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Identification
NameVarenicline
Accession NumberDB01273
TypeSmall Molecule
GroupsApproved, Investigational
Description

Varenicline is a prescription medication used to treat smoking addiction. This medication is the first approved nicotinic receptor partial agonist. Specifically, varenicline is a partial agonist of the alpha4/beta2 subtype of the nicotinic acetylcholine receptor. In addition it acts on alpha3/beta4 and weakly on alpha3beta2 and alpha6-containing receptors. A full agonism was displayed on alpha7-receptors.

On March 9, 2015, the U.S. Food and Drug Administration warned that Varenicline, in the form of Pfizer Inc’s quit-smoking drug, Chantix, has been associated with seizures and that some patients who drink while taking the drug may become aggressive or black out. Pfizer is conducting an additional safety study of the drug, results of which are expected in late 2015. The FDA said it is keeping the black box in place at least until the results of the trial are announced.

Structure
Thumb
Synonyms
CP-526,555
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Champixtablet0.5 mgoralPfizer Canada Inc2007-04-11Not applicableCanada
Champixtablet1.0 mgoralPfizer Canada Inc2007-04-11Not applicableCanada
ChantixkitProficient Rx LP2006-05-10Not applicableUs
Chantixtablet, film coated1 mg/1oralLake Erie Medical & Surgical Supply DBA Quality Care Products LLC2012-02-23Not applicableUs
Chantixtablet, film coated.5 mg/1oralPfizer Laboratories Div Pfizer Inc2006-05-10Not applicableUs
Chantixtablet, film coated.5 mg/1oralCarilion Materials Management2006-05-10Not applicableUs
Chantixtablet, film coated1 mg/1oralLake Erie Medical & Surgical Supply DBA Quality Care Products LLC2012-02-23Not applicableUs
Chantixtablet, film coated1 mg/1oralCarilion Materials Management2006-05-10Not applicableUs
Chantixtablet, film coated.5 mg/1oralLake Erie Medical & Surgical Supply DBA Quality Care Products LLC2011-12-28Not applicableUs
ChantixkitU.S. Pharmaceuticals2006-05-10Not applicableUs
Chantixtablet, film coated1 mg/1oralRebel Distributors Corp2006-05-10Not applicableUs
Chantixtablet, film coated.5 mg/1oralCardinal Health2006-05-10Not applicableUs
ChantixkitRebel Distributors Corp2006-05-10Not applicableUs
Chantixtablet, film coated1 mg/1oralPhysicians Total Care, Inc.2006-09-01Not applicableUs
Chantixtablet, film coated.5 mg/1oralRebel Distributors Corp2006-05-10Not applicableUs
ChantixkitPhysicians Total Care, Inc.2006-09-01Not applicableUs
ChantixkitPfizer Laboratories Div Pfizer Inc2006-05-10Not applicableUs
ChantixkitLake Erie Medical & Surgical Supply DBA Quality Care Products LLC2006-05-10Not applicableUs
Chantixtablet, film coated1 mg/1oralPfizer Laboratories Div Pfizer Inc2006-05-10Not applicableUs
Gd-vareniclinetablet1.0 mgoralGenmed A Division Of Pfizer Canada IncNot applicableNot applicableCanada
Gd-vareniclinetablet0.5 mgoralGenmed A Division Of Pfizer Canada IncNot applicableNot applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixtures
NameLabellerIngredients
ChampixPfizer Canada Inc
Gd-vareniclineGenmed A Division Of Pfizer Canada Inc
Salts
Name/CASStructureProperties
Varenicline tartrate
Thumb
  • InChI Key: TWYFGYXQSYOKLK-LREBCSMRSA-N
  • Monoisotopic Mass: 361.127385355
  • Average Mass: 361.3493
DBSALT000548
Categories
UNIIW6HS99O8ZO
CAS number249296-44-4
WeightAverage: 211.2624
Monoisotopic: 211.110947431
Chemical FormulaC13H13N3
InChI KeyInChIKey=JQSHBVHOMNKWFT-DTORHVGOSA-N
InChI
InChI=1S/C13H13N3/c1-2-16-13-5-11-9-3-8(6-14-7-9)10(11)4-12(13)15-1/h1-2,4-5,8-9,14H,3,6-7H2/t8-,9+
IUPAC Name
(1R,12S)-5,8,14-triazatetracyclo[10.3.1.0²,¹¹.0⁴,⁹]hexadeca-2,4,6,8,10-pentaene
SMILES
[H][C@]12C[C@]([H])(CNC1)C1=CC3=NC=CN=C3C=C21
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as benzazepines. These are organic compounds containing a benzene ring fused to an azepine ring (unsaturated seven-membered heterocycle with one nitrogen atom replacing a carbon atom).
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassBenzazepines
Sub ClassNot Available
Direct ParentBenzazepines
Alternative Parents
Substituents
  • Benzazepine
  • Quinoxaline
  • Indane
  • Aralkylamine
  • Azepine
  • Benzenoid
  • Pyrazine
  • Piperidine
  • Heteroaromatic compound
  • Azacycle
  • Secondary amine
  • Secondary aliphatic amine
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor use as an aid in smoking cessation.
PharmacodynamicsVarenicline is a partial nicotinic acetylcholine receptor agonist, designed to partially activate this system while displacing nicotine at its sites of action in the brain.
Mechanism of actionVarenicline is an alpha-4 beta-2 neuronal nicotinic acetylcholine receptor partial agonist. The drug shows high selectiviyty for this receptor subclass, relative to other nicotinic receptors (>500-fold alpha-3 beta-4, >3500-fold alpha-7, >20,000-fold alpha-1 beta gamma delta) or non-nicotinic receptors and transporters (>2000-fold). The drug competitively inhibits the ability of nicotine to bind to and activate the alpha-4 beta-2 receptor. The drug exerts mild agonistic activity at this site, though at a level much lower than nicotine; it is presumed that this activation eases withdrawal symptoms.
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingLess than 20%.
Metabolism

Metabolism is limited (<10%). Most of the active compound is excreted renally (81%). A small proportion is glucuronidated, oxidated, N-formylated or conjugated to a hexose.

Route of eliminationVarenicline undergoes minimal metabolism, with 92% excreted unchanged in the urine. Renal elimination of varenicline is primarily through glomerular filtration along with active tubular secretion possibly via the organic cation transporter, OCT2.
Half lifeThe elimination half-life of varenicline is approximately 24 hours
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9969
Blood Brain Barrier+0.9908
Caco-2 permeable-0.5233
P-glycoprotein substrateSubstrate0.5458
P-glycoprotein inhibitor INon-inhibitor0.7453
P-glycoprotein inhibitor IINon-inhibitor0.9637
Renal organic cation transporterInhibitor0.5489
CYP450 2C9 substrateNon-substrate0.8933
CYP450 2D6 substrateNon-substrate0.6522
CYP450 3A4 substrateNon-substrate0.7428
CYP450 1A2 substrateNon-inhibitor0.507
CYP450 2C9 inhibitorNon-inhibitor0.881
CYP450 2D6 inhibitorInhibitor0.6251
CYP450 2C19 inhibitorNon-inhibitor0.8029
CYP450 3A4 inhibitorNon-inhibitor0.6589
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5453
Ames testNon AMES toxic0.7128
CarcinogenicityNon-carcinogens0.9592
BiodegradationNot ready biodegradable0.9906
Rat acute toxicity2.5914 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9382
hERG inhibition (predictor II)Inhibitor0.5497
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Kit; tabletoral
Tabletoral0.5 mg
Tabletoral1.0 mg
Kit
Tablet, film coatedoral.5 mg/1
Tablet, film coatedoral1 mg/1
Prices
Unit descriptionCostUnit
Chantix Continuing Month Pak 56 1 mg tablet Disp Pack148.5USD disp
Chantix Starting Month Pak 0.5 mg X 11, 1 mg X 42 Disp Pack148.5USD disp
Chantix 1 mg tablet2.61USD tablet
Chantix 0.5 mg tablet2.56USD tablet
Chantix 1 mg cont month pak2.56USD each
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2316921 No2004-12-072018-11-13Canada
CA2525874 No2007-11-272024-05-07Canada
US6410550 No2000-05-102020-05-10Us
US6890927 No2002-05-062022-05-06Us
US7265119 No2002-08-032022-08-03Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
logP0.9Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0877 mg/mLALOGPS
logP1.39ALOGPS
logP1.01ChemAxon
logS-3.4ALOGPS
pKa (Strongest Basic)9.73ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area37.81 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity61.3 m3·mol-1ChemAxon
Polarizability23.12 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Vinod Kumar Kansal, Suhail Ahmad, Amit Gupta, “PROCESSES FOR THE PREPARATION OF VARENICLINE AND INTERMEDIATES THEREOF.” U.S. Patent US20090318695, issued December 24, 2009.

US20090318695
General References
  1. Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, Billing CB, Gong J, Reeves KR: Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA. 2006 Jul 5;296(1):56-63. [PubMed:16820547 ]
  2. Mihalak KB, Carroll FI, Luetje CW: Varenicline is a partial agonist at alpha4beta2 and a full agonist at alpha7 neuronal nicotinic receptors. Mol Pharmacol. 2006 Sep;70(3):801-5. Epub 2006 Jun 9. [PubMed:16766716 ]
  3. Obach RS, Reed-Hagen AE, Krueger SS, Obach BJ, O'Connell TN, Zandi KS, Miller S, Coe JW: Metabolism and disposition of varenicline, a selective alpha4beta2 acetylcholine receptor partial agonist, in vivo and in vitro. Drug Metab Dispos. 2006 Jan;34(1):121-30. Epub 2005 Oct 12. [PubMed:16221753 ]
  4. Coe JW, Brooks PR, Vetelino MG, Wirtz MC, Arnold EP, Huang J, Sands SB, Davis TI, Lebel LA, Fox CB, Shrikhande A, Heym JH, Schaeffer E, Rollema H, Lu Y, Mansbach RS, Chambers LK, Rovetti CC, Schulz DW, Tingley FD 3rd, O'Neill BT: Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation. J Med Chem. 2005 May 19;48(10):3474-7. [PubMed:15887955 ]
  5. Kuehn BM: FDA speeds smoking cessation drug review. JAMA. 2006 Feb 8;295(6):614. [PubMed:16467225 ]
External Links
ATC CodesN07BA03
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (334 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
BupropionThe serum concentration of Varenicline can be increased when it is combined with Bupropion.
CimetidineThe serum concentration of Varenicline can be increased when it is combined with Cimetidine.
CiprofloxacinThe serum concentration of Varenicline can be increased when it is combined with Ciprofloxacin.
EthanolThe risk or severity of adverse effects can be increased when Varenicline is combined with Ethanol.
FamotidineThe serum concentration of Varenicline can be increased when it is combined with Famotidine.
GemifloxacinThe serum concentration of Varenicline can be increased when it is combined with Gemifloxacin.
LevofloxacinThe serum concentration of Varenicline can be increased when it is combined with Levofloxacin.
MoxifloxacinThe serum concentration of Varenicline can be increased when it is combined with Moxifloxacin.
NicotineThe risk or severity of adverse effects can be increased when Varenicline is combined with Nicotine.
NizatidineThe serum concentration of Varenicline can be increased when it is combined with Nizatidine.
NorfloxacinThe serum concentration of Varenicline can be increased when it is combined with Norfloxacin.
OfloxacinThe serum concentration of Varenicline can be increased when it is combined with Ofloxacin.
RanitidineThe serum concentration of Varenicline can be increased when it is combined with Ranitidine.
SparfloxacinThe serum concentration of Varenicline can be increased when it is combined with Sparfloxacin.
TrimethoprimThe serum concentration of Varenicline can be increased when it is combined with Trimethoprim.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
partial agonist
General Function:
Ligand-gated ion channel activity
Specific Function:
After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeable to sodium ions.
Gene Name:
CHRNA4
Uniprot ID:
P43681
Molecular Weight:
69956.47 Da
References
  1. Nakamura M, Oshima A, Fujimoto Y, Maruyama N, Ishibashi T, Reeves KR: Efficacy and tolerability of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, in a 12-week, randomized, placebo-controlled, dose-response study with 40-week follow-up for smoking cessation in Japanese smokers. Clin Ther. 2007 Jun;29(6):1040-56. [PubMed:17692720 ]
  2. McColl SL, Burstein AH, Reeves KR, Billing CB Jr, Stolar M, Sellers EM: Human abuse liability of the smoking cessation drug varenicline in smokers and nonsmokers. Clin Pharmacol Ther. 2008 Apr;83(4):607-14. doi: 10.1038/sj.clpt.6100510. Epub 2008 Feb 20. [PubMed:18288085 ]
  3. Rollema H, Coe JW, Chambers LK, Hurst RS, Stahl SM, Williams KE: Rationale, pharmacology and clinical efficacy of partial agonists of alpha4beta2 nACh receptors for smoking cessation. Trends Pharmacol Sci. 2007 Jul;28(7):316-25. Epub 2007 Jun 18. [PubMed:17573127 ]
  4. Steensland P, Simms JA, Holgate J, Richards JK, Bartlett SE: Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking. Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12518-23. Epub 2007 Jul 11. [PubMed:17626178 ]
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
agonist
General Function:
Toxic substance binding
Specific Function:
After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. The channel is blocked by alpha-bungarotoxin.
Gene Name:
CHRNA7
Uniprot ID:
P36544
Molecular Weight:
56448.925 Da
References
  1. Mihalak KB, Carroll FI, Luetje CW: Varenicline is a partial agonist at alpha4beta2 and a full agonist at alpha7 neuronal nicotinic receptors. Mol Pharmacol. 2006 Sep;70(3):801-5. Epub 2006 Jun 9. [PubMed:16766716 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
partial agonist
General Function:
Ligand-gated ion channel activity
Specific Function:
After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
Gene Name:
CHRNA3
Uniprot ID:
P32297
Molecular Weight:
57479.54 Da
References
  1. Mihalak KB, Carroll FI, Luetje CW: Varenicline is a partial agonist at alpha4beta2 and a full agonist at alpha7 neuronal nicotinic receptors. Mol Pharmacol. 2006 Sep;70(3):801-5. Epub 2006 Jun 9. [PubMed:16766716 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
partial agonist
General Function:
Acetylcholine-activated cation-selective channel activity
Specific Function:
After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
Gene Name:
CHRNA6
Uniprot ID:
Q15825
Molecular Weight:
56897.745 Da
References
  1. Mihalak KB, Carroll FI, Luetje CW: Varenicline is a partial agonist at alpha4beta2 and a full agonist at alpha7 neuronal nicotinic receptors. Mol Pharmacol. 2006 Sep;70(3):801-5. Epub 2006 Jun 9. [PubMed:16766716 ]
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Drug created on May 16, 2007 14:24 / Updated on May 26, 2016 02:09