Rationale, pharmacology and clinical efficacy of partial agonists of α4β2 nACh receptors for smoking cessation

Rollema, Hans; Coe, Jotham W.; Chambers, Leslie K.; Hurst, Raymond S; Stahl, Stephen M.; Williams, Kathryn E

doi:10.1016/j.tips.2007.05.003

Cited by 383 publications

(228 citation statements)

References 50 publications

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“…However, it has significantly lower affinity and functional activity at these other subunits, with reported EC 50 values ranging from 1.1 to 55 M (39,44,57). The relevance of in vitro binding affinities and in vitro functional potencies for behavioral effects is not well understood; subunits other than ␣4␤2 nAChRS may be involved.…”

Section: Discussionmentioning

confidence: 99%

Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking

Steensland

Simms

Holgate

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

342

370

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Alcohol dependence is a disease that impacts millions of individuals worldwide. There has been some progress with pharmacotherapy for alcohol-dependent individuals; however, there remains a critical need for the development of novel and additional therapeutic approaches. Alcohol and nicotine are commonly abused together, and there is evidence that neuronal nicotinic acetylcholine receptors (nAChRs) play a role in both alcohol and nicotine dependence. Varenicline, a partial agonist at the ␣4␤2 nAChRs, reduces nicotine intake and was recently approved as a smoking cessation aid. We have investigated the role of varenicline in the modulation of ethanol consumption and seeking using three different animal models of drinking. We show that acute administration of varenicline, in doses reported to reduce nicotine reward, selectively reduced ethanol but not sucrose seeking using an operant self-administration drinking paradigm and also decreased voluntary ethanol but not water consumption in animals chronically exposed to ethanol for 2 months before varenicline treatment. Furthermore, chronic varenicline administration decreased ethanol consumption, which did not result in a rebound increase in ethanol intake when the varenicline was no longer administered. The data suggest that the ␣4␤2 nAChRs may play a role in ethanol-seeking behaviors in animals chronically exposed to ethanol. The selectivity of varenicline in decreasing ethanol consumption combined with its reported safety profile and mild side effects in humans suggest that varenicline may prove to be a treatment for alcohol dependence.A lcohol dependence constitutes one of the most serious public health problems worldwide. There are only three medications available for the treatment of alcohol dependence; disulfiram, acamprosate, and naltrexone. The opioid antagonist, naltrexone, has demonstrated the most consistent effect in reducing alcohol consumption in the context of behavioral therapy (1). Naltrexone has been shown to decrease ethanol consumption in numerous animal (2-6) and clinical studies (7-10) and has been shown to be more effective in heavy or excessive drinkers (11). However, not all patients respond to naltrexone, which is partly explained by genetic variations in the opioid receptor gene (12). Furthermore, opioid receptor antagonists decrease both ethanol and sucrose intake in rodents (13,14). Alcohol dependence is a complex disorder that will require the use of different therapeutic approaches to treat the disease effectively.Environmental and genetic factors contribute to an individual's risk of becoming dependent on drugs of abuse such as ethanol and nicotine. Approximately 85% of alcoholics smoke, and it has been suggested that common genes control the development of both alcohol and nicotine dependence (15). Furthermore, heavy drinkers tend to be heavy smokers, and alcohol influences nicotine dependence (16). Both nicotine and ethanol can either directly or indirectly activate the brain reward system through neuronal nicotinic acetylcholine re...

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Section: Discussionmentioning

confidence: 99%

Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking

Steensland

Simms

Holgate

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

342

370

View full text Add to dashboard Cite

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“…The pharmacological profile of varenicline has been described in detail elsewhere and is consistent with that of a potent and selective partial agonist of the α 4 β 2 nicotinic acetylcholine receptor, the subtype that plays a key role in the addictive effects of nicotine. [4][5][6] Because of its dual agonistantagonist properties, varenicline offers the potential therapeutic benefit of simultaneously relieving symptoms of nicotine withdrawal and cigarette craving during abstinence, while attenuating the reinforcing effects of nicotine and psychological reward associated with smoking. 4,7 Clinical evidence from self-report data have indeed indicated that, unlike other cessation medications, abstinence increased over the first weeks of varenicline use; this suggests that smoking whilst on varenicline is gradually less rewarding, thereby helping to initiate abstinence and perhaps setting the stage for a more stable quit.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic-Pharmacodynamic Modeling of the Effect of Varenicline on Nicotine Craving in Adult Smokers

Ravva

Gastonguay

Faessel

et al. 2014

Nicotine &Amp; Tobacco Research

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Introduction: Varenicline has been shown to significantly reduce craving and several aspects of smoking reinforcement in clinical trials, compared with placebo. This is the first report describing the concentration-effect relationship of varenicline on relief of craving. Methods: The pharmacokinetics (PK) and pharmacodynamics (PD) of a single 2 mg dose of varenicline were investigated in 40 smokers in a randomized, crossover study comparing the effect of varenicline with placebo on ameliorating abstinence-and cue-induced craving and withdrawal symptoms. Subjects were asked to complete self-reported questionnaires (Smoking Urges Scale and Minnesota Nicotine Withdrawal Scale [MNWS]) and blood samples were simultaneously collected for measurement of varenicline concentrations. Only the data from the 4-hr postdose abstinence period (just prior to the cue session) were analyzed. Data were described by a 2-compartment PK model and a linear PD model with first-order onset/offset rate constants describing the placebo response "kinetics. " Response was described as the net effect of the baseline, placebo, and drug responses. Results: Varenicline significantly decreased mean craving score when compared with placebo and the magnitude of this response was related to varenicline concentration. The time-course and magnitude of both placebo and varenicline craving response were characterized by a large degree of unexplained variability. Simulations were used to illustrate the expected craving response over time and its associated random variability after chronic dosing. Conclusions: Craving reduction is associated with increased varenicline concentrations. The relatively rapid onset of this effect within 4 hr postdose suggests that, smokers may experience some craving relief after acute administration of varenicline.

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“…In line with a cholinomimetic approach but devoid of typical cholinergic adverse effects, especially subtype-selective agonists, both full and partial, have been investigated in pre-clinical and clinical studies [1][2][3][4][5]; especially in neurodegenerative diseases, the therapeutic rationale has been that full agonists will provide beneficial effects by compensating for reduced cholinergic neurotransmission. On the other hand, a partial agonist can function as both an agonist and a functional antagonist, depending on its efficacy and the cholinergic tone facing the receptor [66]. These properties have formed the rationale for using a4b2 partial agonists as a treatment of tobacco addiction, as such compounds will through their agonism stimulate dopamine release in VTA, thereby relieving craving when quitting smoking, but through functional antagonism provide an upper ceiling for receptor activation that will prevent the reinforcing effects of the full agonist nicotine [66].…”

Section: Drug Development Targeting A4b2 Nachrsmentioning

confidence: 99%

“…On the other hand, a partial agonist can function as both an agonist and a functional antagonist, depending on its efficacy and the cholinergic tone facing the receptor [66]. These properties have formed the rationale for using a4b2 partial agonists as a treatment of tobacco addiction, as such compounds will through their agonism stimulate dopamine release in VTA, thereby relieving craving when quitting smoking, but through functional antagonism provide an upper ceiling for receptor activation that will prevent the reinforcing effects of the full agonist nicotine [66]. This has resulted in the development of varenicline, an a4b2 partial agonist, which has been approved by the FDA for smoking cessation [6].…”

Section: Drug Development Targeting A4b2 Nachrsmentioning

confidence: 99%

Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

Grupe

Grunnet

Bastlund

et al. 2014

Basic Clin Pharma Tox

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Abstract:The nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels broadly involved in regulating neurotransmission in the central nervous system (CNS) by conducting cation currents through the membrane of neurons. Many different nAChR subtypes exist with each their functional characteristics, expression pattern and pharmacological profile. The focus of the present MiniReview is on the heteromeric a4b2 nAChR, as activity at this subtype contributes to cognitive functioning through interactions with multiple neurotransmitter systems and is implicated in various CNS disorders, for example schizophrenia and Alzheimer's disease. Additionally, the a4b2 nAChR provides an extra layer of molecular complexity by existing in two different stoichiometries determined by the subunit composition. Such findings have founded the rationale that pharmacological modulation of the a4b2 nAChR may be used as a treatment approach in various CNS disorders. As subtype-selective agonists and other cholinergic ligands have only shown limited therapeutic success, the focus of recent drug development endeavours has largely shifted to positive allosteric modulators (PAMs). By potentiating the action of an agonist through binding to an allosteric site, a PAM can enhance cholinergic neurotransmission, thus compensating for compromised neuronal communication in a pathophysiological setting. The pharmacological advantages of PAMs compared to other types of ligands include minimal interference with spatial and temporal aspects of neurotransmission as well as higher subtype selectivity, hypothetically resulting in high clinical efficacy with minimal adverse effects. In this MiniReview, we describe the currently identified compounds, which potentiate the effects of agonists at the a4b2 nAChR. The potential clinical advantages and concerns of PAMs are discussed in the light of the role of a4b2 nAChRs as key regulators of fast synaptic transmission.For decades, the a4b2 subtype of nicotinic acetylcholine (ACh) receptors (nAChRs) has been extensively investigated as a putative drug target in different therapeutic areas. Being widely involved in central neurotransmission as well as implicated in various pathophysiological states, much research has been aimed at developing pharmacological ligands targeting this subtype as a treatment approach in both psychiatric and neurodegenerative diseases [1][2][3][4][5]. The ligand class having received most attention within nAChR drug development aimed at diseases of the central nervous system (CNS) is subtype-selective agonists [1]. However, the success of these efforts must so far be considered limited as the only a4b2 ligands currently approved for medical use are the partial a4b2 nAChR agonists, varenicline and cytisine [6], which are used as smoking cessation aids. This has set off a drug hunt for novel types of modulators targeting the a4b2 nAChR as well as other subtypes of the nAChR family, where the focus has switched from agonists to positive allosteric modulators (PAMs) of the recepto...

show abstract

Rationale, pharmacology and clinical efficacy of partial agonists of α4β2 nACh receptors for smoking cessation

Cited by 383 publications

References 50 publications

Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking

Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking

Pharmacokinetic-Pharmacodynamic Modeling of the Effect of Varenicline on Nicotine Craving in Adult Smokers

Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

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