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Pre‐clinical properties of the α4β2 nicotinic acetylcholine receptor partial agonists varenicline, cytisine and dianicline translate to clinical efficacy for nicotine dependence
Open accessAbstract
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.
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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.
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43 Own result · 25 Not checked yet · 24 Own interpretation · 8 No basis given
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“It has 15-fold higher affinity than nicotine (Ki= 6.1 nM)”
plain- Asserted: passes — The authors put it forward as true.
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“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).”
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In the paper
“and that varenicline binds to the α4β2 subtype with higher receptor affinity (Ki= 0.4 nM) than the other compounds.”
plain- Asserted: passes — The authors put it forward as true.
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“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).”
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“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).”
plain- Asserted: passes — The authors put it forward as true.
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- The authors state this as an assumption: Rat and human have the same brain-to-plasma ratio for each compound.
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In the paper
“while in addition, central exposures were 4- to 19-fold lower for dianicline and cytisine than for nicotine and varenicline.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
plain- Asserted: passes — The authors put it forward as true.
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- The authors state this as an assumption: Rat and human have the same brain-to-plasma ratio for each compound.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Each compound, in a dose-dependent manner, increased dopamine turn-over in rat nucleus accumbens.”
plaindirect- Asserted: passes — The authors put it forward as true.
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“while varenicline is moderately protein bound (fu > 0.5) in plasma and brain (Table 1).”
plain- Asserted: passes — The authors put it forward as true.
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“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).”
plain- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 29
- Probably not a substantial claim. 5
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“that dianicline is unbound in plasma and 60% bound in brain”
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“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.”
plaindirect- Asserted: passes — The authors put it forward as true.
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“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.”
boosteddirect- Asserted: passes — The authors put it forward as true.
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“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).”
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“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).”
What the sources say
- Not checked yetcites Rollema et al., 2007b
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In the paper
“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).”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
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In the paper
“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).”
plain- Asserted: passes — The authors put it forward as true.
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“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.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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)”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
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In the paper
“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).”
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In the paper
“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.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“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.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
What the sources say
- Not checked yetcites Cahill et al., 2008
- Not checked yetcites Nides et al., 2008
- Not checked yetcites Etter, 2006
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“suggesting either overestimation of unbound brain exposures or active transport of both compounds into the brain or underestimation of CSF concentrations.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
What the sources say
- Not checked yetcites Drenan et al., 2008
- Not checked yetcites Exley et al., 2008
- Not checked yetcites Pons et al., 2008
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
What the sources say
- Not checked yetcites Picciotto et al., 2008
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This is likely insufficient to significantly reduce craving when quitting, and will only marginally reduce nicotine-evoked reinforcing effects.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- 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.
In the paper
“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.”
What the sources say
- Not checked yetcites Rose et al., 1999
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
What the sources say
- Not checked yetcites Reavill et al., 1990
- Not checked yetcites Tutka and Zatoński, 2005
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At therapeutic doses, varenicline is predicted to minimally desensitize α7 nAChRs and not causing detectable activation of this receptor.”
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
What the sources say
- Not checked yetcites Mihalak et al., 2006
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
What the sources say
- Not checked yetcites Mansvelder and McGehee, 2002
- Not checked yetcites Mansvelder et al., 2002
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
What the sources say
- Not checked yetcites Fiore et al., 2008
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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.”
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?
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Abstract
“recommended doses of cytisine, despite its high in vitro potency, are predicted to result in brain concentrations that are insufficient to affect α4β2 nAChRs.”
§ Results
“the low Bu for 1.5 mg QID cytisine (2–10 nM) is predicted to cause significant desensitization, but not α4β2 nAChR activation.”
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Results
“Cytisine is the only compound showing moderate affinity for the muscle α1-containing nAChRs (Ki= 430 nM)”
§ Results
“α1β1γδ ([ 3 H]-α bungarotoxin) 2090 ± 620 8200 ± 1530 492 ± 11 >12 500”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
“It has 15-fold higher affinity than nicotine (Ki= 6.1 nM)”
Reported 15 · recomputed 40.25
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Results
“to be 36 and 216 nM, respectively (Table 3).”
§ Results
“Dianicline 2 × 40 14.1 3.3 2.7 0.82 1 214 37–84”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
“it binds to this nAChR subtype with at least 20-fold higher affinity than the other compounds (Ki values > 2.1 µM).”
Reported 20 · recomputed 16.88
Citations
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“This is consistent with nAChR-mediated dopamine release being predominantly mediated via activation and desensitization of a4b2-containing nAChRs located on dopaminergic and GABAergic neurons (Picciotto et al., 1998; 2008; Mansvelder and McGehee, 2002; Mansvelder et al., 2002; Laviolette and Van der Kooy, 2004; Maskos…”
Background
Research works printed but not linked: 1
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Cited by
Sorted by citations
Nicotinic acetylcholine receptors: From basic science to therapeutics
Hurst, R. S., Rollema, H., & Bertrand, D. (2012) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2012.08.012 · Cited by 543
Self-citationPlacebo-controlled trial of cytisine for smoking cessation
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Ultrapotent chemogenetics for research and potential clinical applications
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“Varenicline is an especially attractive molecule for chemogenetic applications in the central nervous system because (i) it is well-tolerated by patients at low doses (16, 17), (ii) it has excellent brain penetrance (18), (iii) it is not a PgP substrate (19), (iv) it has low binding to plasma proteins, and (v) it has…”
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Pharmacokinetic Drug Interactions with Tobacco, Cannabinoids and Smoking Cessation Products
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Treatment of nicotine addiction: present therapeutic options and pipeline developments
Polosa, R., & Benowitz, N. L. (2011) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2010.12.008 · Cited by 135
Neurobiological Mechanisms of Nicotine Reward and Aversion
Wills, L. P., Ables, J. L., Braunscheidel, K. M., Caligiuri, S. P. B., Elayouby, K. S., Fillinger, C., Ishikawa, M., Moen, J. K., & Kenny, P. J. (2022) · Pharmacological Reviews · doi:10.1124/pharmrev.121.000299 · Cited by 134
“These compounds have shown clinical utility as smoking cessation medications in humans (Barlow and McLeod, 1969; Reavill et al., 1990; Etter, 2006; Rollema et al., 2010).”
BackgroundA Review of the Clinical Pharmacokinetics and Pharmacodynamics of Varenicline for Smoking Cessation
Faessel, H. M., Obach, R. S., Rollema, H., Ravva, P., Williams, K. E., & Burstein, A. H. (2010) · Clinical Pharmacokinetics · doi:10.2165/11537850-000000000-00000 · Cited by 127
Self-citationTutka, P., Vinnikov, D. V., Courtney, R. J., & Benowitz, N. L. (2019) · Addiction · doi:10.1111/add.14721 · Cited by 134
Booth, R., & Kim, H. (2014) · Annals of Biomedical Engineering · doi:10.1007/s10439-014-1086-5 · Cited by 120
Hendrickson, L. M., Zhao-Shea, R., Pang, X.-Y., Gardner, P. D., & Tapper, A. R. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.2601-10.2010 · Cited by 101
“…and behavioral experiments, varenicline doses were chosen based on previous studies of varenicline effects on nicotine self-administration and DA turnover in addition to predicted therapeutic concentrations achieved in smokers’ brains (O’Connor et al., 2010; Rollema et al., 2010).”
BackgroundMethodInfluentialChatterjee, S., Steensland, P., Simms, J. A., Holgate, J. Y., Coe, J. W., Hurst, R. S., Shaffer, C. L., Lowe, J. A., III, Rollema, H., & Bartlett, S. E. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2010.191 · Cited by 103
“As shown previously (Rollema et al., 2007; Rollema et al., 2010), varenicline can potently interact with α 4 β 2 nAChRs and at the C b,u achieved after 1 and 2 mg/kg it will mainly inhibit this subtype (Figure S1 C).”
Self-citationCognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Froestl, W., Muhs, A., & Pfeifer, A. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-121186 · Cited by 94
Cytisine and cytisine derivatives. More than smoking cessation aids
Gotti, C., & Clementi, F. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105700 · Cited by 86
Functional alterations by a subgroup of neonicotinoid pesticides in human dopaminergic neurons
Loser, D., Hinojosa, M. G., Blum, J. H., Schaefer, J., Brüll, M., Johansson, Y., Suciu, I., Grillberger, K., Danker, T., Möller, C., et al. (2021) · Archives of Toxicology · doi:10.1007/s00204-021-03031-1 · Cited by 77
Pérez, E. G., Méndez‐Gálvez, C., & Cassels, B. K. (2012) · Natural Product Reports · doi:10.1039/c2np00100d · Cited by 75
Igari, M., Alexander, J. C., Ji, Y. R., Qi, X., Papke, R. L., & Bruijnzeel, A. W. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.216 · Cited by 75
Loser, D., Grillberger, K., Hinojosa, M. G., Blum, J. H., Haufe, Y., Danker, T., Johansson, Y., Möller, C., Nicke, A., Bennekou, S. H., et al. (2021) · Archives of Toxicology · doi:10.1007/s00204-021-03168-z · Cited by 83
Wong, D. F., Kuwabara, H., Pomper, M. G., Holt, D. P., Brašić, J. R., George, N., Фролов, Б. А., Willis, W. D., Gao, Y., Valentine, H., et al. (2014) · Molecular Imaging and Biology · doi:10.1007/s11307-014-0779-3 · Cited by 74
“Here, we have presented evidence for blockade in the mice brain with DMXB-A and measurable blockade with the α7-nAChR partial agonist EVP-6124 [45] and varenicline, which binds at two main CNS nAChR subtypes, α7-nAChR and α4β2 [46].”
BackgroundMethodFeduccia, A. A., Simms, J. A., Mill, D., Yi, H. Y., & Bartlett, S. E. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12690 · Cited by 70
“The efficacy of varenicline for smoking cessation is attributed to a dual action of (1) moderately enhancing DA release in the NAc and (2) the attenuation of nicotine-induced DA release by competitively blocking the nAChR binding site (Rollema et al., 2007; 2010).”
BackgroundVarenicline Is a Potent Agonist of the Human 5-Hydroxytryptamine3 Receptor
Lummis, S. C. R., Thompson, A. J., Bencherif, M., & Lester, H. A. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.185306 · Cited by 71
“This study shows that varenicline is a relatively potent agonist of human 5-HT3A receptors and binds to these recep- tors at clinically relevant concentrations (32–131 nM; Rollema et al., 2010).”
BackgroundBillen, B., Spurný, R., Brams, M., van Elk, R., Valera-Kummer, S., Yakel, J. L., Voets, T., Bertrand, D., Smit, A. B., & Ulens, C. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1116397109 · Cited by 71
“Lobeline and varenicline both display partial agonist action at α4β2 nAChR (7, 9).”
BackgroundResultInfluentialSelf-citationIon channels gated by acetylcholine and serotonin: structures, biology, and drug discovery
Wu, Z., Cheng, H. D., Jiang, Y., Melcher, K., & Xu, H. E. (2015) · Acta Pharmacologica Sinica · doi:10.1038/aps.2015.66 · Cited by 67
Determining the pharmacokinetics of nicotinic drugs in the endoplasmic reticulum using biosensors
Shivange, A. V., Borden, P. M., Muthusamy, A. K., Nichols, A. L., Bera, K., Bao, H., Bishara, I., Jeon, J., Mulcahy, M. J., Cohen, B. N., et al. (2019) · The Journal of General Physiology · doi:10.1085/jgp.201812201 · Cited by 62
“Varenicline also permeates modestly well into the central nervous system (Rollema et al., 2010).”
InfluentialHannestad, J. O., Cosgrove, K. P., DellaGioia, N. F., Perkins, E., Bois, F., Bhagwagar, Z., Seibyl, J. P., McClure-Begley, T. D., Picciotto, M. R., & Esterlis, I. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.04.004 · Cited by 63
Derivatives of dibenzothiophene for PET imaging of α7-Nicotinic Acetylcholine Receptors
Gao, Y.-J., Kellar, K., Yasuda, R., Tran, T., Xiao, Y.-X., Dannals, R., & Horti, A. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm401184f · Cited by 59
Role for the nicotinic cholinergic system in movement disorders; therapeutic implications
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Hillmer, A. T., Li, S., Zheng, M., Scheunemann, M., Lin, S.-F., Nabulsi, N., Holden, D., Pracitto, R., Labaree, D. C., Ropchan, J. R., et al. (2017) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-017-3621-8 · Cited by 54
“While varenicline has an order of magnitude higher affinity for α7 nAChRs than nicotine [16], its affinity is still roughly three orders of magnitude lower than that of ASEM [9], and therapeutic doses of varenicline are not expected to induce functional effects on α7 nAChRs [38].”
Nicotinic receptor modulation to treat alcohol and drug dependence
Rahman, S., Engleman, E. A., & Bell, R. L. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2014.00426 · Cited by 60
“As with alcohol abuse and its treatment, nicotinic ligands that target α4β2∗ subtypes, particularly those expressed in the mesolimbic DA system, show promise for the management of nicotine addiction (Damaj et al., 1997; Coe et al., 2005; Rollema et al., 2007, 2010; Benowitz, 2009).”
BackgroundRecent Developments in Novel Antidepressants Targeting α4β2-Nicotinic Acetylcholine Receptors
Yu, L.-F., Zhang, H.-K., Caldarone, B. J., Eaton, J. B., Lukas, R. J., & Kozikowski, A. P. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm401937a · Cited by 56
Mineur, Y. S., Einstein, E. B., Seymour, P. A., Coe, J. W., O'Neill, B. T., Rollema, H., & Picciotto, M. R. (2011) · Behavioural Pharmacology · doi:10.1097/fbp.0b013e328347546d · Cited by 49
Self-citationDesigner receptor technology for the treatment of epilepsy
Lieb, A., Weston, M., & Kullmann, D. M. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.04.059 · Cited by 44
Yu, L.-F., Tückmantel, W., Eaton, J. B., Caldarone, B. J., Fedolak, A., Hanania, T., Brunner, D., Lukas, R. J., & Kozikowski, A. P. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm201301h · Cited by 48
Jeong, S. H., Newcombe, D. A. L., Sheridan, J. L., & Tingle, M. D. (2014) · Drug Testing and Analysis · doi:10.1002/dta.1707 · Cited by 48
AlSharari, S. D., Carroll, F. I., McIntosh, J. M., & Damaj, M. I. (2012) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.194506 · Cited by 43
“These results are consistent with in vitro assays showing that varenicline is a full agonist at α3β4* nAChR subtypes (Mihalak et al., 2006; Rollema et al., 2010).”
BackgroundResultDrug Discrimination in Methamphetamine-Trained Rats: Effects of Cholinergic Nicotinic Compounds
Desai, R. I., & Bergman, J. (2010) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.110.173773 · Cited by 46
Large Variation in Brain Exposure of Reference CNS Drugs: a PET Study in Nonhuman Primates
Schou, M., Varnäs, K., Lundquist, S., Nakao, R., Amini, N., Takano, A., Finnema, S. J., Halldin, C., & Farde, L. (2015) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyv036 · Cited by 45
The Nicotinic Acetylcholine Receptor as a Target for Antidepressant Drug Development
Philip, N. S., Carpenter, L. L., Tyrka, A. R., & Price, L. H. (2012) · The Scientific World JOURNAL · doi:10.1100/2012/104105 · Cited by 43
“The preclinical profile of dianicline is similar to that of varenicline, with its ability to affect dopamine release [70], although it has relatively weak CNS penetration [71].”
BackgroundQuik, M., Campos, C., Bordia, T., Strachan, J., Zhang, J., McIntosh, J. M., Letchworth, S. R., & Green-Jordan, K. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.03.038 · Cited by 43
“In fact, it has been suggested that nAChR agonists such as varenicline and sazetidine may act via nAChR desensitization or inactivation (Hussmann et al., 2012; Rezvani et al., 2012; Rollema et al., 2010; Zwart et al., 2008).”
BackgroundKurosawa, T., Higuchi, K., Okura, T., Kobayashi, K., Kusuhara, H., & Deguchi, Y. (2017) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2017.04.032 · Cited by 33
Development of Novel Pharmacotherapeutics for Tobacco Dependence: Progress and Future Directions
Harmey, D., Griffin, P. R., & Kenny, P. J. (2012) · Nicotine & Tobacco Research · doi:10.1093/ntr/nts201 · Cited by 37
“Similarly, the α4β2* nAChR partial agonist dianicline (SSR-591,813), developed by SanofiAventis for smoking cessation, is less efficacious than varenicline likely because of its poorer brain penetration properties (Rollema et al., 2010).”
BackgroundNeuronal Nicotinic Acetylcholine Receptor Modulators Reduce Sugar Intake
Shariff, M. R., Quik, M., Holgate, J. Y., Morgan, M., Patkar, O. L., Tam, V., Belmer, A., & Bartlett, S. E. (2016) · PLoS ONE · doi:10.1371/journal.pone.0150270 · Cited by 40
“Varenicline displays efficacy for smoking cessation by firstly, moderately enhancing DA release in the NAc and secondly, attenuating nicotine-induced DA release by competitively blocking the nAChR binding site [43, 44].”
BackgroundHorti, A. (2015) · Biochemical Pharmacology · doi:10.1016/j.bcp.2015.07.030 · Cited by 33
Gould, R. W., Czoty, P. W., Nader, S. H., & Nader, M. A. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.185538 · Cited by 37
“Consistent with the observation that nicotinic ACh receptor (nAChR) agonists can increase DA release (Rollema et al., 2007, 2010), nicotine, a high-efficacy agonist that binds nonselectively to all nAChR subtypes, fully substituted for cocaine in monkeys and rodents (Garza and Johanson, 1983; Desai…”
BackgroundResultInfluentialRollema, H., & Hurst, R. S. (2018) · Psychopharmacology · doi:10.1007/s00213-018-4921-9 · Cited by 42
“…190:157–170 1.15 Rollema 2007 Neuropharmacol 52:985–94 0.11 3100 45 6 Carroll 2008 Bioorg Med Chem 16:746–754 0.12 Anderson 2009 Biochem Pharmacol 78:844–851 0.08 160 17 Rollema 2010 Brit J Pharmacol 160: 334–345 2100 23 0.4 1400 22 0.07 50 Marks 2010 Biochem Pharmacol 80:1238–1251 Grady 2010…”
InfluentialSelf-citationSala, M., Braida, D., Pucci, L., Manfredi, I., Marks, M. J., Wageman, C. R., Grady, S. R., Loi, B., Fucile, S., Fasoli, F., et al. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.02204.x · Cited by 36
“…(Coe et al., 2005)] has high binding affinity for the a4b2 subtype and has demonstrated therapeutic potential for smoking cessation (reviewed in Rollema et al., 2007b; 2010), as well as for the treatment of alcohol dependence (McKee et al., 2009) and depression (reviewed in Mineur and…”
BackgroundSotomayor‐Zárate, R., Gysling, K., Busto, U. E., Cassels, B. K., Tampier, L., & Quintanilla, M. E. (2013) · Psychopharmacology · doi:10.1007/s00213-013-2974-3 · Cited by 37
“The greater effectiveness of varenicline than cytisine was suggested not only to be associated with their respective pharmacodynamic properties (Rollema et al. 2010) but also to their different pharmacokinetics.”
InfluentialPhase II Crossover Trial of Varenicline in Mild-to-Moderate Alzheimer's Disease
Kim, S. Y., Choi, S. H., Rollema, H., Schwam, E. M., McRae, T., Dubrava, S., & Jacobsen, J. (2013) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000355373 · Cited by 39
Self-citationStokes, C. A., & Papke, R. L. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.04.035 · Cited by 34
“and varenicline are agents presently in use as smoking cessation aids (Rollema et al., 2010).”
The Role of Mesoaccumbens Dopamine in Nicotine Dependence
Balfour, D. J. K. (2015) · Current topics in behavioral neurosciences · doi:10.1007/978-3-319-13482-6_3 · Cited by 36
Hussmann, G. P., Turner, J. R., Lomazzo, E., Venkatesh, R., Cousins, V., Xiao, Y., Yasuda, R. P., Wolfe, B. B., Perry, D. C., Rezvani, A. H., et al. (2012) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.198085 · Cited by 34
“This is in marked contrast to both nicotine and varenicline, which were highly concentrated in brain during both methods of chronic administration; 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.,…”
Probing Binding Interactions of Cytisine Derivatives to the α4β2 Nicotinic Acetylcholine Receptor.
Blom, A. M., Campello, H., Lester, H., Gallagher, T., & Dougherty, D. (2019) · Journal of the American Chemical Society · doi:10.1021/jacs.9b06580 · Cited by 22
Batsikadze, G., Paulus, W., Grundey, J., Kuo, M., & Nitsche, M. A. (2014) · Cerebral Cortex · doi:10.1093/cercor/bhu126 · Cited by 32
“As varenicline is a full agonist of α7 and potent partial agonist of α4β2 receptors, with a far greater affinity (4000- to 5000-fold) to α4β2 when compared with α7 receptors (Avalos et al. 2002; Jensen et al. 2005; Mihalak et al. 2006; Rollema et al. 2010), the α4β2 receptor might have a larger relevance for the resul…”
BackgroundMethodInfluentialKuwabara, H., Wong, D. F., Gao, Y., Valentine, H., Holt, D. P., Ravert, H. T., Dannals, R. F., & Horti, A. G. (2011) · Journal of Nuclear Medicine · doi:10.2967/jnumed.111.092338 · Cited by 33
“The blockade of 18F-AZAN was performed by pretreatment with cytisine, a partial agonist of nicotine that is selective for b2/b4-containing nAChR subtypes versus a7-nAChR (36,37).”
MethodSmoking cessation: present status and future perspectives
Caponnetto, P., Russo, C., & Polosa, R. (2012) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2012.02.005 · Cited by 30
“A number of partial agonists have been synthesized or purified and evaluated as possible smoking cessation treatments including dianacline, sazetidine-A and cytisine [44,45].”
BackgroundDivergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal
Turner, J. R., Wilkinson, D. S., Poole, R. L., Gould, T. J., Carlson, G. C., & Blendy, J. A. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.105 · Cited by 29
Bolchi, C., Valoti, E., Gotti, C., Fasoli, F., Ruggeri, P., Fumagalli, L., Binda, M., Mucchietto, V., Sciaccaluga, M., Budriesi, R., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00904 · Cited by 30
Yu, L.-F., Eaton, J. B., Fedolak, A., Zhang, H.-K., Hanania, T., Brunner, D., Lukas, R. J., & Kozikowski, A. P. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm301177j · Cited by 29
Nichols, A. L., Blumenfeld, Z., Fan, C., Luebbert, L., Blom, A. E. M., Cohen, B. N., Marvin, J. S., Borden, P. M., Kim, C. H., Muthusamy, A. K., et al. (2022) · eLife · doi:10.7554/elife.74648 · Cited by 25
Paolone, G., Mallory, C. S., Cherian, A. K., Miller, T. R., Blakely, R., & Sarter, M. F. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.07.032 · Cited by 24
“…the SAT at levels similar to those seen in wildtype mice despite exhibiting significantly attenuated levels of ACh (see Results), we conduced [3H]cytisine saturation binding assays to determine the state of a4b2containing nAChRs (Pabreza et al., 1991; Bitner et al., 2007; Rollema et al., 2010).”
MethodSimilar activity of mecamylamine stereoisomers in vitro and in vivo
Papke, R. L., Stokes, C. A., Muldoon, P. P., & Damaj, M. I. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.10.018 · Cited by 26
“…making it seem more likely that the future of nicotinic cholinergic therapeutics will come from designing well-tuned partial agonists that improve on current drugs such as varenicline (Benowitz, 2009; Coe et al., 2005; Rollema et al., 2010) or other cytisine derivatives (Mineur et al., 2009).”
DeBaker, M. C., Moen, J. K., Robinson, J. M., Wickman, K. D., & Lee, A. M. (2019) · Psychopharmacology · doi:10.1007/s00213-019-05426-6 · Cited by 24
“Varenicline (an α4β2 nicotinic acetylcholine receptor (nAChR) partial agonist) is approved for smoking cessation (Rollema et al., 2010), and naltrexone (an opioid receptor antagonist) and acamprosate (an NMDA receptor antagonist) are approved for alcohol use disorder (Franck and Jayaram-Lindström,…”
BackgroundOrthosteric and Allosteric Ligands of Nicotinic Acetylcholine Receptors for Smoking Cessation
Mohamed, T. S., Jayakar, S. S., & Hamouda, A. K. (2015) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2015.00071 · Cited by 27
“However, it did not increase cigarette smoking abstinence rates and was therefore discontinued in Phase 3 due to a lack of efficacy (end of treatment odds ratio of 1.2; Rollema et al., 2010; Tonstad et al., 2011).”
BackgroundInfluentialLotfipour, S., Mandelkern, M. A., Alvarez-Estrada, M., & Brody, A. L. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.20 · Cited by 26
“Based on in-vivo measurements of free drug exposures in the brain, the extracellular brain concentration is expected to be nearly identical to the plasma concentration (Rollema et al, 2010).”
BackgroundInfluentialPharmacologic Characterization of a Nicotine-Discriminative Stimulus in Rhesus Monkeys
Cunningham, C. S., Javors, M. A., & McMahon, L. R. (2012) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.193078 · Cited by 26
“Varenicline and cytisine were reported to have lower agonist efficacy than nicotine as evidenced by electrophysiological responses in vitro (Coe et al., 2005; Rollema et al., 2010).”
BackgroundArias, H. R., Feuerbach, D., Targowska‐Duda, K. M., Kaczor, A. A., Poso, A., & Jóźwiak, K. (2014) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2014.11.003 · Cited by 25
Cunningham, C. S., & McMahon, L. R. (2010) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.12.003 · Cited by 24
“Nicotine, varenicline, and cytisine were shown to have similar rank order binding affinity at receptor subtypes in the central nervous system as follows: heteromeric α4β2 > heteromeric α3β4 > homomeric α7subunits (Rollema et al., 2010).”
BackgroundInfluentialTonstad, S., Holme, I., & Tønnesen, P. (2010) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntq191 · Cited by 25
Pieńko, T., Grudzień, M. K., Taciak, P., et al. (2015) · Journal of Molecular Graphics and Modelling · doi:10.1016/j.jmgm.2015.11.003 · Cited by 25
Dose-dependent and sustained effects of varenicline on dopamine D2/3 receptor availability in rats
Crunelle, C. L., Schulz, S., de Bruin, K. M., Miller, M. L., van den Brink, W., & Booij, J. (2010) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2010.11.001 · Cited by 23
Ortiz, N. C., O'Neill, H. C., Marks, M. J., & Grady, S. R. (2012) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntr284 · Cited by 22
Varenicline in smoking cessation
Tonstad, S., & Rollema, H. (2010) · Expert Review of Respiratory Medicine · doi:10.1586/ers.10.27 · Cited by 18
Self-citationNicotinic receptors in airway disease
Borkar, N. A., Thompson, M. A., Bartman, C. M., Khalfaoui, L., Sine, S. M., Sathish, V., Prakash, Y. S., & Pabelick, C. M. (2023) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00268.2023 · Cited by 18
Weber, M. L., Hofland, C. M., Shaffer, C. L., Flik, G., Cremers, T. I. F. H., Hurst, R. S., & Rollema, H. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.04.027 · Cited by 19
“…fluoxetine, sertraline, paroxetine, citalopram) and, for comparison, two potent inhibitors of nAChRs: the non-selective nAChR channel blocker ( )-mecamylamine (Young et al., 2001; Shytle et al., 2002; Bacher et al., 2009) and the a4b2 nAChR partial agonist varenicline (Rollema et al., 2007; 2010).”
BackgroundMethodSelf-citationMotschman, C. A., Gass, J. C., Wray, J. M., Germeroth, L. J., Schlienz, N. J., Munoz, D. A., Moore, F. E., Rhodes, J. D., Hawk, L. W., & Tiffany, S. T. (2016) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2016.10.018 · Cited by 20
Govind, A. P., Vallejo, Y. F., Stolz, J. R., Yan, J.-Z., Swanson, G. T., & Green, W. N. (2017) · eLife · doi:10.7554/elife.25651 · Cited by 17
“It should also be noted that in order to estimate human brain varenicline concentrations, Rollema et al. (Rollema et al., 2010) used rat brain lysates to measure the high-affinity binding.”
BackgroundMethodInfluentialPetruczynik, A., Wróblewski, K., Misiurek, J., et al. (2020) · Toxins · doi:10.3390/toxins12090557 · Cited by 20
“Cytisine has an effect comparable to that of nicotine in stimulating dopamine release from striatal synaptosomes [3].”
BackgroundSajja, R. K., & Rahman, S. (2013) · Alcohol · doi:10.1016/j.alcohol.2013.02.003 · Cited by 20
Laikowski, M. M., Reisdorfer, F., & Moura, S. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867325666180410105135 · Cited by 17
Gass, J. C., Wray, J. M., Hawk, L. W., Mahoney, M. C., & Tiffany, S. T. (2012) · Psychopharmacology · doi:10.1007/s00213-012-2698-9 · Cited by 19
“This extinction may lead to a diminution in cue-specific craving (Rollema et al. 2007).”
Ravva, P., Gastonguay, M. R., Faessel, H. M., Lee, T. C., & NIAURA, R. S. (2014) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntu154 · Cited by 16
Nau, J. A., Wyatt, D. J., Rollema, H., et al. (2021) · Clinical Therapeutics · doi:10.1016/j.clinthera.2021.07.020 · Cited by 18
Self-citationAgonist and antagonist effects of cytisine in vivo
Radchenko, E. V., Драволина, О. А., & Bespalov, A. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.03.019 · Cited by 19
“However, one should note that cytisine is a very weak agonist at a4b2* receptors and, in functional assays, cytisine's potency is in micromolar range (Rollema et al., 2010).”
InfluentialZaveri, N. T., Bertrand, S., Yasuda, D. M., & Bertrand, D. (2014) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntu170 · Cited by 16
Self-citationRodriguez, J. S., Cunningham, C. S., de Moura, F. B., Ondachi, P. W., Carroll, F. I., & McMahon, L. R. (2014) · Psychopharmacology · doi:10.1007/s00213-014-3589-z · Cited by 15
“Nicotine, varenicline, and cytisine bind with high affinity at α4β2 nAChR receptors (Grady et al. 2010; Rollema et al. 2010).”
BackgroundResultHone, A. J., Rueda‐Ruzafa, L., Gordon, T. J., Gajewiak, J., Christensen, S. B., Dyhring, T., Albillos, A., & McIntosh, J. M. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.14966 · Cited by 15
Cytisine inhibits the anticonvulsant activity of phenytoin and lamotrigine in mice
Tutka, P., Mróz, T., Bednarski, J., Styk, A., Ognik, J., Mosiewicz, J., & Łuszczki, J. J. (2013) · Pharmacological Reports · doi:10.1016/s1734-1140(13)70978-2 · Cited by 16
Hone, A. J., McIntosh, J. M., Rueda‐Ruzafa, L., Passas, J., Guerín, C. D. C., Blázquez, J., Enguita, C. G., & Albillos, A. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13883 · Cited by 15
“Varenicline’s mechanism of action for reducing the consumption of nicotine is believed to be mediated by partial agonism of central nervous system a4b2 nAChRs (Coe et al. 2005; Rollema et al. 2010).”
BackgroundMethamphetamine-Like Discriminative-Stimulus Effects of Nicotinic Agonists
Desai, R. I., & Bergman, J. (2014) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.113.211235 · Cited by 15
“Varenicline previously has been characterized as a nicotinic partial agonist at the a4b2 receptor subtype (Rollema et al., 2007, 2010) and, depending on experimental conditions, may substitute partially or fully for nicotine in nicotine-trained rats and monkeys (Rollema et al., 2007; Smith et al.,…”
BackgroundNicotinic receptor partial agonists modulate alcohol deprivation effect in C57BL/6J mice
Sajja, R. K., & Rahman, S. (2013) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2013.07.009 · Cited by 15
Absolute Configuration and Pharmacology of the Poison Frog Alkaloid Phantasmidine
Fitch, R. W., Snider, B. B., Zhou, Q., Foxman, B. M., Pandya, A. A., Yakel, J. L., Olson, T. T., Al‐Muhtasib, N., Xiao, Y., Welch, K. D., et al. (2018) · Journal of Natural Products · doi:10.1021/acs.jnatprod.8b00062 · Cited by 15
Translational PET applications for brain circuit mapping with transgenic neuromodulation tools
Boehm, M. A., Bonaventura, J., Gomez, J. L., Solís, Ó., Stein, E. A., Bradberry, C. W., & Michaelides, M. (2021) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2021.173147 · Cited by 14
Farías-Cea, A., Leal, C., Hödar-Salazar, M., Esparza, E., Martínez-Duran, L., Fuentes, I., & Iturriaga-Vásquez, P. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310635 · Cited by 14
LaGamma, E. F., Kirtok, N., Chan, O. T. M., & Nankova, B. B. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00237.2014 · Cited by 15
“However, since they are less effective than the endogenous ligand, partial agonists can also act as antagonists by suppressing the effects of high concentrations of endogenous ligand (32, 35, 36).”
BackgroundMethodResultInfluentialRollema, H., Russ, C., Lee, T. C., Hurst, R. S., & Bertrand, D. (2014) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntt208 · Cited by 14
Self-citationGoutier, W., Kloeze, M. B., & McCreary, A. C. (2013) · Addiction Biology · doi:10.1111/adb.12108 · Cited by 15
“The high clinical efficacy of varenicline may also be accounted by the combination of high functional potency at α4β2 nAChRs, its ability to extensively desensitize these receptors, its high brain penetration (Rollema et al. 2010) and favorable kinetics in human (Faessel et al. 2006).”
BackgroundConstantin, A., & Clarke, P. B. S. (2017) · Psychopharmacology · doi:10.1007/s00213-017-4778-3 · Cited by 14
“After SC injection, plasma and brain nicotine levels peak within 5–10 min of injection, and then decline slowly over the next hour (Ghosheh et al. 1999; Hirschhorn and Rosecrans 1974; Pratt et al. 1983; Rollema et al. 2010; Tripathi et al. 1982; Turner 1975).”
BackgroundBrain Nicotinic Receptors as Emerging Targets for Drug Addiction
Rahman, S. (2011) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-385506-0.00008-9 · Cited by 14
Esaki, H., Deyama, S., Izumi, S., Katsura, A., Nishikawa, K., Nishitani, N., & Kaneda, K. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109672 · Cited by 13
Zaccarelli‐Magalhães, J., Sandini, T. M., Abreu, G., Petrocelli, B. M., Moreira, N. C. D. S., Reis-Silva, T. M., Lebrun, I., Flório, J. C., Ricci, E. L., Fukushima, A. R., et al. (2019) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2019.03.009 · Cited by 12
Metadata
- 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
- 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
- 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
- green
- www.ncbi.nlm.nih.gov
- 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 › Public Health, Environmental and Occupational Health › 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
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