in older rats. The present results indicate that when appropriate treatment procedures are used, a pronounced, selective, age-dependent, and long-lasting MPTP-induced reduction in striatal dopamine concentrations can be observed in the rat brain. The present results are discussed in reference to the putative mechanisms and species differences of MPTP-induced neurotoxicity.

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The importance of the ‘4–5’ double bond for neurotoxicity in primates of the pyridine derivative MPTP

Cited by 50 publications

References 12 publications

Molecular determinants in the bioactivation of the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Molecular determinants in the bioactivation of the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Acetylsalicylic acid and acetaminophen protect against MPP+-induced mitochondrial damage and superoxide anion generation

1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine‐Induced neurotoxicity in the rat: Characterization and age‐dependent effects

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