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Molecular Pharmacology

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Research ArticleArticle

Effects of 2-and/or 5-Methylated Analogues of 6-Hydroxydopamine on Norepinephrine- and Dopamine-Containing Neurons

RONALD T. BORCHARDT, SUSAN K. BURGESS, JACK R. REID, YUEH-O LIANG and RALPH N. ADAMS
Molecular Pharmacology September 1977, 13 (5) 805-818;
RONALD T. BORCHARDT
Department of Biochemistry, McCollum Laboratories, University of Kansas, Lawrence, Kansas 66044
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SUSAN K. BURGESS
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JACK R. REID
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YUEH-O LIANG
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RALPH N. ADAMS
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Abstract

To characterize further the molecular mechanism whereby 6-hydroxydopamine (6-OHDA) exerts its cytotoxic effects, a series of 2-and/or 5-methylated derivatives of 6-OHDA was prepared. These analogs exhibit oxidation-reduction potentials similar to that of 6-OHDA, but the corresponding quinones showed different reactivities toward nucleophiles in vitro. The quinone forms of 6-OHDA and 5-methyl-6-OHDA reacted with glutathione, whereas 2-methyl-6-OHDA quinone reacted very slowly, if at all, and 2,5-dimethyl-6-OHDA quinone was unreactive. In vivo both 6-OHDA and 5-methyl-6-OHDA were shown to produce long-term depletion of norepinephrine in mouse brain, whereas 2-methyl-6-OHDA and 2,5-dimethyl-6-OHDA were substantially less active. Only 6-OHDA produced long-term depletion of dopamine. These compounds were also tested for their abilities to inhibit uptake or cause release of [3H]norepinephrine or [3H]dopamine, using chopped rat cerebral cortex or corpus striatum. The observed order of potencies for both release and inhibition of uptake was 6-OHDA > 2-methyl-6-OHDA ≅ 5-methyl-6-OHDA > 2,5-dimethyl-6-OHDA. The differences in potency between 6-OHDA and 5-methyl-6-OHDA in producing long-term depletion of catecholamines can be explained on the basis of differences in affinities for the uptake systems. However, the differences in potency between 5-methyl-6-OHDA and 2-methyl-6-OHDA in producing long-term norepinephrine depletion cannot be rationalized on a similar basis. A more reasonable explanation for this difference is that 5-methyl-6-OHDA quinone can react with cellular nucleophiles, whereas 2-methyl-6-OHDA quinone cannot. Therefore 5-methyl-6-OHDA produces neuronal destruction through a mechanism similar to that of 6-OHDA, that being generation of a reactive electrophilic species, as well as hydrogen peroxide, superoxide anion, and hydroxyl radical. In contrast, the neurotoxicity produced by 2-methyl-6-OHDA probably results only from the effects of hydrogen peroxide, superoxide anion, and hydroxyl radical.

  • Copyright © 1977 by Academic Press, Inc.

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Molecular Pharmacology
Vol. 13, Issue 5
1 Sep 1977
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Research ArticleArticle

Effects of 2-and/or 5-Methylated Analogues of 6-Hydroxydopamine on Norepinephrine- and Dopamine-Containing Neurons

RONALD T. BORCHARDT, SUSAN K. BURGESS, JACK R. REID, YUEH-O LIANG and RALPH N. ADAMS
Molecular Pharmacology September 1, 1977, 13 (5) 805-818;

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Research ArticleArticle

Effects of 2-and/or 5-Methylated Analogues of 6-Hydroxydopamine on Norepinephrine- and Dopamine-Containing Neurons

RONALD T. BORCHARDT, SUSAN K. BURGESS, JACK R. REID, YUEH-O LIANG and RALPH N. ADAMS
Molecular Pharmacology September 1, 1977, 13 (5) 805-818;
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