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 bupropion (1a) analogues (1b-1ff) were synthesized, and their in vitro and in vivo pharmacological properties evaluated with the goal of developing a 1a analogue that had better properties for treating addictions. Their in vitro pharmacological properties were examined by [(3)H]dopamine ([(3)H]DA), [(3)H]serotonin ([(3)H]5HT), and [(3)H]norepinephrine ([(3)H]NE) uptake inhibition studies, and by binding studies at the dopamine, serotonin, and norepinephrine transporters using [(125)I]RTI-55 in cloned transporters. Several analogues showed increased [(3)H]DA uptake inhibition with reduced or little change in [(3)H]5HT and [(3)H]NE uptake inhibition relative to bupropion. Thirty-five analogues were evaluated in a 1 h locomotor activity observation test and 32 in an 8 h locomotor activity observation test and compared to the locomotor activity of cocaine. Twenty-four analogues were evaluated for generalization to cocaine drug discrimination after i.p. administration, and twelve analogues were tested in a time course cocaine discrimination study using oral administration. 2-(N-Cyclopropylamino)-3-chloropropiophenone (1x) had the most favorable in vitro efficacy and in vivo pharmacological profile for an indirect dopamine agonist pharmacotherapy for treating cocaine, methamphetamine, nicotine, and other drugs of abuse addiction.

A convenient, high-yield synthesis of 7-tert-butoxycarbonyl-7-azabicyclo[2.2.1]hept-2-ene (5), which involved the addition of tributyltin hydride to 7-tert-butoxycarbonyl-2-p-toluenesulfonyl-7-azabicyclo[2.2.1]hept-2-ene (4) followed by elimination of the tributyltin and p-tolylsulfonyl groups using tetrabutylammonium fluoride was developed. The addition of 2-amino-5-iodopyridine to 5 under reductive Heck conditions provided 7-tert-butoxycarbonyl-2-exo-(2'-amino-5'-pyridinyl)-7-azabicyclo[2.2.1]heptane (6). Compound 6 was the key intermediate used to prepare epibatidine analogues where the 2'-chloro group on the pyridine ring was replaced with a fluorine (1b), bromine (1c), iodine (1d), hydroxy (1e), amino (1f), dimethylamino (1g), trifluoromethanesulfonate (1h), and hydrogen (1i) group. (+)- and (-)-Epibatidine and compounds 1b-d and 1i all possess similar binding affinities at the alpha(4)beta(2) nAChR receptors labeled by [(3)H]epibatidine. Compound 1f has affinity similar to nicotine, whereas compounds 1e, 1g, and 1h have much lower affinity. The binding affinity appears to be dependent upon the electronic nature of the substituent. However, other factors are also involved. None of the compounds possesses appreciable affinity for the alpha(7) nAChR labeled by [(125)I]iodo-MLA. With the exception of 1f and 1g, all the epibatidine analogues are full agonists (tail flick test) in producing antinociception after intrathecal injection in mice.