Varenicline: An α4β2 Nicotinic Receptor Partial Agonist for Smoking Cessation

Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, USA.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 06/2005; 48(10):3474-7. DOI: 10.1021/jm050069n
Source: PubMed


Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued alpha4beta2 nicotinic receptor partial agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high alpha4beta2 nAChR affinity and the desired in vivo dopaminergic profile.

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Available from: Michael G. Vetelino, Oct 09, 2014
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    • "Varenicline, in addition to its known partial agonist activity at a4b2 nAChRs (Coe et al., 2005; Rollema et al., 2007), has recently been shown to posses high affinity for and partial agonist activity at a6 ⁄ nAChRs in the DA system. Using agonist-evoked DA release from mouse striatal synaptosomes, Grady and colleagues measured varenicline-induced release at aCtxMIIresistant (a4b2 and a4a5b2 nAChRs) and aCtxMIIsensitive (a4a6b2b3, a4a6b2, a6b2b3, and a6b2 "
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    ABSTRACT: Acetylcholine acts through nicotinic and muscarinic acetylcholine (ACh) receptors in ventral midbrain and striatal areas to influence dopamine (DA) transmission. This cholinergic control of DA transmission is important for processes such as attention and motivated behavior, and is manipulated by nicotine in tobacco products. Identifying and characterizing the key ACh receptors involved in cholinergic control of DA transmission could lead to small molecule therapeutics for treating disorders involving attention, addiction, Parkinson's disease, and schizophrenia. α6-containing nicotinic acetylcholine receptors (nAChRs) are highly and specifically expressed in midbrain DA neurons, making them an attractive drug target. Here, we used genetic, pharmacological, behavioral, and biophysical approaches to study this nAChR subtype. For many experiments, we used mice expressing mutant α6 nAChRs ("α6L9S" mice) that increase the sensitivity of these receptors to agonists such as ACh and nicotine. Taking advantage of a simple behavioral phenotype exhibited by α6L9S mice, we compared the ability of full versus partial α6∗ nAChR agonists to activate α6∗ nAChRs in vivo. Using local infusions of both agonists and antagonists into brain, we demonstrate that neurons and nAChRs in the midbrain are sufficient to account for this behavioral response. To complement these behavioral studies, we studied the ability of in vivo α6∗ nAChR activation to support plasticity changes in midbrain DA neurons that are relevant to behavioral sensitization and addiction. By coupling local infusion of drugs and brain slice patch clamp electrophysiology, we show that activating α6∗ nAChRs in midbrain DA areas is sufficient to enhance glutamatergic transmission in VTA DA neurons. Together, these results from in vivo studies strongly suggest that α6∗ nAChRs expressed by VTA DA neurons are positioned to strongly influence both DA-mediated behaviors and the induction of synaptic plasticity by nicotine. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 07/2015; 304. DOI:10.1016/j.neuroscience.2015.07.052 · 3.36 Impact Factor
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    • "Pharmacologically, varenicline behaves as a partial agonist of α4β2 nAChRs and a full agonist of α7 nAChRs [9] [10] [11] [12]. Through its intrinsic partial activation of α4β2 nAChRs, varenicline elicits a moderate and sustained increase of dopamine levels in the brain reward system, which would elevate low dopamine levels observed during smoking cessation attempts [4,11–14]. "
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    ABSTRACT: To determine the structural components underlying differences in affinity, potency, and selectivity of varenicline for several human (h) nicotinic acetylcholine receptors (nAChRs), functional and structural experiments were performed. The Ca(2+) influx results established that: (a) varenicline activates (μM range) nAChR subtypes with the following rank sequence: hα7>hα4β4>hα4β2>hα3β4≫>hα1β1γδ; (b) varenicline binds to nAChR subtypes with the following affinity order (nM range): hα4β2~hα4β4>hα3β4>hα7≫>Torpedo α1β1γδ. The molecular docking results indicating that more hydrogen bond interactions are apparent for α4-containing nAChRs in comparison to other nAChRs may explain the observed higher affinity; and that (c) varenicline is a full agonist at hα7 (101%) and hα4β4 (93%), and a partial agonist at hα4β2 (20%) and hα3β4 (45%), relative to (±)-epibatidine. The allosteric sites found at the extracellular domain (EXD) of hα3β4 and hα4β2 nAChRs could explain the partial agonistic activity of varenicline on these nAChR subtypes. Molecular dynamics simulations show that the interaction of varenicline to each allosteric site decreases the capping of Loop C at the hα4β2 nAChR, suggesting that these allosteric interactions limit the initial step in the gating process. In conclusion, we propose that in addition to hα4β2 nAChRs, hα4β4 nAChRs can be considered as potential targets for the clinical activity of varenicline, and that the allosteric interactions at the hα3β4- and hα4β2-EXDs are alternative mechanisms underlying partial agonism at these nAChRs. Copyright © 2014 Elsevier B.V. All rights reserved.
    Biochimica et Biophysica Acta (BBA) - Biomembranes 12/2014; 1848(2). DOI:10.1016/j.bbamem.2014.11.003 · 3.84 Impact Factor
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    • "cessation. It is a partial agonist of a4b2 nicotinic acetylcholine receptors (nAChRs), and a full agonist of a7 nAChR [4] [5]. Varenicline is more effective than nicotine replacement therapy and frequently used clinically for smoking cessation [6] [7] [8]. "
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    ABSTRACT: Varenicline is one of the most widely used drugs for smoking cessation. However, whether an adverse effect of varenicline is associated with the risk of serious cardiovascular events remains controversial. In this study, we determined if varenicline increases the risk of cardiovascular events using apolipoprotein E knockout (ApoE KO) mice. ApoE KO mice (8 weeks old) were injected with varenicline 0.5 mg kg(-1) day(-1) for 3 weeks. Varenicline aggravated atherosclerotic plaque formation in whole aorta from ApoE KO mice compared with vehicle. Methyllycaconitine, an alpha 7 nicotinic acetylcholine receptor (nAChR) antagonist, inhibited varenicline-induced aggravated plaque formation. Our findings show that varenicline progresses atherosclerotic plaque formation through alpha 7 nAChR, and thereby increases the risk of cardiovascular events. (C) 2014 The Authors. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 11/2014; 455(3-4). DOI:10.1016/j.bbrc.2014.10.150 · 2.30 Impact Factor
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