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 [(3)H]norepinephrine (NE) uptake with similar potency (IC(50) values of 1.9 and 1.7 microM, respectively), but most of the latter activity resides in the (2S,3S)-hydroxy isomer (IC(50) = 520 nM) rather than (2S,3R)-hydroxybupropion (IC(50) > 10,000 nM). Similar results were found with [(3)H]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 alpha(4)beta(2) (functional IC(50) = 3.3 microM). 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.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Damaj MI,Carroll FI,Eaton JB,Navarro HA,Blough BE,Mirza S,Lukas RJ,Martin BRdoi
10.1124/mol.104.001313keywords:
subject
Has Abstractpub_date
2004-09-01 00:00:00pages
675-82issue
3eissn
0026-895Xissn
1521-0111pii
mol.104.001313journal_volume
66pub_type
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