Nicotinic receptor partial agonists as novel compounds for the treatment of smoking cessation

Tutka, Piotr

doi:10.1517/13543784.17.10.1473

Cited by 31 publications

(21 citation statements)

References 65 publications

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“…Currently, smoking cessation therapies include nicotine replacement products and the monoamine reuptake inhibitor bupropion. In addition, the U.S. Food and Drug Administration (FDA) has recently approved the nicotine receptor agonist varenicline and nicotine vaccines as newer medications for smoking cessation (Rollema et al, 2007b; Tutka, 2008; Xi et al, in press). …”

Section: Introductionmentioning

confidence: 99%

Varenicline attenuates nicotine-enhanced brain-stimulation reward by activation of α4β2 nicotinic receptors in rats

Spiller

et al. 2009

Neuropharmacology

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Varenicline, a partial α4β2 and full α7 nicotinic receptor agonist, has been shown to inhibit nicotine self-administration and nicotine-induced increases in extracellular dopamine in the nucleus accumbens. In the present study, we investigated whether varenicline inhibits nicotine-enhanced electrical brain-stimulation reward (BSR), and if so, which receptor subtypes are involved. Systemic administration of nicotine (0.25–1.0 mg/kg, i.p.) or varenicline (0.03–3 mg/kg, i.p.) produced biphasic effects, with low doses producing enhancement (e.g., decreased BSR threshold), and high doses inhibiting BSR. Pretreatment with low dose (0.03–1.0 mg/kg) varenicline dose-dependently attenuated nicotine (0.25 or 0.5 mg/kg)-enhanced BSR. The BSR-enhancing effect produced by varenicline was blocked by mecamylamine (a high affinity nicotinic receptor antagonist) or dihydro-β-erythroidine (a relatively selective nicotinic α4-containing receptor antagonist), but not methyllycaconitine (a selective α7 receptor antagonist), suggesting an effect mediated by activation of α4β2 receptors. This suggestion is supported by findings that the α4β2 receptor agonist SIB-1765F produced a dose-dependent enhancement of BSR, while pretreatment with SIB-1765F attenuated nicotine (0.5 mg/kg)-enhanced BSR. In contrast, the selective α7 receptor agonist ARR-17779, altered neither BSR itself nor nicotine-enhanced BSR, at any dose tested. These findings suggest that: 1) varenicline inhibits nicotine-enhanced BSR, supporting its use as a smoking cessation aid; and 2) varenicline-enhanced BSR by itself and varenicline's anti-nicotine effects are mediated by activation of α4β2, but not α7, receptors.

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Section: Introductionmentioning

confidence: 99%

Varenicline attenuates nicotine-enhanced brain-stimulation reward by activation of α4β2 nicotinic receptors in rats

Spiller

et al. 2009

Neuropharmacology

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“…α 4 β 2 nAChRs [37] . Cytisine demonstrates little binding to non-nicotinic neurotransmitter receptors or other receptors [38] . However, animal studies have demonstrated that the penetration of cytisine into the central nervous system is poor compared to nicotine [39] .…”

Section: Vareniclinementioning

confidence: 99%

“…Varenicline was developed from the plant alkaloid cytisine, which had been recognized as a partial agonist of nAChRs mediating the drug-reinforcing effects of nicotine in the midbrain, as discussed above [38] . Through the modulation of nAChRs, varenicline provides the opportunity to modify tobacco dependence directly and with high specificity.…”

Section: Scientifi C Rationalementioning

confidence: 99%

Emerging drugs for the treatment of tobacco dependence

Ebbert

2009

Expert Opinion on Emerging Drugs

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“…Both nonpharmacological and pharmacological interventions have demonstrated efficacy in smoking cessation 7. At present, first-line pharmaceutical treatments include nicotine replacement therapy (NRT),8 bupropion ( 2 ) and varenicline ( 3 ) 9,10. While these treatments are useful in helping 5–20% of smokers abstain long-term, new pharmacotherapies are needed that are either more effective or can impact those individuals not helped by existing treatments.…”

Section: Introductionmentioning

confidence: 99%

“…The effectiveness of varenicline in smoking cessation is thought to be due to its action as a partial agonist at α4β2-containing nicotinic acetylcholine receptors (nAChR) 9,10. The mechanism for bupropion’s effectiveness as a smoking-cessation aid appears to be more multi-faceted 11.…”

Section: Introductionmentioning

confidence: 99%

Nicotinic Acetylcholine Receptor Efficacy and Pharmacological Properties of 3-(Substituted phenyl)-2β-substituted Tropanes

et al. 2010

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There is a need for different and better aids to tobacco product use cessation. Useful smoking cessation aids, bupropion (2) and varenicline (3), share some chemical features with 3-phenyltropanes (4), which have promise in cocaine dependence therapy. Here we report studies to generate and characterize pharmacodynamic features of 3-phenyltropane analogues. These studies extend our work on the multiple molecular target model for aids to smoking cessation. We identified several new 3-phenyltropane analogues that are superior to 2 in inhibition of dopamine, norepinephrine, and sometimes serotonin reuptake. All of these ligands also act as inhibitors of nicotinic acetylcholine receptor (nAChR) function with a selectivity profile that favors, like 2, inhibition of α3β4*-nAChR. Many of these ligands also block acute effects of nicotine-induced antinociception, locomotor activity, and hypothermia. Importantly, all except one of the analogues tested have better potencies in inhibition of nicotine conditioned place preference than 2. We have identified new compounds that have utility as research tools and possible promise for treatment of nicotine dependence.

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Nicotinic receptor partial agonists as novel compounds for the treatment of smoking cessation

Cited by 31 publications

References 65 publications

Varenicline attenuates nicotine-enhanced brain-stimulation reward by activation of α4β2 nicotinic receptors in rats

Varenicline attenuates nicotine-enhanced brain-stimulation reward by activation of α4β2 nicotinic receptors in rats

Emerging drugs for the treatment of tobacco dependence

Nicotinic Acetylcholine Receptor Efficacy and Pharmacological Properties of 3-(Substituted phenyl)-2β-substituted Tropanes

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