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Record Information
Version2.0
Creation Date2009-07-05 03:36:25 UTC
Update Date2014-12-24 20:25:43 UTC
Accession NumberT3D2577
Identification
Common NameVarenicline
ClassSmall Molecule
DescriptionVarenicline 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.
Compound Type
  • Amine
  • Drug
  • Metabolite
  • Nicotinic Agonist
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
Champix
Chantix
CP-526,555
Varenicline tartrate
Chemical FormulaC13H13N3
Average Molecular Mass211.262 g/mol
Monoisotopic Mass211.111 g/mol
CAS Registry Number249296-44-4
IUPAC Name(1R,12S)-5,8,14-triazatetracyclo[10.3.1.0²,¹¹.0⁴,⁹]hexadeca-2,4,6,8,10-pentaene
Traditional Namechantix
SMILES[H][C@]12C[C@]([H])(CNC1)C1=CC3=C(C=C21)N=CC=N3
InChI IdentifierInChI=1/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+
InChI KeyInChIKey=JQSHBVHOMNKWFT-DTORHVGONA-N
Chemical Taxonomy
Description 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
  • Diazanaphthalene
  • Quinoxaline
  • Indane
  • Azepine
  • Aralkylamine
  • Piperidine
  • Benzenoid
  • Pyrazine
  • Heteroaromatic compound
  • Secondary aliphatic amine
  • Azacycle
  • Secondary amine
  • Hydrocarbon derivative
  • Amine
  • Organopnictogen compound
  • Organonitrogen compound
  • Organic nitrogen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceSolid (1).
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
Solubility8.77e-02 g/L
LogP0.9
Predicted Properties
PropertyValueSource
Water Solubility0.088 g/LALOGPS
logP1.39ALOGPS
logP1.01ChemAxon
logS-3.4ALOGPS
pKa (Strongest Basic)9.73ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area37.81 ŲChemAxon
Rotatable Bond Count0ChemAxon
Refractivity61.3 m³·mol⁻¹ChemAxon
Polarizability23.12 ųChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-00lr-1910000000-6dbc451aea83e1d014b6JSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-03di-0190000000-4f145434c13b3afcb533JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-03di-0590000000-9e05cfabbf6c1eb096b1JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0159-3900000000-82a1aaedcfa4ad0c47d4JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-03di-0090000000-213d1987d097fb210ee1JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-03di-0190000000-c719b55058a71a235995JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-01po-3930000000-7accc44141f8030a7a2bJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-03di-0090000000-151eb25ddf9df2d6bfbeJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-03di-0090000000-151eb25ddf9df2d6bfbeJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0lz9-0920000000-ff0909b76eb139f2276aJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-03di-0090000000-4dafdcd63f1115768fe9JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-03di-0090000000-4dafdcd63f1115768fe9JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0a4i-0190000000-1ec0bedd3eb5b1bc4034JSpectraViewer
Toxicity Profile
Route of ExposureIngestion (1)
Mechanism of ToxicityVarenicline 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.
MetabolismMetabolism 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. Varenicline 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 (MSDS, A308). Route of Elimination: Varenicline 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 Life: The elimination half-life of varenicline is approximately 24 hours
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor use as an aid in smoking cessation (1).
Minimum Risk LevelNot Available
Health EffectsSome disorders may include anemia, lymphadenopathy, angina pectoris, arrhythmia, bradycardia, ventricular extrasystoles, myocardial infarction, palpitations, tachycardia, deafness, meniere's disease, dhyroid gland disorders, conjunctivitis, acquired night blindness, blindness transient, cataract subcapsular, gastric ulcer, intestinal obstruction, pancreatitis acute, chest pain, influenza like illness, edema, diabetes mellitus, facial palsy, mental impairment, multiple sclerosis, polyuria, and menstrual disorder.(1).
SymptomsNausea, sleep disturbance, constipation, flatulence, and vomiting.
TreatmentIn case of overdose, standard supportive measures should be instituted as required. (8)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01273
HMDB IDHMDB15398
PubChem Compound ID5310966
ChEMBL IDCHEMBL1396
ChemSpider ID4470510
KEGG IDNot Available
UniProt IDNot Available
OMIM ID
ChEBI IDNot Available
BioCyc IDNot Available
CTD IDNot Available
Stitch IDVarenicline
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkVarenicline
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.

MSDST3D2577.pdf
General References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  2. 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. [16820547 ]
  3. 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. [16766716 ]
  4. 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. [16221753 ]
  5. 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. [15887955 ]
  6. Kuehn BM: FDA speeds smoking cessation drug review. JAMA. 2006 Feb 8;295(6):614. [16467225 ]
  7. RxList: The Internet Drug Index (2009). [Link]
  8. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

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. [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. [18288085 ]
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. [16766716 ]
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. [16766716 ]
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. [16766716 ]