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 M, respectively), but most of the latter activity resides in the (2S,3S)-hydroxy isomer (IC 50 ϭ 520 nM) rather than (2S,3R)-hydroxybupropion (IC 50 Ͼ 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 ␣ 4 ␤ 2 (functional IC 50 ϭ 3.3 M). In addition, (2S,3S)-hyroxybupropion and bupropion were considerably more potent than (2R, Ϫ3R)-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.Tobacco use is the leading cause of premature death in the United States. The vast majority of smokers (70%) report a desire to quit smoking, but poor smoking-cessation results indicate a need to explore innovative approaches to treating nicotine addiction. In addition to nicotine-replacement therapy, the atypical antidepressant bupropion is now recognized as an effective aid to smoking cessation. The efficacy of bupropion in the treatment of nicotine dependence was believed to involve the modulation of dopaminergic (dopamine, DA) and noradrenergic (norepinephrine, NE) systems. Indeed, bupropion is a relatively weak DA-reuptake inhibitor and inhibits the firing of locus coeruleus NE neurons at high concentrations (Cooper et al., 1994). Its inhibition of transporter function is associated with increases in extracellular DA and NE concentrations, which may substitute for nicotine-evoked neurotransmitter release during smoking, mimicking nicotine reinforcement and alleviating withdrawal symptoms stemming from the absence of nicotine. No other neuronal sites were believed to play a role in bupropion's because of its lack of binding affinity for almost all of the major classes of neuronal receptors (Ascher et al., 1995).However, findings from our laboratories that bupropion acted as a relatively potent, noncompetitive nAChR antagonist suggested that actions of bupropion at nAChR were of possible relevance for smoking cessation, especially given the ABBREVIAT...

A series of 2'-fluoro-3'-(substituted phenyl)deschloroepibatidine analogues (5a-k) showed high affinity for alpha4beta2 binding with no affinity at alpha7 nAChRs. The most potent compound was 2'-fluoro-3'-(4-nitrophenyl)deschloroepibatidine (5g) which possessed a Ki value of 0.009 nM. Surprisingly, none of the compounds showed agonist effects in pain tests and body temperature changes in mice even when tested at 10-15 mg/kg with the exception of 5b, which showed only very weak agonist effects. In contrast, all the compounds were potent functional antagonists of nicotine-induced antinociception. Interestingly, the 3'-substituted phenyl analogues 5b-k were 10-870-fold more effective as antagonists in the tail-flick test versus the hot-plate procedure. They failed to antagonize nicotine-induced hypothermia. The 4-chlorophenyl analogue (5e) (AD50 = 0.0003 in the tail-flick test) was the most potent and selective analogue. These results suggest that these compounds will be highly useful for identifying which specific receptor subtypes are involved in each of nicotine's pharmacological effects. These compounds also deserve consideration as potential pharmacotherapies for treatment of smoking cessation.

Chronic pain is a highly prevalent and poorly managed human health problem. We used microarray-based expression genomics in 25 inbred mouse strains to identify dorsal root ganglion (DRG)-expressed genetic contributors to mechanical allodynia, a prominent symptom of chronic pain. We identified expression levels of Chrna6, which encodes the α6 subunit of the nicotinic acetylcholine receptor (nAChR), as highly associated with allodynia. We confirmed the importance of α6* (i.e., α6-containing) nAChRs by analyzing both gain- and loss-of-function mutants. We find that mechanical allodynia associated with neuropathic and inflammatory injuries is significantly altered in α6* mutants, and that α6* but not α4* nicotinic receptors are absolutely required for peripheral and/or spinal nicotine analgesia. Furthermore, we show that Chrna6’s role in analgesia is at least partially due to direct interaction and cross-inhibition of α6* nAChRs with P2X2/3 receptors in DRG nociceptors. Finally, we establish relevance of our results to humans by the observation of genetic association in patients suffering from chronic postsurgical pain and temporomandibular pain.