Tobacco use is the leading preventable cause of disease, disability, and death in the United States. Cigarette smoking results in more than 400,000 premature deaths in the United States each year, accounting for about 1 in every 5 deaths according to the Centers for Disease Control 2008 Smoking and Tobacco Use Fact Sheet. Statistics from the U.S. Department of Health and Human Services show that, on average, adults who smoke die 14 years earlier than nonsmokers.
Cigarette smoking accounts for about one-third of all cancers, including 90% of lung cancer cases. Smoking also causes lung diseases such as chronic bronchitis and emphysema and increases the risk of stroke, heart attack, vascular disease, and aneurysm. In spite of these documented connections between tobacco use and disease, a large number of people continue to use tobacco products. In 2008, 28.6% of the U.S. population 12 years of age and older (70.9 million people) had used a tobacco product at least once in the month prior to being interviewed. This figure includes 3.1 million young people aged 12-17 (12.4% of this age group).
Nicotine is considered the main psychoactive component in tobacco smoke that causes people to use and continue to use tobacco products. The pharmacological and behavioral effects result from the activation of different nicotinic acetylcholine receptor (nAChR) subtypes. The subtypes are either homo or hetero pentameric ion channels, consisting of different combinations of genetically distinct subunits, (α1, α2-α10, β1-β4, γ, δ, ε). The predominant nAChR subtypes found in the brain are thought to be heteromeric α4β2 nAChR or homomeric α7-nAChR; however, appreciable amounts of α3β4* and α6β2* nAChRs (where the * indicates that other subunits are known or are possible assembly partners with those specified) are also in the brain regions implicated in reward and drug dependence.
Nicotine exposure can stimulate activity of somatodendritic nAChRs to alter neuronal electrical activity and neurotransmitter release as a consequence of neuronal activation. However, by acting at nAChRs positioned on nerve terminals, nicotine can also increase neurotransmitter release as a consequence of local depolarization of the nerve terminal membrane potential and/or calcium ion mobilization in terminals. The integration of these effects is likely to contribute to nicotine's actions, including those that are presumably involved in its reinforcement of tobacco product use, such as effects in monoaminergic reward pathways.
Even though nicotine dependence has a huge impact on global health, pharmacotherapies for treating tobacco use are limited. Current treatments include nicotine-replacement therapies (NRTs), bupropion, and varenicline. Bupropion [(±)-2-tert-butylamino-3′-chloropropiophenone] is used clinically for the treatment of nicotine addiction as a racemic mixture of its (R)- and (S)-isomers (formulated in a sustained release formulation and currently marketed for this purpose as Zyban®). Bupropion is extensively metabolized with less than 1% recovered intact in urine. Major metabolites result from hydroxylation of the N-tert-butyl group by the P450-(CYP)2B6 isoenzyme. The resulting hydroxylated metabolites cyclize to give (2R,3R)- and (2S,3S)-hydroxybupropion. Several studies suggest that (2S,3S)-hydroxybupropion contributes to the antidepressant and smoking cessation efficacy of bupropion. Peak plasma and cerebrospinal fluid concentrations of (2S,3S)-hydroxybupropion exceed those of bupropion by 4- to 7-fold and have a longer elimination half-life than the parent drug.
The compound (2S,3S)-hydroxybupropion has previously been shown to act as an inhibitor of both dopamine (DA) and norepinephrine (NE) uptake. Furthermore, it has been determined to be a noncompetitive functional antagonist at α4β2-nAChRs with an IC50 value of 3.3 μM, a concentration that is comparable to those needed to inhibit DA and NE uptake. In addition, (2S,3S)-hydroxybupropion was demonstrated to be 3-10 times more potent than bupropion after acute administration in mice in antagonizing nicotine-induced hypomobility and hypothermia and nicotine-induced analgesia in tail-flick and hot-plate tests. It was also equally potent with bupropion in the antidepressant mouse forced-swimming test.
Although bupropion is a successful treatment for nicotine addiction, relatively few chemical analogues have been prepared and evaluated. Since only about one-fifth of smokers are able to maintain long-term (12 months) abstinence with any of the present pharmacotherapies, there is a need in the art for new and improved pharmaceutical compositions for treating drug addiction.
USPTO Backgrounds
USPTO Backgrounds