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Identification
NameCinnarizine
Accession NumberDB00568  (APRD00332)
TypeSmall Molecule
GroupsApproved
Description

Cinnarizine is an anti-histaminic drug which is mainly used for the control of vomiting due to motion sickness. Cinnarizine was first synthesized by Janssen Pharmaceutica in 1955.

It acts by interfering with the signal transmission between vestibular apparatus of the inner ear and the vomiting centre of the hypothalamus. The disparity of signal processing between inner ear motion receptors and the visual senses is abolished, so that the confusion of brain whether the individual is moving or standing is reduced. Vomiting in motion sickness is actually a physiological compensatory mechanism of the brain to keep the individual from moving so that it can adjust to the signal perception.

Cinnarizine could be also viewed as a nootropic drug because of its vasorelaxating abilities (due to calcium channel blockage), which happen mostly in brain. It is also effectively combined with other nootropics, primarily piracetam; in such combination each drug potentiate the other in boosting brain oxygen supply.

Structure
Thumb
Synonyms
SynonymLanguageCode
1-(Diphenylmethyl)-4-(3-phenyl-2-propenyl)piperazineNot AvailableNot Available
1-Benzhydryl-4-cinnamylpiperazinNot AvailableNot Available
1-Cinnamyl-4-(diphenylmethyl)piperazineNot AvailableNot Available
CinarizinaSpanishINN
CinnarizinGermanINN
CinnarizineFrenchINN
CinnarizinumLatinINN
SaltsNot Available
Brand names
NameCompany
CinazynItalchimici
CinnageronStreuli Pharma
FolcodalIvax
SepanJanssen-Cilag
StugeronJanssen
Stugeron ForteJanssen
TolimanScharper
Brand mixtures
Brand NameIngredients
ArlevertCinnarizine and Dimenhydrinate
ArlevertanCinnarizine and Dimenhydrinate
Azinorm-CCinnarizine and Domperidone
Cinacris forteCinnarizine and Dihydroergocristine
CinageronCinnarizine and Dihydroergocristine
ClinadilCinnarizine and Dihydroergocristine
CombitropilCinnarizine and Piracetam
Domstal-CZCinnarizine and Domperidone
ExitCinnarizine and Piracetam
FesamolCinnarizine and Piracetam
OmaronCinnarizine and Piracetam
PhezamCinnarizine and Piracetam
PrimatourCinnarizine and Chlorcyclizine
RinomarCinnarizine and Phenylpropanolamine
TouristilCinnarizine and Domperidone
VernavoCinnarizine and Domperidone
CategoriesNot Available
CAS number298-57-7
WeightAverage: 368.5139
Monoisotopic: 368.225248906
Chemical FormulaC26H28N2
InChI KeyDERZBLKQOCDDDZ-JLHYYAGUSA-N
InChI
InChI=1S/C26H28N2/c1-4-11-23(12-5-1)13-10-18-27-19-21-28(22-20-27)26(24-14-6-2-7-15-24)25-16-8-3-9-17-25/h1-17,26H,18-22H2/b13-10+
IUPAC Name
1-(diphenylmethyl)-4-(3-phenylprop-2-en-1-yl)piperazine
SMILES
C(C=CC1=CC=CC=C1)N1CCN(CC1)C(C1=CC=CC=C1)C1=CC=CC=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassDiphenylmethanes
Direct parentDiphenylmethanes
Alternative parentsPhenylpropenes; Styrenes; Diazinanes; Piperazines; Tertiary Amines; Polyamines
Substituentsphenylpropene; styrene; 1,4-diazinane; piperazine; tertiary amine; polyamine; organonitrogen compound; amine
Classification descriptionThis compound belongs to the diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
Pharmacology
IndicationFor the treatment of vertigo/meniere's disease, nausea and vomiting, motion sickness and also useful for vestibular symptoms of other origins.
PharmacodynamicsCinnarizine is an antihistamine and a calcium channel blocker. Histamines mediate a number of activities such as contraction of smooth muscle of the airways and gastrointestinal tract, vasodilatation, cardiac stimulation, secretion of gastric acid, promotion of interleukin release and chemotaxis of eosinophils and mast cells. Competitive antagonists at histamine H1 receptors may be divided into first (sedating) and second (non-sedating) generation agents. Some, such as Cinnarizine also block muscarinic acetylcholine receptors and are used as anti-emetic agents. Cinnarizine through its calcium channel blocking ability also inhibits stimulation of the vestibular system.
Mechanism of actionCinnarizine inhibits contractions of vascular smooth muscle cells by blocking L-type and T-type voltage gated calcium channels. Cinnarizine has also been implicated in binding to dopamine D2 receptors, histamine H1 receptors, and muscarinic acetylcholine receptors.
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism
SubstrateEnzymesProduct
Cinnarizine
Cinnarizine metabolite M1Details
Cinnarizine
Cinnarizine metabolite M2Details
Cinnarizine
BenzophenoneDetails
Cinnarizine
Cinnarizine metabolite M4Details
Route of eliminationNot Available
Half lifeNot Available
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
Property Value Probability
Human Intestinal Absorption + 0.9506
Blood Brain Barrier + 0.977
Caco-2 permeable + 0.6409
P-glycoprotein substrate Substrate 0.7107
P-glycoprotein inhibitor I Inhibitor 0.7461
P-glycoprotein inhibitor II Non-inhibitor 0.8398
Renal organic cation transporter Inhibitor 0.7902
CYP450 2C9 substrate Non-substrate 0.8549
CYP450 2D6 substrate Substrate 0.8919
CYP450 3A4 substrate Non-substrate 0.7558
CYP450 1A2 substrate Inhibitor 0.7732
CYP450 2C9 substrate Non-inhibitor 0.9488
CYP450 2D6 substrate Inhibitor 0.8931
CYP450 2C19 substrate Non-inhibitor 0.9026
CYP450 3A4 substrate Non-inhibitor 0.9346
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.5
Ames test Non AMES toxic 0.9279
Carcinogenicity Non-carcinogens 0.9496
Biodegradation Not ready biodegradable 0.9968
Rat acute toxicity 2.0618 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Strong inhibitor 0.5724
hERG inhibition (predictor II) Non-inhibitor 0.524
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubility750 mg/L (at 25 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP5.77BIOBYTE (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.00172ALOGPS
logP5.19ALOGPS
logP5.88ChemAxon
logS-5.3ALOGPS
pKa (Strongest Basic)8.4ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area6.48 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity119.86 m3·mol-1ChemAxon
Polarizability43.96 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Janssen, P.A.J.; U.S. Patent 2,882,271; April 14, 1959; assigned to Laboratoria Pharmaceutica Dr. C. Janssen, Belgium.

General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD01295
PubChem Compound1547484
PubChem Substance46506769
ChemSpider2659
ChEBI31403
ChEMBLCHEMBL43064
Therapeutic Targets DatabaseDAP000325
PharmGKBPA164749342
WikipediaCinnarizine
ATC CodesN07CA02
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. Histamine H1 receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Histamine H1 receptor P35367 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Paton DM, Webster DR: Clinical pharmacokinetics of H1-receptor antagonists (the antihistamines). Clin Pharmacokinet. 1985 Nov-Dec;10(6):477-97. Pubmed

2. Voltage-dependent L-type calcium channel subunit alpha-1C

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent L-type calcium channel subunit alpha-1C Q13936 Details

References:

  1. Singh BN: The mechanism of action of calcium antagonists relative to their clinical applications. Br J Clin Pharmacol. 1986;21 Suppl 2:109S-121S. Pubmed
  2. Cohen CJ, Spires S, Van Skiver D: Block of T-type Ca channels in guinea pig atrial cells by antiarrhythmic agents and Ca channel antagonists. J Gen Physiol. 1992 Oct;100(4):703-28. Pubmed

3. Voltage-dependent L-type calcium channel subunit alpha-1D

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent L-type calcium channel subunit alpha-1D Q01668 Details

References:

  1. Singh BN: The mechanism of action of calcium antagonists relative to their clinical applications. Br J Clin Pharmacol. 1986;21 Suppl 2:109S-121S. Pubmed
  2. Cohen CJ, Spires S, Van Skiver D: Block of T-type Ca channels in guinea pig atrial cells by antiarrhythmic agents and Ca channel antagonists. J Gen Physiol. 1992 Oct;100(4):703-28. Pubmed

4. Voltage-dependent L-type calcium channel subunit alpha-1F

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent L-type calcium channel subunit alpha-1F O60840 Details

References:

  1. Singh BN: The mechanism of action of calcium antagonists relative to their clinical applications. Br J Clin Pharmacol. 1986;21 Suppl 2:109S-121S. Pubmed
  2. Cohen CJ, Spires S, Van Skiver D: Block of T-type Ca channels in guinea pig atrial cells by antiarrhythmic agents and Ca channel antagonists. J Gen Physiol. 1992 Oct;100(4):703-28. Pubmed

5. Voltage-dependent L-type calcium channel subunit alpha-1S

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent L-type calcium channel subunit alpha-1S Q13698 Details

References:

  1. Singh BN: The mechanism of action of calcium antagonists relative to their clinical applications. Br J Clin Pharmacol. 1986;21 Suppl 2:109S-121S. Pubmed
  2. Cohen CJ, Spires S, Van Skiver D: Block of T-type Ca channels in guinea pig atrial cells by antiarrhythmic agents and Ca channel antagonists. J Gen Physiol. 1992 Oct;100(4):703-28. Pubmed

6. Voltage-dependent T-type calcium channel subunit alpha-1G

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent T-type calcium channel subunit alpha-1G O43497 Details

References:

  1. Singh BN: The mechanism of action of calcium antagonists relative to their clinical applications. Br J Clin Pharmacol. 1986;21 Suppl 2:109S-121S. Pubmed
  2. Cohen CJ, Spires S, Van Skiver D: Block of T-type Ca channels in guinea pig atrial cells by antiarrhythmic agents and Ca channel antagonists. J Gen Physiol. 1992 Oct;100(4):703-28. Pubmed

7. Voltage-dependent T-type calcium channel subunit alpha-1H

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent T-type calcium channel subunit alpha-1H O95180 Details

References:

  1. Singh BN: The mechanism of action of calcium antagonists relative to their clinical applications. Br J Clin Pharmacol. 1986;21 Suppl 2:109S-121S. Pubmed
  2. Cohen CJ, Spires S, Van Skiver D: Block of T-type Ca channels in guinea pig atrial cells by antiarrhythmic agents and Ca channel antagonists. J Gen Physiol. 1992 Oct;100(4):703-28. Pubmed

8. Voltage-dependent T-type calcium channel subunit alpha-1I

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent T-type calcium channel subunit alpha-1I Q9P0X4 Details

References:

  1. Singh BN: The mechanism of action of calcium antagonists relative to their clinical applications. Br J Clin Pharmacol. 1986;21 Suppl 2:109S-121S. Pubmed
  2. Cohen CJ, Spires S, Van Skiver D: Block of T-type Ca channels in guinea pig atrial cells by antiarrhythmic agents and Ca channel antagonists. J Gen Physiol. 1992 Oct;100(4):703-28. Pubmed

9. D(2) dopamine receptor

Kind: protein

Organism: Human

Pharmacological action: no

Actions: other/unknown

Components

Name UniProt ID Details
D(2) dopamine receptor P14416 Details

References:

  1. Hirose G: Drug induced parkinsonism: A review. J Neurol. 2006 Aug;253 Suppl 3:iii22-iii24. doi:10.1007/s00415-006-3004-8
  2. Brucke T, Wober C, Podreka I, Wober-Bingol C, Asenbaum S, Aull S, Wenger S, Ilieva D, Harasko-van der Meer C, Wessely P, et al.: D2 receptor blockade by flunarizine and cinnarizine explains extrapyramidal side effects. A SPECT study. J Cereb Blood Flow Metab. 1995 May;15(3):513-8. Pubmed
  3. Kuzuhara S: [Drug-induced parkinsonism] Nippon Rinsho. 1997 Jan;55(1):112-7. Pubmed

10. D(1) dopamine receptor

Kind: protein group

Organism: Human

Pharmacological action: unknown

Actions: binder

Components

Name UniProt ID Details
D(1A) dopamine receptor P21728 Details
D(1B) dopamine receptor P21918 Details

References:

  1. Nasu R, Matsuo H, Takanaga H, Ohtani H, Sawada Y: Quantitative prediction of catalepsy induced by amoxapine, cinnarizine and cyclophosphamide in mice. Biopharm Drug Dispos. 2000 May;21(4):129-38. Pubmed

11. Muscarinic acetylcholine receptor

Kind: protein group

Organism: Human

Pharmacological action: unknown

Actions: binder

Components

Name UniProt ID Details
Muscarinic acetylcholine receptor M1 P11229 Details
Muscarinic acetylcholine receptor M2 P08172 Details
Muscarinic acetylcholine receptor M3 P20309 Details
Muscarinic acetylcholine receptor M4 P08173 Details
Muscarinic acetylcholine receptor M5 P08912 Details

References:

  1. Nasu R, Matsuo H, Takanaga H, Ohtani H, Sawada Y: Quantitative prediction of catalepsy induced by amoxapine, cinnarizine and cyclophosphamide in mice. Biopharm Drug Dispos. 2000 May;21(4):129-38. Pubmed

Enzymes

1. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

4. Cytochrome P450 2B6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

5. Cytochrome P450 2A6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2A6 P11509 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

6. Cytochrome P450 1A1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A1 P04798 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on April 04, 2014 13:49