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Hans Rollema - One of the best experts on this subject based on the ideXlab platform.
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the α4β2 nicotinic acetylcholine Receptor Partial Agonist varenicline inhibits both nicotine self administration following repeated dosing and reinstatement of nicotine seeking in rats
Psychopharmacology, 2010Co-Authors: Eoin C Oconnor, Hans Rollema, Dale Parker, Andy N MeadAbstract:Introduction The α4β2 nicotinic acetylcholine Receptor Partial Agonist varenicline has greater efficacy than other pharmacotherapeutic aids for smoking cessation. This presents an opportunity to evaluate the predictive validity of rat models of nicotine taking and relapse. The aim of this study was to evaluate the ability of varenicline to attenuate nicotine self-administration and relapse, as modelled by the reinstatement model of nicotine relapse in rats.
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varenicline has antidepressant like activity in the forced swim test and augments sertraline s effect
European Journal of Pharmacology, 2009Co-Authors: Hans Rollema, Patricia A Seymour, Victor Guanowsky, Alka Shrikhande, Yann S Mineur, Marina R. PicciottoAbstract:Varenicline, an α4β2 nicotinic acetylcholine Receptor Partial Agonist developed as a smoking cessation aid, showed antidepressant-like activity in the forced swim test in two mouse strains. In addition, a low varenicline dose significantly enhanced the effects of moderately active doses of the selective serotonin reuptake inhibitor sertraline. These findings are consistent with the notion that reducing α4β2 nicotinic acetylcholine Receptor activity either by antAgonists or by Partial Agonists that can Partially activate or desensitize acetylcholine Receptors is associated with antidepressant-like properties. These data suggest that varenicline may have antidepressant potential and can, when combined, augment antidepressant responses of selective serotonin reuptake inhibitors.
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pharmacological profile of the α4β2 nicotinic acetylcholine Receptor Partial Agonist varenicline an effective smoking cessation aid
Neuropharmacology, 2007Co-Authors: Hans Rollema, Leslie K Chambers, John Glowa, Raymond S Hurst, Charles C Rovetti, Robert J Mather, Robert S Mansbach, Lorraine A Lebel, Yi Lu, Steven Bradley SandsAbstract:The preclinical pharmacology of the α4β2 nicotinic acetylcholine Receptor (nAChR) Partial Agonist varenicline, a novel smoking cessation agent is described. Varenicline binds with subnanomolar affinity only to α4β2 nAChRs and in vitro functional patch clamp studies in HEK cells expressing nAChRs show that varenicline is a Partial Agonist with 45% of nicotine's maximal efficacy at α4β2 nAChRs. In neurochemical models varenicline has significantly lower (40–60%) efficacy than nicotine in stimulating [3H]-dopamine release from rat brain slices in vitro and in increasing dopamine release from rat nucleus accumbens in vivo, while it is more potent than nicotine. In addition, when combined with nicotine, varenicline effectively attenuates the nicotine-induced dopamine release to the level of the effect of varenicline alone, consistent with Partial agonism. Finally, varenicline reduces nicotine self-administration in rats and supports lower self-administration break points than nicotine. These data suggest that varenicline can reproduce to some extent the subjective effects of smoking by Partially activating α4β2 nAChRs, while preventing full activation of these Receptors by nicotine. Based on these findings, varenicline was advanced into clinical development and recently shown to be an effective and safe aid for smoking cessation treatment.
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in pursuit of α4β2 nicotinic Receptor Partial Agonists for smoking cessation carbon analogs of cytisine
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Michael G Vetelino, Crystal G Bashore, Michael C Wirtz, Paige R Brooks, Eric P Arnold, Lorraine A Lebel, Steven Bradley Sands, Thomas I Davis, David W Schulz, Hans RollemaAbstract:Abstract The preparation and biological activity of analogs of (−)-cytisine, an α4β2 nicotinic Receptor Partial Agonist, are discussed. All-carbon-containing phenyl ring replacements of the pyridone ring system, generated via Heck cyclization protocols, exhibited weaker affinity and lower efficacy Partial Agonist profiles relative to (−)-cytisine. In vivo, selected compounds exhibit lower efficacy Partial Agonist profiles than that of (−)-cytisine.
Steven Bradley Sands - One of the best experts on this subject based on the ideXlab platform.
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pharmacological profile of the α4β2 nicotinic acetylcholine Receptor Partial Agonist varenicline an effective smoking cessation aid
Neuropharmacology, 2007Co-Authors: Hans Rollema, Leslie K Chambers, John Glowa, Raymond S Hurst, Charles C Rovetti, Robert J Mather, Robert S Mansbach, Lorraine A Lebel, Yi Lu, Steven Bradley SandsAbstract:The preclinical pharmacology of the α4β2 nicotinic acetylcholine Receptor (nAChR) Partial Agonist varenicline, a novel smoking cessation agent is described. Varenicline binds with subnanomolar affinity only to α4β2 nAChRs and in vitro functional patch clamp studies in HEK cells expressing nAChRs show that varenicline is a Partial Agonist with 45% of nicotine's maximal efficacy at α4β2 nAChRs. In neurochemical models varenicline has significantly lower (40–60%) efficacy than nicotine in stimulating [3H]-dopamine release from rat brain slices in vitro and in increasing dopamine release from rat nucleus accumbens in vivo, while it is more potent than nicotine. In addition, when combined with nicotine, varenicline effectively attenuates the nicotine-induced dopamine release to the level of the effect of varenicline alone, consistent with Partial agonism. Finally, varenicline reduces nicotine self-administration in rats and supports lower self-administration break points than nicotine. These data suggest that varenicline can reproduce to some extent the subjective effects of smoking by Partially activating α4β2 nAChRs, while preventing full activation of these Receptors by nicotine. Based on these findings, varenicline was advanced into clinical development and recently shown to be an effective and safe aid for smoking cessation treatment.
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in pursuit of α4β2 nicotinic Receptor Partial Agonists for smoking cessation carbon analogs of cytisine
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Michael G Vetelino, Crystal G Bashore, Michael C Wirtz, Paige R Brooks, Eric P Arnold, Lorraine A Lebel, Steven Bradley Sands, Thomas I Davis, David W Schulz, Hans RollemaAbstract:Abstract The preparation and biological activity of analogs of (−)-cytisine, an α4β2 nicotinic Receptor Partial Agonist, are discussed. All-carbon-containing phenyl ring replacements of the pyridone ring system, generated via Heck cyclization protocols, exhibited weaker affinity and lower efficacy Partial Agonist profiles relative to (−)-cytisine. In vivo, selected compounds exhibit lower efficacy Partial Agonist profiles than that of (−)-cytisine.
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in pursuit of α4β2 nicotinic Receptor Partial Agonists for smoking cessation carbon analogs of cytisine
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Jotham Wadsworth Coe, Michael G Vetelino, Crystal G Bashore, Michael C Wirtz, Paige R Brooks, Eric P Arnold, Lorraine A Lebel, Steven Bradley Sands, Carol B Fox, Thomas I DavisAbstract:The preparation and biological activity of analogs of (-)-cytisine, an alpha4beta2 nicotinic Receptor Partial Agonist, are discussed. All-carbon-containing phenyl ring replacements of the pyridone ring system, generated via Heck cyclization protocols, exhibited weaker affinity and lower efficacy Partial Agonist profiles relative to (-)-cytisine. In vivo, selected compounds exhibit lower efficacy Partial Agonist profiles than that of (-)-cytisine.
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varenicline an α4β2 nicotinic Receptor Partial Agonist for smoking cessation
Journal of Medicinal Chemistry, 2005Co-Authors: Jotham Wadsworth Coe, Michael G Vetelino, Michael C Wirtz, Paige R Brooks, Eric P Arnold, Lorraine A Lebel, Steven Bradley Sands, Thomas I Davis, Jianhua Huang, Carol B FoxAbstract:Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine Receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued α4β2 nicotinic Receptor Partial Agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high α4β2 nAChR affinity and the desired in vivo dopaminergic profile.
Karen R Reeves - One of the best experts on this subject based on the ideXlab platform.
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efficacy and tolerability of varenicline an α4β2 nicotinic acetylcholine Receptor Partial Agonist in a 12 week randomized placebo controlled dose response study with 40 week follow up for smoking cessation in japanese smokers
Clinical Therapeutics, 2007Co-Authors: Masakazu Nakamura, Akira Oshima, Y Fujimoto, Nami Maruyama, Taro Ishibashi, Karen R ReevesAbstract:Abstract Background: Varenicline, a selective α 4 β 2 nicotinic acetylcholine Receptor Partial Agonist, has been developed specifically for smoking cessation. In Japan, 39.3% of men smoke and this is a major public health concern. Objective: The primary objective of this study was to evaluate the efficacy and dose-response relationship of varenicline in Japanese smokers. Methods: In this double-blind, placebo-controlled, randomized, parallel-group study, subjects were randomized to receive varenicline at 0.25 mg BID, 0.5 mg BID, 1 mg BID, or placebo for 12 weeks followed by a 40-week, nontreatment follow-up phase. The primary efficacy variable was the continuous abstinence rate (CAR), defined as no reported smoking (not even a puff) or other nicotine use and confirmed by end-expiratory carbon monoxide level ≤10 ppm, during the last 4 weeks of treatment (weeks 9–12). Secondary end points included CARs for weeks 9–24 and 9–52. Craving, withdrawal, and smoking satisfaction were determined by the Minnesota Nicotine Withdrawal Scale, the Brief Questionnaire on Smoking Urges, and the modified Cigarette Evaluation Questionnaire. The tolerability of varenicline was also evaluated. Results: Of 618 subjects who received treatment, 515 (83.3%) were classified as nicotine dependent (scoring ≥5 on the Tobacco Dependence Screener), and constituted the primary analysis group. Of these, 385 (74.8%) subjects were male, and the mean age was within the range of 39.0 to 40.2 years. Across treatment groups, subjects claimed to have smoked a mean of 23.1 to 24.9 cigarettes per day in the preceding 30 days, and the mean score on the Fagerstrom Test for Nicotine Dependence was within the range from 5.4 to 5.7. The CAR for weeks 9–12 was significantly higher for all doses of varenicline compared with placebo (39.5% [51/129]). The highest CAR of 65.4% (85/130) was achieved with varenicline 1 mg BID (odds ratio [OR] [95% CI] = 2.98 [1.78–4.99]; P P = 0.036). The CARs for weeks 9–24 at 0.25, 0.5, and 1 mg BID were 33.6% (43/128), 35.2% (45/128), 37.7% (49/130), and for weeks 9–52 at 0.25 and 0.5 mg BID were 27.3% (35/128) and 28.9% (37/128) but failed to reach significance versus the placebo (29.5% [38/129] for weeks 9–24 and 23.3% [30/129] for weeks 9–52). Treatment-emergent adverse events (AEs) were more prevalent among varenicline-treated subjects (79.1% [121/153] at 0.25 mg BID, 80.6% [125/155] at 0.5 mg BID, and 80.1% [125/156] at 1 mg BID) than placebo subjects (71.4% [110/154]). The 3 most prevalent AEs at varenicline 1 mg BID were nasopharyngitis (35.9% [56/156]), nausea (24.4% [38/156]), and headache (10.3% [16/156]), all of which were of mild or moderate intensity. Nausea was the only AE that appeared dose related (7.2% [11/153] at 0.25 mg BID, 9.7% [15/155] at 0.5 mg BID, and 24.4% [38/156] at 1 mg BID) versus placebo (7.8% [12/154]). Conclusions: Varenicline was associated with dose-dependent improvement in smoking abstinence rates during the last 4 weeks of treatment and in the longer term over 40 weeks of nontreatment follow-up. The dose associated with the highest efficacy was varenicline 1 mg BID.
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efficacy and safety of the novel selective nicotinic acetylcholine Receptor Partial Agonist varenicline for smoking cessation
JAMA Internal Medicine, 2006Co-Authors: Cheryl Oncken, R J Anziano, Clare B Billing, Mitchell A Nides, David Gonzales, Eric Jacob Watsky, Stephen I Rennard, Karen R ReevesAbstract:Background The selective nicotinic acetylcholine Receptor Partial Agonist, varenicline tartrate, represents a novel type of therapy for smoking cessation. This study evaluated the efficacy, safety, and tolerability of 4 varenicline dose regimens, 2 with progressive dosing over the first week (eg, titrated) and 2 with a fixed dosing schedule (eg, non-titrated), for promoting smoking cessation. Methods This multicenter, double-blind, placebo-controlled study randomized healthy smokers (aged 18-65 years) to varenicline tartrate, 0.5 mg twice daily nontitrated (n = 129), 0.5 mg twice daily titrated (n = 130), 1.0 mg twice daily nontitrated (n = 129), 1.0 mg twice daily titrated (n = 130), or placebo (n = 129) for 12 weeks to aid in smoking cessation. A 40-week follow-up period assessed long-term efficacy. The primary efficacy measures were the carbon monoxide–confirmed 4-week continuous quit rates by pooled dosage group for weeks 4 through 7 and 9 through 12 and the continuous abstinence rates for weeks 9 through 52. Results Weeks 9 through 12 continuous quit rates were greater in the 1.0-mg group (49.4%) and the 0.5-mg group (44.0%) vs placebo (11.6%; P P P Conclusion Varenicline tartrate, 0.5 mg and 1.0 mg twice daily, is efficacious for smoking cessation.
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smoking cessation with varenicline a selective α4β2 nicotinic Receptor Partial Agonist results from a 7 week randomized placebo and bupropion controlled trial with 1 year follow up
JAMA Internal Medicine, 2006Co-Authors: Mitchell A Nides, R J Anziano, Cheryl Oncken, David Gonzales, Stephen I Rennard, Watsky Eric Jacob, Karen R ReevesAbstract:Background: Currently available smoking cessation therapies have limited success rates. Varenicline tartrate is a novel, selective nicotinic Receptor Partial Agonist developed specifically for smoking cessation. This study evaluated the efficacy, tolerability, and safety of 3 varenicline doses for smoking cessation. Bupropion hydrochloride was included as an active control. Methods: A phase 2, multicenter, randomized, doubleblind, placebo-controlled study of healthy smokers (18-65 years old). Subjects were randomized to varenicline tartrate, 0.3 mg once daily (n =1 28), 1.0 mg once daily (n=128), or 1.0 mg twice daily (n=127), for 6 weeks plus placebo for 1 week; to 150-mg sustained-release bupropion hydrochloride twice daily (n=128) for 7 weeks; or to placebo (n=127) for 7 weeks. Results: During the treatment phase, the continuous quit rates for any 4 weeks were significantly higher for varenicline tartrate, 1.0 mg twice daily (48.0%;P.001) and 1.0 mg once daily (37.3%;P.001), than for placebo (17.1%). Thebupropionratewas33.3%(P=.002vsplacebo).Thecarbon monoxide–confirmed continuous quit rates from week 4 to week 52 were significantly higher in the varenicline tartrate, 1.0 mg twice daily, group compared with the placebo group(14.4%vs4.9%;P=.002).Thebupropionratewas6.3%
Jotham Wadsworth Coe - One of the best experts on this subject based on the ideXlab platform.
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metabolism and disposition of varenicline a selective α4β2 acetylcholine Receptor Partial Agonist in vivo and in vitro
Drug Metabolism and Disposition, 2006Co-Authors: Scott R Obach, Thomas N Oconnell, Anne E Reedhagen, Suzanne S Krueger, Beth J Obach, Kathleen S Zandi, Sandra A Miller, Jotham Wadsworth CoeAbstract:The metabolism and disposition of varenicline (7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine), a Partial Agonist of the nicotinic acetylcholine Receptor for the treatment of tobacco addiction, was examined in rats, mice, monkeys, and humans after oral administration of [14C]varenicline. In the circulation of all species, the majority of drug-related material was composed of unchanged varenicline. In all four species, drug-related material was primarily excreted in the urine. A large percentage was excreted as unchanged parent drug (90, 84, 75, and 81% of the dose in mouse, rat, monkey, and human, respectively). Metabolites observed in excreta arose via N-carbamoyl glucuronidation and oxidation. These metabolites were also observed in the circulation, in addition to metabolites that arose via N-formylation and formation of a novel hexose conjugate. Experiments were conducted using in vitro systems to gain an understanding of the enzymes involved in the formation of the N-carbamoylglucuronide metabolite in humans. N-Carbamoyl glucuronidation was catalyzed by UGT2B7 in human liver microsomes when incubations were conducted under a CO2 atmosphere. The straightforward dispositional profile of varenicline should simplify its use in the clinic as an aid in smoking cessation.
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in pursuit of α4β2 nicotinic Receptor Partial Agonists for smoking cessation carbon analogs of cytisine
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Jotham Wadsworth Coe, Michael G Vetelino, Crystal G Bashore, Michael C Wirtz, Paige R Brooks, Eric P Arnold, Lorraine A Lebel, Steven Bradley Sands, Carol B Fox, Thomas I DavisAbstract:The preparation and biological activity of analogs of (-)-cytisine, an alpha4beta2 nicotinic Receptor Partial Agonist, are discussed. All-carbon-containing phenyl ring replacements of the pyridone ring system, generated via Heck cyclization protocols, exhibited weaker affinity and lower efficacy Partial Agonist profiles relative to (-)-cytisine. In vivo, selected compounds exhibit lower efficacy Partial Agonist profiles than that of (-)-cytisine.
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varenicline an α4β2 nicotinic Receptor Partial Agonist for smoking cessation
Journal of Medicinal Chemistry, 2005Co-Authors: Jotham Wadsworth Coe, Michael G Vetelino, Michael C Wirtz, Paige R Brooks, Eric P Arnold, Lorraine A Lebel, Steven Bradley Sands, Thomas I Davis, Jianhua Huang, Carol B FoxAbstract:Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine Receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued α4β2 nicotinic Receptor Partial Agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high α4β2 nAChR affinity and the desired in vivo dopaminergic profile.
Andy N Mead - One of the best experts on this subject based on the ideXlab platform.
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the α4β2 nicotinic acetylcholine Receptor Partial Agonist varenicline inhibits both nicotine self administration following repeated dosing and reinstatement of nicotine seeking in rats
Psychopharmacology, 2010Co-Authors: Eoin C Oconnor, Hans Rollema, Dale Parker, Andy N MeadAbstract:Introduction The α4β2 nicotinic acetylcholine Receptor Partial Agonist varenicline has greater efficacy than other pharmacotherapeutic aids for smoking cessation. This presents an opportunity to evaluate the predictive validity of rat models of nicotine taking and relapse. The aim of this study was to evaluate the ability of varenicline to attenuate nicotine self-administration and relapse, as modelled by the reinstatement model of nicotine relapse in rats.
