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Cited by 168Nicotinic Acetylcholine Receptors StudySmoking Behavior and CessationAlkaloids: synthesis and pharmacology

Pre‐clinical properties of the α4β2 nicotinic acetylcholine receptor partial agonists varenicline, cytisine and dianicline translate to clinical efficacy for nicotine dependence

Open access
Rollema, H, Shrikhande, A, Ward, KM, Tingley III, FD, Coe, JW, O'Neill, BT, Tseng, E, Wang, EQ +7 more·2010·British Journal of Pharmacology
DOI 10.1111/j.1476-5381.2010.00682.xPMC PMC2874855
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Abstract

Background and purpose: Smoking cessation trials with three high‐affinity partial agonists of α4β2 neuronal nicotinic acetylcholine receptors (nAChRs) have demonstrated differences in their clinical efficacy. This work examines the origin of the differences by taking into account brain exposure and pharmacological effects at human α4β2 nAChRs. Experimental approach: Rat plasma and brain pharmacokinetics were characterized and used to predict human steady‐state plasma and brain concentrations following recommended doses of each of the three compounds. The pharmacological characterization included in vitro affinities at different nAChR subtypes, functional efficacies and potencies at the human α4β2 nAChR, as well as in vivo effects on rat mesolimbic dopamine turn‐over. Key results: A comparison of predicted human brain concentrations following therapeutic doses demonstrated that varenicline and nicotine, but not dianicline and cytisine, can extensively desensitize and, to a lesser extent, activate α4β2 nAChRs. The limited clinical efficacy of dianicline may be accounted for by a combination of weak functional potency at α4β2 nAChRs and moderate brain penetration, while recommended doses of cytisine, despite its high in vitro potency, are predicted to result in brain concentrations that are insufficient to affect α4β2 nAChRs. Conclusions and implications: The data provide a plausible explanation for the higher abstinence rate in smoking cessation trials following treatment with varenicline than with the two other α4β2 nAChR partial agonists. In addition, this retrospective analysis demonstrates the usefulness of combining in vitro and in vivo parameters with estimated therapeutic human brain concentrations for translation to clinical efficacy.

AI snapshot

Written from the paper’s full text.

TL;DR

This retrospective translational study compared varenicline, cytisine, and dianicline using rat pharmacokinetics, predicted human unbound brain concentrations, and in vitro/in vivo α4β2 nAChR pharmacology. It concludes that varenicline’s higher predicted brain exposure and functional potency at α4β2 nAChRs plausibly explain its greater clinical efficacy for smoking cessation than cytisine or dianicline.

Key findings

  • Predicted human unbound steady-state brain concentrations after recommended doses were 32–131 nM for varenicline, 2–10 nM for cytisine, and 37–84 nM for dianicline; varenicline and nicotine were predicted to extensively desensitize and, to a lesser extent, activate α4β2 nAChRs, whereas cytisine was predicted to cause significant desensitization but not activation, and dianicline only minimal desensitization.
  • At human α4β2 nAChRs, binding affinities were Ki 0.4 nM for varenicline, 2.0 nM for cytisine, and 105 nM for dianicline; agonist efficacies versus ACh were 22 ± 2.5% for varenicline, 6.5 ± 0.2% for cytisine, and 8.0 ± 0.3% for dianicline.
  • In rat nucleus accumbens dopamine turnover, varenicline (ED20 ∼0.12 mg kg−1 p.o.) was about 20-fold more potent than cytisine (ED20 ∼2.5 mg kg−1) and at least 100-fold more potent than dianicline (ED20 ∼20 mg kg−1); partial agonists increased turnover to less than 140% of controls versus 180% for 1 mg kg−1 s.c. nicotine.
  • Clinical context cited: varenicline OR 3.7 (95% CI 2.86–4.68) versus placebo; cytisine OR 1.9 (95% CI 1.2–3.1); dianicline phase 2 end-of-treatment quit rates 16% versus 8% for placebo.

Methods

  • Rat and mouse pharmacokinetic/brain-disposition studies measured protein binding, plasma/brain/CSF/extracellular fluid exposures, ultra-slow-flow microdialysis, P-gp-deficient versus wild-type mice, and i.v./p.o. PK; human steady-state plasma and brain exposures were predicted by allometric scaling and rat brain-to-plasma ratios after recommended doses.
  • In vitro pharmacology used radioligand binding at nAChR subtypes and two-electrode voltage clamp in Xenopus oocytes expressing human α4β2 nAChRs for activation/desensitization; in vivo rat nucleus accumbens dopamine turnover was measured by HPLC-EC after oral partial agonists versus 1 mg kg−1 s.c. nicotine.
  • Samples included male Sprague-Dawley rats (n = 75), male FVB/N and mdr1a/1b knockout mice (n = 12 each), Xenopus females (n = 5), and dopamine turnover groups of n = 4–6.

Limitations

  • Stated: no head-to-head clinical comparisons among the three partial agonists; dianicline data were preliminary phase 2 only and development was halted; further work is needed to evaluate other nAChR subtypes (e.g., α7, α3*, α5*, α6*) in varenicline’s effects.
  • Stated/evident: human brain concentrations for cytisine and dianicline were predicted by allometric scaling from rat PK and assumed the same rat/human brain-to-plasma ratios, not directly measured; varenicline human plasma data came from prior reports.
  • Evident: in vitro α4β2 experiments used a mixed receptor population not enriched for specific stoichiometry; microdialysis ECF exposures were lower than unbound brain estimates, and the paper notes possible overestimation of unbound brain exposure or active transport for nicotine/varenicline.

Model-written summary. Check it against the paper before relying on it.

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Crossref · 10.1111/j.1476-5381.2010.00682.x

Cites

48 of 48 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 49 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Results

    Varenicline has 15-fold higher affinity than nicotine (Ki= 6.1 nM) for α4β2 nAChRs.

    “It has 15-fold higher affinity than nicotine (Ki= 6.1 nM)”
    Quote in the paperSubstantial claim
  • Findingreasoning
    § Results

    Human steady-state unbound brain concentrations (Bu) after recommended doses of varenicline are predicted to be much higher than those of cytisine due to the reduced brain entry of cytisine.

    “However, in brain, human steady-state unbound concentrations (Bu) after recommended doses of varenicline are predicted to be much higher than those of cytisine due to the reduced brain entry of cytisine (Table 2).”
    Quote in the paperSubstantial claim
  • Findingown data
    § Results

    Varenicline binds to the α4β2 subtype with higher receptor affinity (Ki= 0.4 nM) than the other compounds.

    “and that varenicline binds to the α4β2 subtype with higher receptor affinity (Ki= 0.4 nM) than the other compounds.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Results

    Other molecular properties that can affect brain penetration, such as ELogD7.4, polar surface area, membrane permeability, MDR1 and BCRP transporter susceptibility, do not significantly differ between the three partial agonists.

    “Other molecular properties that can affect brain penetration, such as ELogD7.4, polar surface area, membrane permeability, multidrug resistance protein (MDR1) and breast cancer resistance protein (BCRP) transporter susceptibility, do not significantly differ between the three partial agonists (Supporting Information Table S3).”
    Quote in the paperSubstantial claim
  • Findingreasoning
    § Results

    The unbound Css,avg in human brain after therapeutic doses was predicted to range from 32 to 131 nM for varenicline.

    “In this way, the unbound Css,avg in human brain after therapeutic doses was predicted to range from 32 to 131 nM for varenicline, from 2 to 10 nM for cytisine and from 37 to 84 nM for dianicline (Table 3).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Rat and human have the same brain-to-plasma ratio for each compound.
  • May combine two claims. 29
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Findingown data
    § Results

    Dianicline is unbound in plasma and 60% bound in brain.

    “that dianicline is unbound in plasma and 60% bound in brain”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    Following oral administration, both cytisine and dianicline were rapidly and fully absorbed into the systemic circulation as indicated by short Tmax (0.63 and 0.5 h) and complete oral bioavailability.

    “Following oral administration, both compounds were rapidly and fully absorbed into the systemic circulation as indicated by the short time to maximum plasma concentration (Tmax) (0.63 and 0.5 h) and complete oral bioavailability.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    Oral administration of varenicline, cytisine or dianicline in rat resulted in comparable unbound plasma exposures, but there are important differences between the unbound brain concentrations of the agents.

    “In vivo pharmacokinetic studies in rat demonstrated that oral administration of varenicline, cytisine or dianicline resulted in comparable unbound plasma exposures, but there are important differences between the unbound brain concentrations of the agents.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    Rat single species allometry predicted that human unbound Css,avg after 1.5 mg QID cytisine was in the same range as reported values for unbound Css,avg after 1 mg BID varenicline, while 40 mg BID dianicline was estimated to result in a proportionally higher unbound Css,avg.

    “Rat single species allometry predicted that human unbound Css,avg after 1.5 mg QID cytisine was in the same range as reported values for unbound Css,avg after 1 mg BID varenicline, while 40 mg BID dianicline was estimated to result in a proportionally higher unbound Css,avg (Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation
    § Results

    Higher doses of the partial agonists were either poorly tolerated and not further assessed, or caused lower turn-over increases than after the previous test dose, resulting in an inverted U-shaped dose-response curve.

    “Higher doses of the partial agonists were either poorly tolerated and not further assessed, or caused lower turn-over increases than after the previous test dose, resulting in an inverted U-shaped dose–response curve, consistent with previous findings (Rollema et al., 2007b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rollema et al., 2007b

      Not checked in the free run.

  • May combine two claims.

    Findingown data
    § Results

    Varenicline and dianicline do not bind to muscle α1-containing nAChRs (Ki values > 8 μM).

    “Cytisine is the only compound showing moderate affinity for the muscle α1-containing nAChRs (Ki= 430 nM) to which nicotine binds with low affinity (Ki= 2 µM), while varenicline and dianicline do not bind to this subtype (Ki values > 8 µM).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    The concentration range between onset of activation and complete desensitization is approximately 10-100 μM for dianicline, and 0.01-10 μM for nicotine, varenicline and cytisine.

    “This concentration range between onset of activation and complete desensitization is approximately 10–100 µM for dianicline, and 0.01–10 µM for the other three compounds (Figure 3).”
    • Also stated in: § Results · plain
      “This pharmacologically relevant range between the activation and desensitization curves is 10–100 µM for dianicline, compared to 0.01–10 µM for nicotine, varenicline and cytisine (Figure 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    Oral administration to rats of 1 mg/kg of each compound yielded comparable unbound plasma concentrations for the four compounds, with AUC0-6h values of 512, 397, 702 and 448 h ng-1 mL-1 for nicotine, varenicline, cytisine and dianicline respectively.

    “Oral administration to rats of 1 mg kg–1 of each compound yielded comparable unbound plasma concentrations for the four compounds, with AUC0–6h values of 512, 397, 702 and 448 h ng–1 mL–1for nicotine, varenicline, cytisine and dianicline respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    Unbound rat brain peak concentrations associated with a dose that significantly increased dopamine turn-over were ∼4 μM for nicotine (1 mg kg-1 s.c.), ∼0.4 μM for varenicline (1 mg kg-1 p.o.), ∼0.7 μM for cytisine (10 mg kg-1 p.o.) and ∼3.2 μM for dianicline (20 mg kg-1 p.o.).

    “These doses and unbound concentrations were for nicotine 1 mg kg–1 s.c. and ∼4 µM, for varenicline 1 mg kg–1 p.o. and ∼0.4 µM, for cytisine 10 mg kg–1 p.o. and ∼0.7 µM and for dianicline 20 mg kg–1 p.o. and ∼3.2 µM.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    Although varenicline has significantly lower affinity for α7 (Ki= 125 nM) than for α4β2 nAChRs, it binds to this nAChR subtype with at least 20-fold higher affinity than the other compounds (Ki values > 2.1 μM).

    “Although varenicline has significantly lower affinity for α7 (Ki= 125 nM) than for α4β2 nAChRs, it binds to this nAChR subtype with at least 20-fold higher affinity than the other compounds (Ki values > 2.1 µM).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    Both cytisine and dianicline showed moderate volumes of distribution (Vd 2.7 to 3.8 L kg-1) and short half-lives of 1.5 and 0.95 h respectively.

    “Both compounds showed moderate volumes of distribution (Vd) with values ranging from 2.7 to 3.8 L kg–1, and short half-lives of 1.5 and 0.95 h respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    Nicotine and cytisine are essentially non-protein bound in plasma and brain (fu > 0.8).

    “Measurements of unbound fractions (fu) of each of the four compounds show that nicotine and cytisine are essentially non-protein bound in plasma and brain (fu > 0.8)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    The EC50 values for high-affinity activation of α4β2 nAChRs ranged from 0.06 to 18 μM, while the IC50 values for high-affinity desensitization were 0.05-2.8 nM.

    “The EC50 values for high-affinity activation of α4β2 nAChRs ranged from 0.06 to 18 µM, while the IC50 values for high-affinity desensitization were 0.05–2.8 nM (Table 5, Figure 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    Varenicline is about 20-fold more potent than cytisine and at least 100-fold more potent than dianicline in increasing dopamine turn-over in rat nucleus accumbens.

    “These data revealed that varenicline (ED20∼0.12 mg kg–1) is about 20-fold more potent in increasing dopamine turn-over than cytisine (ED20∼2.5 mg kg–1), and at least 100-fold more potent than dianicline (ED20∼20 mg kg–1).”
    • Also stated in: § Results · plain
      “After oral administration, varenicline was found to be 20- and 100-fold more potent than cytisine and dianicline, respectively, in stimulating dopamine turn-over in rat nucleus accumbens (Figure 5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    There are very small differences in other molecular properties of the partial agonists that impact permeability and transport, and none of the compounds was found to be a substrate for P-gp or BCRP efflux transporters.

    “Moreover, there are very small differences in other molecular properties of the partial agonists that impact permeability and transport, and none of the compounds was found to be a substrate for P-gp or BCRP efflux transporters (Supporting Information Tables S2 and S3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    There are substantial quantitative differences in binding affinities and functional potencies of dianicline versus the other two partial agonists, and much higher dianicline concentrations are required for an interaction with α4β2 nAChRs.

    “However, there are substantial quantitative differences in binding affinities and functional potencies of dianicline versus the other two partial agonists, and much higher dianicline concentrations are required for an interaction with α4β2 nAChRs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data
    § Results

    Varenicline has moderate affinity for α7 nAChRs (Ki= 125 nM).

    “As varenicline has moderate affinity for α7 nAChRs (Ki= 125 nM; Table 4), we are also investigating the interactions of varenicline with this receptor subtype.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    Dianicline has comparable permeability and hydrophilicity as varenicline, and is not a substrate for P-gp or BCRP efflux transporters, but has limited brain penetration.

    “Dianicline has comparable permeability and hydrophilicity as varenicline, and is not a substrate for P-gp or BCRP efflux transporters (Supporting Information Tables S2 and S3), but has limited brain penetration.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning
    § Results

    At physiological pH, the partial agonists have approximately the same distribution coefficient (ElogD7.4), because at pH 7.4 much less cytisine is in the protonated form than varenicline and dianicline.

    “At physiological pH, the partial agonists have approximately the same distribution coefficient (ElogD7.4), because at pH 7.4 much less cytisine, which has an acid dissociation constant (pKa) of 7.8, is in the protonated form than varenicline and dianicline (pKa 9.3–9.8; Supporting Information Table S3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Introduction

    Achieved abstinence rates and odds ratios versus placebo are higher for varenicline than for either cytisine or dianicline.

    “Achieved abstinence rates and odds ratios (ORs) versus placebo are higher for varenicline (Cahill et al., 2008; Nides et al., 2008) than for either cytisine (Etter, 2006; Cahill et al., 2008) or dianicline (Fagerström and Balfour, 2006).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cahill et al., 2008

      Not checked in the free run.

    • cites Nides et al., 2008

      Not checked in the free run.

    • cites Etter, 2006

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given
    § Introduction

    Compounds with reduced agonist efficacy at α4β2 nAChRs with a slower onset and much longer half-life than inhaled nicotine should exhibit a low potential for abuse liability.

    “Compounds with reduced agonist efficacy at α4β2 nAChRs with a slower onset and much longer half-life than inhaled nicotine should exhibit a low potential for abuse liability.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data
    § Results

    The lower CSF exposures of nicotine and varenicline suggest either overestimation of unbound brain exposures or active transport of both compounds into the brain or underestimation of CSF concentrations.

    “suggesting either overestimation of unbound brain exposures or active transport of both compounds into the brain or underestimation of CSF concentrations.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Results

    Additional nAChR subtypes, including α3*, α5* and α6* nAChRs, have been proposed to contribute to mesolimbic activity and nicotine dependence.

    “Additional nAChR subtypes, including α3*, α5* and α6* nAChRs, have been proposed to contribute to mesolimbic activity and nicotine dependence (Drenan et al., 2008; Exley et al., 2008; Pons et al., 2008; Grady et al., 2009; Livingstone et al., 2009; Ramiro et al., 2009).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Drenan et al., 2008

      Not checked in the free run.

    • cites Exley et al., 2008

      Not checked in the free run.

    • cites Pons et al., 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Results

    Fluctuating nicotine concentrations in smokers, with a fast rising phase in seconds and a slow decline over hours, are expected to produce receptor activation followed by desensitization that likely contributes to the wide range of effects of nicotine.

    “Fluctuating nicotine concentrations in smokers, with a fast rising phase in seconds and a slow decline over hours, are expected to produce receptor activation followed by desensitization that likely contributes to the wide range of effects of nicotine (Picciotto et al., 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Picciotto et al., 2008

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Results

    Treatment with 40 mg BID dianicline is predicted to result in unbound brain concentrations of 40-80 nM, which will cause only minimal desensitization of α4β2 nAChRs.

    “Finally, treatment with 40 mg BID dianicline is predicted to result in unbound brain concentrations of 40–80 nM, which will cause only minimal desensitization of α4β2 nAChRs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Results

    The predicted dianicline exposure is likely insufficient to significantly reduce craving when quitting, and will only marginally reduce nicotine-evoked reinforcing effects.

    “This is likely insufficient to significantly reduce craving when quitting, and will only marginally reduce nicotine-evoked reinforcing effects.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Differences in functional interactions between the partial agonist and the α4β2 nAChR will result in varying degrees of relief of craving and attenuation of nicotine reinforcement, and hence in clinical efficacy.

  • May combine two claims.

    Interpretationreasoning
    § Results

    Unbound nicotine concentrations from tobacco smoking (50-300 nM) and varenicline concentrations after therapeutic doses (30-130 nM) will markedly, but not fully, desensitize the receptors.

    “These data (grey bars in Figure 3) show that unbound nicotine concentrations from tobacco smoking (50–300 nM; Rose et al., 1999) and varenicline concentrations after therapeutic doses (30–130 nM) will markedly, but not fully, desensitize the receptors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rose et al., 1999

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Results

    Working together, the properties of potent α4β2 binding, sufficiently high unbound brain concentrations to allow desensitization and some activation, and prevention of inhaled nicotine binding result in a significant increase in efficacy over other treatments that do not meet these criteria.

    “Working together, these properties result in a significant increase in efficacy over other treatments that do not meet these criteria, either because of insufficient CNS drug exposure at the target site or because of inadequate functional potency.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The clinical outcome of treatment with partial agonists is determined both by their unbound human brain concentrations and their functional potencies at the target α4β2 nAChR.
    • The authors state this as an assumption: Differences in functional interactions between the partial agonist and the α4β2 nAChR will result in varying degrees of relief of craving and attenuation of nicotine reinforcement, and hence in clinical efficacy.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Results

    The poor brain penetration of cytisine has previously been attributed to its high hydrophilicity, that is, a lower logP value than nicotine and the other agonists.

    “The poor brain penetration of cytisine has previously been attributed to its high hydrophilicity, that is, a lower logP value than nicotine and the other agonists (Reavill et al., 1990; Tutka and Zatoński, 2005; Supporting Information Table S3).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Reavill et al., 1990

      Not checked in the free run.

    • cites Tutka and Zatoński, 2005

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Results

    At therapeutic doses, varenicline is predicted to minimally desensitize α7 nAChRs and not cause detectable activation of this receptor.

    “At therapeutic doses, varenicline is predicted to minimally desensitize α7 nAChRs and not causing detectable activation of this receptor.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Results

    The low Bu for 1.5 mg QID cytisine (2-10 nM) is predicted to cause significant desensitization, but not α4β2 nAChR activation.

    “In contrast, the low Bu for 1.5 mg QID cytisine (2–10 nM) is predicted to cause significant desensitization, but not α4β2 nAChR activation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Results

    Varenicline acts as a full α7 nAChR agonist (107% v ACh), but at concentrations significantly higher than estimated human brain concentrations.

    “Functional data confirm that varenicline acts as a full α7 nAChR agonist (107% v ACh) (Mihalak et al., 2006), but at concentrations that are significantly higher than estimated human brain concentrations.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mihalak et al., 2006

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Results

    The α7 nAChR has been implicated in the effects of nicotine.

    “In addition to β2-containing subtypes, the α7 nAChR has been implicated in the effects of nicotine (Mansvelder and McGehee, 2002; Mansvelder et al., 2002).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Mansvelder and McGehee, 2002

      Not checked in the free run.

    • cites Mansvelder et al., 2002

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Results

    A comparative meta-analysis showed an estimated OR of 3.1 (2.5-3.8) for varenicline versus placebo at 6 months post-quit, while those for individual nicotine replacement therapies were 2.3 (1.7-3.0) or lower.

    “A comparative meta-analysis of abstinence rates versus placebo at 6 months post-quit for available smoking cessation medications showed an estimated OR (95% CI) of 3.1 (2.5–3.8) for varenicline, while those for individual nicotine replacement therapies were 2.3 (1.7–3.0) or lower (Fiore et al., 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fiore et al., 2008

      Not checked in the free run.

34 of 34

  • The authors state this as an assumption.

    Rat and human have the same brain-to-plasma ratio for each compound.

    “assuming that rat and human have the same B/P ratio for each compound.”

  • The paper relies on this without support.

    The clinical outcome of treatment with partial agonists is determined both by their unbound human brain concentrations and their functional potencies at the target α4β2 nAChR.

    “As with other centrally acting drugs, the clinical outcome of treatment with partial agonists is determined both by their unbound human brain concentrations and their functional potencies at the target α4β2 nAChR, and our aim was to evaluate whether key pharmacokinetic and pharmacodynamic properties of the three partial agonists would have predicted differences in their clinical efficacies.”

  • The authors state this as an assumption.

    Differences in functional interactions between the partial agonist and the α4β2 nAChR will result in varying degrees of relief of craving and attenuation of nicotine reinforcement, and hence in clinical efficacy.

    “The translation of these data to the clinic is based on the hypothesis that differences in functional interactions between the partial agonist and the α4β2 nAChR will result in varying degrees of relief of craving and attenuation of nicotine reinforcement, and hence in clinical efficacy.”

  • The authors state this as an assumption.

    The OR of dianicline is comparable to or lower than that of cytisine.

    “Because in addition, further development of dianicline was halted in 2008 (Sanofi-Aventis press release, 2008), it is reasonable to assume that the OR of dianicline is comparable to or lower than that of cytisine.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • These results may be due to differential effects of varenicline and sazetidine-A on nAChR activation and desensitization.

    “Therefore, these results may be due to differential effects of varenicline and sazetidine-A on nAChR activation and desensitization (Caldarone et al, 2011; Rollema et al, 2010; Xiao et al, 2006; Zwart et al, 2008).”

    From Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal (2013) · cites this paper as Rollema et al, 2010

  • The therapeutic window for varenicline corresponds to the point at which there is enough unbound agonist to elicit combined desensitization and receptor activation.

    “recent evidence suggests that the therapeutic window for varenicline corresponds to the point at which there is enough unbound agonist to elicit combined desensitization and receptor activation (Rollema et al, 2010).”

    From Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal (2013) · cites this paper as Rollema et al, 2010

  • Varenicline levels in brain following acute administration remain in the low micromolar range for up to 6 h.

    “In addition, deposition studies show that varenicline levels in brain following an acute administration remain in the low micromolar range for up to 6 h (Rollema et al, 2010).”

    From Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal (2013) · cites this paper as Rollema et al, 2010

  • The brain levels and brain-to-blood ratios for nicotine and varenicline matched values reported in earlier work.

    “moreover, both the concentrations and the brain-to-blood ratios of nicotine and varenicline were similar to previously reported values (Ghosheh et al., 1999;Doura et al., 2008;Rollema et al., 2010).”

    From Chronic Sazetidine-A at Behaviorally Active Doses Does Not Increase Nicotinic Cholinergic Receptors in Rodent Brain (2012) · cites this paper as Rollema et al., 2010

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Cytisine is described as both ineffective and significantly desensitizing

    Major

    The abstract says recommended cytisine doses produce brain concentrations insufficient to affect α4β2 receptors. The discussion says those same doses are predicted to cause significant receptor desensitization.

  • Cytisine muscle-receptor Ki differs from Table 4

    Major

    The prose reports cytisine's muscle-receptor Ki as 430 nM, whereas Table 4 reports 492 ± 11 nM.

  • Nicotine binding affinity and the stated 15-fold comparison disagree with Table 4

    Minor

    Table 4 gives nicotine and varenicline α4β2 Ki values of 16.1 and 0.4 nM, respectively. Their ratio is 40.25, not 15; the prose also gives nicotine's Ki as 6.1 rather than 16.1 nM.

    Reported 15 · recomputed 40.25

  • Predicted dianicline plasma concentration differs from Table 3

    Minor

    The prose reports 216 nM for dianicline's predicted free steady-state plasma concentration, but the cited table lists 214 nM.

  • The α7 affinity comparison is less than 20-fold for nicotine

    Minor

    Table 4 gives α7 Ki values of 2110 nM for nicotine and 125 nM for varenicline. That is a 16.88-fold affinity difference, contrary to the stated minimum of 20-fold over the other compounds.

    Reported 20 · recomputed 16.88

5 of 5

Cites

Flagged first, then by citations

1 of the 49 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Sanofi‐Aventis press release February 12 2008 p.14.http://en.sanofi‐aventis.com/press/press%20releases/2008/ppc14630.asp.

Cited by

Sorted by citations

Related

Authors
Rollema, H., Shrikhande, A., Ward, K., Tingley III, F., Coe, J., O'Neill, B., Tseng, E., Wang, E., Mather, R., Hurst, R., Williams, K., de Vries, M., Cremers, T., Bertrand, S., & Bertrand, D.
Affiliations
  • Pfizer (United States) (US)
  • University of Groningen (NL)
  • HiQScreen (Switzerland) (CH)
  • University of Geneva (CH)
Corresponding author
Rollema, H
ORCID
Venue
British Journal of Pharmacology
Publisher
Wiley
Published
2010-04-26
Volume
160
Issue
2
Pages
334-345
ISSN
  • 0007-1188 (ISSN-L)
  • 1476-5381
DOI
10.1111/j.1476-5381.2010.00682.x
PMC
PMC2874855
OpenAlex
W2165094621
Semantic Scholar
1191629a1b48d758592ada45966ec228976b716d
Cited by
162
References
49
Citations by year
2026: 7 · 2025: 10 · 2024: 2 · 2023: 8 · 2022: 4 · 2021: 8 · 2020: 6 · 2019: 13 · 2018: 6 · 2017: 7 · 2016: 8 · 2015: 9 · 2014: 20 · 2013: 18 · 2012: 18
FWCI
7.29
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • British Journal of Pharmacology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Funders
  • Pfizer
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Alkaloids: synthesis and pharmacology
Keywords
varenicline, cytisine, α4β2 nicotinic acetylcholine receptor, partial agonists, nicotine dependence, smoking cessation, brain pharmacokinetics, receptor desensitization, receptor activation, brain penetration
MeSH terms
Varenicline, Quinolizidine Alkaloids, ATP-Binding Cassette Sub-Family B Member 4, Alkaloids, Animals, Azepines, Azocines, Benzazepines, Brain, Dopamine, Heterocyclic Compounds, 4 or More Rings, Humans, Limbic System, Male, Quinolizines, Quinoxalines, Receptors, Nicotinic, Tissue Distribution, Tobacco Use Disorder, Xenopus laevis, Smoking Cessation, Rats, Sprague-Dawley, Mice, Knockout, ATP Binding Cassette Transporter, Subfamily B, Nicotinic Agonists, Mice, Rats

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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