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Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for smoking cessation.

ABSTRACT: Bupropion (2a) analogues were synthesized and tested for their ability to inhibit monoamine uptake and to antagonize the effects of human alpha3beta4*, alpha4beta2, alpha4beta4, and alpha1* nAChRs. The analogues were evaluated for their ability to block nicotine-induced effects in four tests in mice. Nine analogues showed increased monoamine uptake inhibition. Similar to 2a, all but one analogue show inhibition of nAChR function selective for human alpha3beta4*-nAChR. Nine analogues have higher affinity at alpha3beta4*-nAChRs than 2a. Four analogues also had higher affinity for alpha4beta2 nAChR. Analogues 2r, 2m, and 2n with AD(50) values of 0.014, 0.015, and 0.028 mg/kg were 87, 81, and 43 times more potent than 2a in blocking nicotine-induced antinociception in the tail-flick test. Analogue 2x with IC(50) values of 31 and 180 nM for DA and NE, respectively, and with IC(50) of 0.62 and 9.8 microm for antagonism of alpha3beta4 and alpha4beta2 nAChRs had the best overall in vitro profile relative to 2a.

SUBMITTER: Carroll FI

PROVIDER: S-EPMC2841507 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for smoking cessation.

Carroll F Ivy FI Blough Bruce E BE Mascarella S Wayne SW Navarro Hernán A HA Eaton J Brek JB Lukas Ronald J RJ Damaj M Imad MI

Journal of medicinal chemistry 20100301 5

Bupropion (2a) analogues were synthesized and tested for their ability to inhibit monoamine uptake and to antagonize the effects of human alpha3beta4*, alpha4beta2, alpha4beta4, and alpha1* nAChRs. The analogues were evaluated for their ability to block nicotine-induced effects in four tests in mice. Nine analogues showed increased monoamine uptake inhibition. Similar to 2a, all but one analogue show inhibition of nAChR function selective for human alpha3beta4*-nAChR. Nine analogues have higher ...[more]

PMID: 20158204

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Project description:Randomized efficacy clinical trials conducted in research settings may not accurately reflect the benefits of tobacco dependence treatments when used in real-world clinical settings. Effectiveness trials (eg, in primary care settings) are needed to estimate the benefits of cessation treatments in real-world use.A total of 1346 primary care patients attending routine appointments were recruited by medical assistants in 12 primary care clinics. Patients were randomly assigned to 5 active pharmacotherapies: 3 monotherapies (nicotine patch, nicotine lozenge, and bupropion hydrochloride sustained release [SR]) and 2 combination therapies (patch + lozenge and bupropion SR + lozenge). Patients were referred to a telephone quit line for cessation counseling. Primary outcomes included 7-day point prevalence abstinence at 1 week, 8 weeks, and 6 months after quitting and number of days to relapse.Among 7128 eligible smokers (> or =10 cigarettes per day) attending routine primary care appointments, 1346 (18.9%) were enrolled in the study. Six-month abstinence rates for the 5 active pharmacotherapies were the following: bupropion SR, 16.8%; lozenge, 19.9%; patch, 17.7%; patch + lozenge, 26.9%; and bupropion SR + lozenge, 29.9%. Bupropion SR + lozenge was superior to all of the monotherapies (odds ratio, 0.46-0.56); patch + lozenge was superior to patch and bupropion monotherapies (odds ratio, 0.56 and 0.54, respectively).One in 5 smokers attending a routine primary care appointment was willing to make a serious quit attempt that included evidence-based counseling and medication. In this comparative effectiveness study of 5 tobacco dependence treatments, combination pharmacotherapy significantly increased abstinence compared with monotherapies. Provision of free cessation medications plus quit line counseling arranged in the primary care setting holds promise for assisting large numbers of smokers to quit. Trial Registration clinicaltrials.gov Identifier: NCT00296647.

Project description:BackgroundMany placebo-controlled trials have demonstrated the efficacy of individual pharmacotherapies approved for smoking cessation. However, few direct or indirect comparisons of such interventions have been conducted. We performed a meta-analysis to compare the treatment effects of 7 approved pharmacologic interventions for smoking cessation.MethodsWe searched the US Centers for Disease Control and Prevention's Tobacco Information and Prevention database as well as MEDLINE, EMBASE and the Cochrane Library for published reports of placebo-controlled, double-blind randomized controlled trials of pharmacotherapies for smoking cessation. We included studies that reported biochemically validated measures of abstinence at 6 and 12 months. We used a hierarchical Bayesian random-effects model to summarize the results for each intervention.ResultsWe identified 70 published reports of 69 trials involving a total of 32 908 patients. Six of the 7 pharmacotherapies studied were found to be more efficacious than placebo: varenicline (odds ratio [OR] 2.41, 95% credible interval [CrI] 1.91-3.12), nicotine nasal spray (OR 2.37, 95% CrI 1.12-5.13), bupropion (OR 2.07, 95% CrI 1.73-2.55), transdermal nicotine (OR 2.07, 95% CrI 1.69-2.62), nicotine tablet (OR 2.06, 95% CrI 1.12-5.13) and nicotine gum (OR 1.71, 95% CrI 1.35-2.21). Similar results were obtained regardless of which measure of abstinence was used. Although the point estimate favoured nicotine inhaler over placebo (OR 2.17), these results were not conclusive because the credible interval included unity (95% CrI 0.95-5.43). When all 7 interventions were included in the same model, all were more efficacious than placebo. In our analysis of data from the varenicline trials that included bupropion control arms, we found that varenicline was superior to bupropion (OR 2.18, 95% CrI 1.09-4.08).InterpretationVarenicline, bupropion and the 5 nicotine replacement therapies were all more efficacious than placebo at promoting smoking abstinence at 6 and 12 months.

Project description:BackgroundAlthough a relatively small proportion of women who become pregnant continue to smoke cigarettes, no smoking cessation medication has been shown to be effective for this subgroup of smokers. Bupropion, a nonnicotine-based medication, is approved for the promotion of smoking cessation in nonpregnant individuals. We chose to study it in pregnant smokers because, although pregnancy increases nicotine metabolism, it does not affect the metabolism of bupropion.ObjectiveWe evaluated the efficacy and safety of sustained-release bupropion for smoking cessation among pregnant women.Study designWe conducted a multiple site, placebo-controlled, randomized clinical trial of bupropion for tobacco use among pregnant women (N=129) (clinical trial number NCT02188459). We enrolled women during the second trimester and randomly assigned them to receive 10 weeks of treatment with either bupropion or placebo, accompanied by a total of 6 smoking cessation counseling sessions (4 during treatment and 2 postpartum). The primary outcome was 7-day point prevalence smoking abstinence, confirmed with breath carbon monoxide measurements, at the end of treatment (week 10) and at week 24. Group differences were assessed as a binary abstinence outcome using a repeated measure generalized estimating equations model with a logit link. Prolonged abstinence and smoking rates were secondary outcomes. Safety measures included maternal treatment-related adverse events, gestational age, the rate of overall and spontaneous preterm births and infant birthweight and size for gestational age, head circumference, and 5-minute Apgar scores.ResultsThere were no significant differences in the safety measures across the treatment arms and bupropion was not efficacious in promoting smoking cessation at the end of treatment (7-day point prevalence quit rates: bupropion, 11.0%; placebo, 18.5%) or week 24 (7-day point prevalence quit rates: bupropion, 9.4%; placebo, 21.5%) (P>.05). African American women and women with a lower severity of nicotine dependence had significantly higher quit rates overall and women with an opioid use disorder who were being treated with opioid agonist therapy had significantly lower quit rates overall, irrespective of the treatment group (all P values <.05).ConclusionAlthough bupropion use was not associated with an elevated risk for pregnancy complications when initiated in the second trimester, it did not increase the likelihood of smoking cessation in this cohort of pregnant women. Because smoking is the major preventable source of poor pregnancy outcomes and psychosocial interventions have only modest beneficial effects, additional studies are needed to identify safe and efficacious smoking cessation medications for pregnant women who continue to smoke.

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Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for smoking cessation.

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Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for smoking cessation.

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