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Molecular Pharmacology

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Research ArticleArticle

Enantioselective Effects of Hydroxy Metabolites of Bupropion on Behavior and on Function of Monoamine Transporters and Nicotinic Receptors

M. Imad Damaj, F. Ivy Carroll, J. Brek Eaton, Hernan A. Navarro, Bruce E. Blough, Sadiq Mirza, Ronald J. Lukas and Billy R. Martin
Molecular Pharmacology September 2004, 66 (3) 675-682; DOI: https://doi.org/10.1124/mol.104.001313
M. Imad Damaj
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F. Ivy Carroll
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J. Brek Eaton
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Hernan A. Navarro
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Bruce E. Blough
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Sadiq Mirza
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Ronald J. Lukas
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Billy R. Martin
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Abstract

Bupropion is an atypical antidepressant that also has usefulness as a smoking-cessation aid. Because hydroxybupropion, a major metabolite of bupropion, is believed to contribute to its antidepressant activity, this metabolite may also contribute to the smoking-cessation properties of bupropion. This study investigated the effects of hydrobupropion enantiomers on monoamine transporters and nicotinic acetylcholine receptor (nAChR) subtypes. Racemic bupropion and hydroxybupropion inhibit [3H]norepinephrine (NE) uptake with similar potency (IC50 values of 1.9 and 1.7 μM, respectively), but most of the latter activity resides in the (2S,3S)-hydroxy isomer (IC50 = 520 nM) rather than (2S,3R)-hydroxybupropion (IC50 > 10,000 nM). Similar results were found with [3H]dopamine (DA) uptake. The effects of bupropion and enantiomers of hydroxybupropion on human nAChR subtypes indicate that the (2S,3S) isomer is more potent than the (2S,3R) isomer or racemic bupropion as an antagonist of α4β2 (functional IC50 = 3.3 μM). In addition, (2S,3S)-hyroxybupropion and bupropion were considerably more potent than (2R, –3R)-hydroxybupropion in a mouse depression model (forced swimming test) and in antagonism of acute nicotine effects in mice. Together, our results suggest that clinical and behavioral effects of bupropion arise from actions at nAChR as well as DA and NE transporters. Furthermore, our data suggest that the (2S,3S)-hydroxybupropion isomer may be a better drug candidate for smoking cessation than bupropion because of its higher potency at the relevant targets.

  • Received April 9, 2004.
  • Accepted June 18, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 66 (3)
Molecular Pharmacology
Vol. 66, Issue 3
1 Sep 2004
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Research ArticleArticle

Enantioselective Effects of Hydroxy Metabolites of Bupropion on Behavior and on Function of Monoamine Transporters and Nicotinic Receptors

M. Imad Damaj, F. Ivy Carroll, J. Brek Eaton, Hernan A. Navarro, Bruce E. Blough, Sadiq Mirza, Ronald J. Lukas and Billy R. Martin
Molecular Pharmacology September 1, 2004, 66 (3) 675-682; DOI: https://doi.org/10.1124/mol.104.001313

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Research ArticleArticle

Enantioselective Effects of Hydroxy Metabolites of Bupropion on Behavior and on Function of Monoamine Transporters and Nicotinic Receptors

M. Imad Damaj, F. Ivy Carroll, J. Brek Eaton, Hernan A. Navarro, Bruce E. Blough, Sadiq Mirza, Ronald J. Lukas and Billy R. Martin
Molecular Pharmacology September 1, 2004, 66 (3) 675-682; DOI: https://doi.org/10.1124/mol.104.001313
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