FLUNARIZINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C26H26F2N2
Molecular Weight	404.4948
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

FC1=CC=C(C=C1)C(N2CCN(C\C=C\C3=CC=CC=C3)CC2)C4=CC=C(F)C=C4

InChI

InChIKey=SMANXXCATUTDDT-QPJJXVBHSA-N

InChI=1S/C26H26F2N2/c27-24-12-8-22(9-13-24)26(23-10-14-25(28)15-11-23)30-19-17-29(18-20-30)16-4-7-21-5-2-1-3-6-21/h1-15,26H,16-20H2/b7-4+

HIDE SMILES / InChI

Description
Sources: https://www.nice.org.uk/advice/esuom33/chapter/Key-points-from-the-evidence

Flunarizine is a selective calcium entry blocker with calmodulin binding properties and histamine H1 / dopamine D2 blocking activity. It is not available in the US but marketed in other countries for prophylaxis of a migraine, occlusive peripheral vascular disease, the vertigo of central and peripheral origin, motion sickness and as an adjuvant in the therapy of epilepsy. The drug is also investigated for the treatment of schizophrenia.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Calmodulin 17 Target ID: CHEMBL6093 Sources: https://www.ncbi.nlm.nih.gov/pubmed/6093793	Inhibitor 8297
Dopamine D2 receptor 297 Target ID: CHEMBL339 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10571163	Antagonist 2778	0.228 µM [IC50]
Voltage-gated T-type calcium channel 17 Target ID: CHEMBL2362995 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10571163	Blocker 537
Sodium channel alpha subunits; brain (Types I, II, III) 28 Target ID: CHEMBL2096682 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10571163	Blocker 537
Histamine H1 receptor 315 Target ID: CHEMBL231 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20493137	Antagonist 2778	86.0 nM [Ki]

Conditions

Condition	Modality	Highest Phase	Product
Migraine 103 Sources: http://www.medicines.ie/medicine/14498/SPC/Sibelium+5+mg+tablets/#INDICATIONS	Preventing	Approved 8429	SIBELIUM Approved Use In the prophylaxis of a migraine. The limited information available for periods longer than 12 months has shown flunarizine to continue to be effective. Patients should be regularly reviewed to assess their response to treatment, and if a sustained attack-free period is established, interrupted flunarizine treatment should be considered. Launch Date 1.23318724E12
Occlusive peripheral vascular disease 2 Sources: https://www.squarepharma.com.bd/downloads/Flurizin.pdf	Primary	Approved 8429	FLURIZIN Approved Use Flurizin is indicated for treatment of peripheral vascular disease
Vestibular vertigo 2 Sources: https://www.squarepharma.com.bd/downloads/Flurizin.pdf	Primary	Approved 8429	FLURIZIN Approved Use Flurizin is indicated for symptomatic treatment of vestibular vertigo (due to a diagnosed functional disorder of the vestibular system).
Motion sickness 43 Sources: https://www.squarepharma.com.bd/downloads/Flurizin.pdf	Primary	Approved 8429	FLURIZIN Approved Use Flurizin is indicated for treatment of motion sickness.
Epilepsy 121 Sources: https://www.squarepharma.com.bd/downloads/Flurizin.pdf	Palliative	Approved 8429	FLURIZIN Approved Use Flurizin is indicated for treatment of refractory epilepsy resistant to conventional antiepileptic therapy
Schizophrenia 298 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19192440	Primary	Phase IV 63	Unknown Approved Use Unknown

PubMed

Title	Date	PubMed
Anticonvulsive properties of cinnarizine and flunarizine in rats and mice.	1975 Sep	1242663
Flunarizine- and cinnarizine-induced extrapyramidal reactions.	1987 May	3574697
Ca2+ modulators as antidotes to imipramine and neurotransmitter toxicity.	1987 Sep	2886994
Aggravation of Parkinson's disease by cinnarizine.	1988 Jan	3351524
Parkinsonism, tremor, and depression induced by cinnarizine and flunarizine.	1988 Sep 17	3147743
Calcium channel inhibitors prevent apomorphine- and oxytocin-induced penile erection and yawning in male rats.	1989 Aug 3	2806374
Extrapyramidal and depressive side reactions with flunarizine and cinarizine.	1989 Feb	2703850
Effect of flunarizine on the attenuation of baroreflex by transient cerebral ischemia.	1989 Jun 8	2767131
Termination of ouabain-induced ventricular tachycardia by flunarizine in conscious dogs.	1989 Jun 8	2767130
Comparison of the efficacy and safety of flunarizine to propranolol in the prophylaxis of migraine.	1992 Aug	1393843
Investigation of anti-motion sickness drugs in the squirrel monkey.	1992 Feb	1613127
[A case report of severe urinary retention and meteorism during flunarizine administration].	1992 Mar	1593790
Calcium-entry blockers-induced parkinsonism: possible role of inherited susceptibility.	1992 Spring	1508427
Profile of capsaicin-induced mouse ear oedema as neurogenic inflammatory model: comparison with arachidonic acid-induced ear oedema.	1993 Dec	7508328
Effect of calcium channel antagonists on cocaine-induced malignant arrhythmias: protection against ventricular fibrillation.	1993 Jul	8331569
Pharmacological studies on a new dihydrothienopyridine calcium antagonist, S-312-d. 5th communication: anticonvulsant effects in mice.	1994 Jun	7967231
Possible pharmacokinetic and pharmacodynamic factors affecting parkinsonism inducement by cinnarizine and flunarizine.	1995 Nov 9	7503767
Catalepsy induced by manidipine, a calcium channel blocker, in mice.	1996 Apr	8794996
Parkinsonism and other movement disorders in outpatients in chronic use of cinnarizine and flunarizine.	2004 Sep	15476069
Atypical antipsychotic profile of flunarizine in animal models.	2005 Jan	15290004
Treatment of migraine with prophylactic drugs.	2008 Oct	18803445
Ameliorative effect of flunarizine in cisplatin-induced acute renal failure via mitochondrial permeability transition pore inactivation in rats.	2011 Jan	21058009
FDA-approved drugs and other compounds tested as inhibitors of human glutathione transferase P1-1.	2013 Sep 5	23769903

Patents

Sample Use Guides

In Vivo Use Guide

Oral; the recommended dose is 10mg/day at bedtime.

Route of Administration: Oral

In Vitro Use Guide

To study the effect of flunarizine on the interaction between calmodulin and phosphodiesterase, proteins were isolated from bovine brain. PDE activity was measured using cAMP (1.2mM) as a substrate and in the presence of 5'-nucleotidase. The liberated Pi was measured in the supernatant by the method of Ames. The reaction was performed in the presence of CaCl2 and Calmodulin (positive control), in the presence of EGTA (negative control) and in the presence of various concentrations of flunarizine. IC50 determined for brain PDE was 21 uM.

Name

Type

Language

FLUNARIZINE

Official Name

English

PIPERAZINE, 1-(BIS(4-FLUOROPHENYL)METHYL)-4-(3-PHENYL-2-PROPENYL)-, (E)-

Common Name

English

Flunarizine [WHO-DD]

Common Name

English

flunarizine [INN]

Common Name

English

(E)-1-(BIS-(P-FLUOROPHENYL)METHYL)-4-CINNAMYLPIPERAZINE

Common Name

English

FLUNARIZINE [MI]

Common Name

English

SIBELIUM

Brand Name

English

Classification Tree Code System Code

NCI_THESAURUS

C29578