Identification

Name
Cytisine
Accession Number
DB09028
Type
Small Molecule
Groups
Experimental
Description

Cytisine is an alkaloid that is found naturally in several plant genera such as Laburnum and Cytisus of the family Fabaceae. Recent studies have shown it to be a more effective and significantly more affordable smoking cessation treatment than nicotine replacement therapy. Also known as baptitoxine or sophorine, cytisine has been used as a smoking cessation treatment since 1964, and is relatively unknown in regions outside of central and Eastern Europe. Cytisine is a partial nicotinic acetylcholine agonist with a half-life of 4.8 hours. Recent Phase III clinical trials using Tabex (a brand of Cytisine marketed by Sopharma AD) have shown similar efficacy to varenicline, but at a fraction of the cost.

Structure
Thumb
Synonyms
  • (1R,5S)-1,2,3,4,5,6-Hexahydro-1,5-methano-8H-pyrido[1,2a][1,5]diazocin-8-one
  • Baptitoxine
  • Sophorine
  • Ulexin
International/Other Brands
Tabex (Sopharma AD)
Categories
UNII
53S5U404NU
CAS number
485-35-8
Weight
Average: 190.2417
Monoisotopic: 190.11061308
Chemical Formula
C11H14N2O
InChI Key
ANJTVLIZGCUXLD-DTWKUNHWSA-N
InChI
InChI=1S/C11H14N2O/c14-11-3-1-2-10-9-4-8(5-12-6-9)7-13(10)11/h1-3,8-9,12H,4-7H2/t8-,9+/m0/s1
IUPAC Name
(1R,9S)-7,11-diazatricyclo[7.3.1.0²,⁷]trideca-2,4-dien-6-one
SMILES
O=C1C=CC=C2[C@H]3CNC[C@H](C3)CN12

Pharmacology

Indication

Indicated for use in smoking cessation.

Pharmacodynamics

Various models have been run where the affinity of nAChR agonists to the receptor subtype are tested to help identify the molecules, groups and steric conformation that are vital to greater affinity. By using a nAChR muscle receptor subtype (α1)2β1δγ model the following results were obtained: anatoxin > epibatidine > acetylcholine > DMPP >> CYTISINE > pyrantel > nicotine > coniine > tubocurare > lobeline, where anatoxin had the highest activity efficacy and tubocurare the lowest. Acetylcholine on the other hand induced a much longer opening time of the receptor though anatoxin is more potent. The results suggest that anatoxin derivatives would be helpful in understanding structure-activity relationships (SAR) for muscle nAChRs (Cooper et al., 1996).

Mechanism of action

Cytisine is a low efficacy partial agonist of ⍺4-β2 nicotinic acetylcholine receptors. These which are believed to be central to the effect of nicotine (NIC) on the reward pathway and facilitate addiction. Cytisine reduces the effects of NIC on dopamine release in the mesolimbic system when given alone, while simultaneously attenuating NIC withdrawal symptoms that accompany cessation attempts.

TargetActionsOrganism
UNeuronal acetylcholine receptor subunit alpha-4
agonist
Human
UNeuronal acetylcholine receptor subunit alpha-7
agonist
Human
UNeuronal acetylcholine receptor subunit alpha-3
agonist
Human
UNeuronal acetylcholine receptor subunit alpha-6
agonist
Human
UNeuronal acetylcholine receptor subunit beta-2
partial agonist
Human
Absorption
Not Available
Volume of distribution

Oral: 6.2 l/kg Oral (5 mg/kg; tested in rabbits).

Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

4.8 hours.

Clearance

Renal: 43 mL/min.

Toxicity

The therapeutic index of cytisine is wide. -Large doses can interfere with breathing and cause death. From MSDS: orl-mus LD50:101 mg/kg ipr-mus LD50:8550 ug/kg ivn-mus LD50:1730 ug/kg scu-rat LD50:8750 ug/kg

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

Synthesis Reference

ORGANIC SYNTHESES, 2006, 83, 141. "Synthesis of (+)-(1R,@S,9S)-11-Methyl-7,11-Diazatricyclo[7.3.1.02.7]tridecane, a (+)sparteine surrogate," DOI: 10.15227/orgsyn.083.0141

General References
  1. Walker N, Howe C, Glover M, McRobbie H, Barnes J, Nosa V, Parag V, Bassett B, Bullen C: Cytisine versus nicotine for smoking cessation. N Engl J Med. 2014 Dec 18;371(25):2353-62. doi: 10.1056/NEJMoa1407764. [PubMed:25517706]
  2. Houlihan LM, Slater Y, Guerra DL, Peng JH, Kuo YP, Lukas RJ, Cassels BK, Bermudez I: Activity of cytisine and its brominated isosteres on recombinant human alpha7, alpha4beta2 and alpha4beta4 nicotinic acetylcholine receptors. J Neurochem. 2001 Sep;78(5):1029-43. [PubMed:11553677]
  3. Tutka P, Zatonski W: Cytisine for the treatment of nicotine addiction: from a molecule to therapeutic efficacy. Pharmacol Rep. 2006 Nov-Dec;58(6):777-98. [PubMed:17220536]
  4. Cooper JC, Gutbrod O, Witzemann V, Methfessel C: Pharmacology of the nicotinic acetylcholine receptor from fetal rat muscle expressed in Xenopus oocytes. Eur J Pharmacol. 1996 Aug 15;309(3):287-98. [PubMed:8874153]
External Links
KEGG Drug
D07770
KEGG Compound
C10763
PubChem Compound
10235
PubChem Substance
310264982
ChemSpider
9818
ChEBI
4055
ChEMBL
CHEMBL497939
HET
C5E
Drugs.com
Drugs.com Drug Page
Wikipedia
Cytisine
PDB Entries
4bqt / 5syo
MSDS
Download (38.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentCessation, Smoking2
1RecruitingOtherCessation, Smoking / Pharmacokinetics1
1, 2RecruitingTreatmentCessation, Smoking1
2Not Yet RecruitingPreventionCessation, Smoking / Diet Modification / Inflammatory Reaction / Lung Cancers / Physical Activity1
2Not Yet RecruitingTreatmentCessation, Smoking1
2, 3RecruitingTreatmentAlcohol Use / Human Immunodeficiency Virus (HIV) Infections / Smoking1
3RecruitingTreatmentCessation, Smoking1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)152-153Not Available
boiling point (°C)218Not Available
Predicted Properties
PropertyValueSource
Water Solubility8.14 mg/mLALOGPS
logP1.06ALOGPS
logP-0.28ChemAxon
logS-1.4ALOGPS
pKa (Strongest Basic)9.82ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area32.34 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity56.93 m3·mol-1ChemAxon
Polarizability20.35 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
MS/MS Spectrum - Linear Ion Trap , negativeLC-MS/MSsplash10-0002-0900000000-ac9adc16d980cac46d03
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0006-0900000000-d9ca1da65d36cbf3159e
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0005-0900000000-3929f9603e36ab32d073
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0k9t-0900000000-595fd68b2d2eece7b2ff
MS/MS Spectrum - Linear Ion Trap , positiveLC-MS/MSsplash10-0002-0900000000-da27c03f716edf4c1164
MS/MS Spectrum - Linear Ion Trap , positiveLC-MS/MSsplash10-001i-0900000000-e43e741d12c5dae90f3a
MS/MS Spectrum - Linear Ion Trap , positiveLC-MS/MSsplash10-0pb9-1930000000-ff52f264a1cca1194562

Taxonomy

Description
This compound belongs to the class of organic compounds known as cytisine and derivatives. These are lupin alkaloids with a structure based on the cytisine skeleton, which is a tetracyclic ketone containing fused pyridine and piperidine rings that form pyrido[1,2a][1,5]diazocin-8-one.
Kingdom
Organic compounds
Super Class
Alkaloids and derivatives
Class
Lupin alkaloids
Sub Class
Cytisine and derivatives
Direct Parent
Cytisine and derivatives
Alternative Parents
Pyridinones / Aralkylamines / Piperidines / Heteroaromatic compounds / Lactams / Dialkylamines / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds / Organic oxides
show 1 more
Substituents
Cytisine / Aralkylamine / Pyridinone / Piperidine / Pyridine / Heteroaromatic compound / Lactam / Secondary aliphatic amine / Azacycle / Organoheterocyclic compound
show 10 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
organic heterotricyclic compound, alkaloid, secondary amino compound, bridged compound, lactam (CHEBI:4055)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
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 permeabl...
Gene Name
CHRNA4
Uniprot ID
P43681
Uniprot Name
Neuronal acetylcholine receptor subunit alpha-4
Molecular Weight
69956.47 Da
References
  1. Walker N, Howe C, Glover M, McRobbie H, Barnes J, Nosa V, Parag V, Bassett B, Bullen C: Cytisine versus nicotine for smoking cessation. N Engl J Med. 2014 Dec 18;371(25):2353-62. doi: 10.1056/NEJMoa1407764. [PubMed:25517706]
  2. Houlihan LM, Slater Y, Guerra DL, Peng JH, Kuo YP, Lukas RJ, Cassels BK, Bermudez I: Activity of cytisine and its brominated isosteres on recombinant human alpha7, alpha4beta2 and alpha4beta4 nicotinic acetylcholine receptors. J Neurochem. 2001 Sep;78(5):1029-43. [PubMed:11553677]
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 cha...
Gene Name
CHRNA7
Uniprot ID
P36544
Uniprot Name
Neuronal acetylcholine receptor subunit alpha-7
Molecular Weight
56448.925 Da
References
  1. Walker N, Howe C, Glover M, McRobbie H, Barnes J, Nosa V, Parag V, Bassett B, Bullen C: Cytisine versus nicotine for smoking cessation. N Engl J Med. 2014 Dec 18;371(25):2353-62. doi: 10.1056/NEJMoa1407764. [PubMed:25517706]
  2. Houlihan LM, Slater Y, Guerra DL, Peng JH, Kuo YP, Lukas RJ, Cassels BK, Bermudez I: Activity of cytisine and its brominated isosteres on recombinant human alpha7, alpha4beta2 and alpha4beta4 nicotinic acetylcholine receptors. J Neurochem. 2001 Sep;78(5):1029-43. [PubMed:11553677]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
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
Uniprot Name
Neuronal acetylcholine receptor subunit alpha-3
Molecular Weight
57479.54 Da
References
  1. Walker N, Howe C, Glover M, McRobbie H, Barnes J, Nosa V, Parag V, Bassett B, Bullen C: Cytisine versus nicotine for smoking cessation. N Engl J Med. 2014 Dec 18;371(25):2353-62. doi: 10.1056/NEJMoa1407764. [PubMed:25517706]
  2. Houlihan LM, Slater Y, Guerra DL, Peng JH, Kuo YP, Lukas RJ, Cassels BK, Bermudez I: Activity of cytisine and its brominated isosteres on recombinant human alpha7, alpha4beta2 and alpha4beta4 nicotinic acetylcholine receptors. J Neurochem. 2001 Sep;78(5):1029-43. [PubMed:11553677]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
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
Uniprot Name
Neuronal acetylcholine receptor subunit alpha-6
Molecular Weight
56897.745 Da
References
  1. Walker N, Howe C, Glover M, McRobbie H, Barnes J, Nosa V, Parag V, Bassett B, Bullen C: Cytisine versus nicotine for smoking cessation. N Engl J Med. 2014 Dec 18;371(25):2353-62. doi: 10.1056/NEJMoa1407764. [PubMed:25517706]
  2. Houlihan LM, Slater Y, Guerra DL, Peng JH, Kuo YP, Lukas RJ, Cassels BK, Bermudez I: Activity of cytisine and its brominated isosteres on recombinant human alpha7, alpha4beta2 and alpha4beta4 nicotinic acetylcholine receptors. J Neurochem. 2001 Sep;78(5):1029-43. [PubMed:11553677]
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 permeabl...
Gene Name
CHRNB2
Uniprot ID
P17787
Uniprot Name
Neuronal acetylcholine receptor subunit beta-2
Molecular Weight
57018.575 Da
References
  1. Rollema H, Shrikhande A, Ward KM, Tingley FD 3rd, Coe JW, O'Neill BT, Tseng E, Wang EQ, Mather RJ, Hurst RS, Williams KE, de Vries M, Cremers T, Bertrand S, Bertrand D: Pre-clinical properties of the alpha4beta2 nicotinic acetylcholine receptor partial agonists varenicline, cytisine and dianicline translate to clinical efficacy for nicotine dependence. Br J Pharmacol. 2010 May;160(2):334-45. doi: 10.1111/j.1476-5381.2010.00682.x. Epub 2010 Mar 22. [PubMed:20331614]

Drug created on December 19, 2014 09:51 / Updated on November 02, 2018 06:57