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 2009
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
Parkinsonism, tardive dyskinesia, akathisia, and depression induced by flunarizine.	1986 Jun 7	2872433
Non-vascular action of calcium blockers in migraine: pupillopharmacological study.	1986 Oct-Dec	3038706
Ca2+ modulators as antidotes to imipramine and neurotransmitter toxicity.	1987 Sep	2886994
Cardiovascular and renal actions of calcium channel blocker chemical subgroups: a search for renal specificity.	1988 Jun	2901472
Calcium channel inhibitors prevent apomorphine- and oxytocin-induced penile erection and yawning in male rats.	1989 Aug 3	2806374
Termination of ouabain-induced ventricular tachycardia by flunarizine in conscious dogs.	1989 Jun 8	2767130
Selective dysfunction of the vagal component of the baroreflex following cerebral ischemia: protection by ifenprodil and flunarizine.	1990 Nov 6	2076755
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
The effect of flunarizine and ryanodine on acquired torsades de pointes arrhythmias in the intact canine heart.	1995 Mar	7620644
Possible pharmacokinetic and pharmacodynamic factors affecting parkinsonism inducement by cinnarizine and flunarizine.	1995 Nov 9	7503767
Postmarketing study of the use of flunarizine in vestibular vertigo and in migraine.	1996	8880046
Catalepsy induced by manidipine, a calcium channel blocker, in mice.	1996 Apr	8794996
Post-marketing cohort study comparing the safety and efficacy of flunarizine and propranolol in the prophylaxis of migraine.	1996 Aug	8869768
A long-term follow-up study of cinnarizine- and flunarizine-induced parkinsonism.	1997 Jan	8990063
Etiology of parkinsonism in a Brazilian movement disorders clinic.	1998 Jun	9698723
Catalepsy induced by calcium channel blockers in mice.	1998 Mar	9533112
[Influence of co-administered antiepileptic drugs on nitrazepam tolerance in mice].	1998 Nov	9844417
Evidence of sex related differences in the effects of calcium channel blockers on neuroleptic-induced catalepsy in mice.	1999 Feb	10368871
Distinct features of seizures induced by cocaine and amphetamine analogs.	1999 Jul 21	10456426
Motor and electrographic response of refractory experimental status epilepticus in rats and effect of calcium channel blockers.	2000 Feb	11218825
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
Amphetamine-induced anxiety-related behavior in animal models.	2007 Nov-Dec	18195452
Treatment of migraine with prophylactic drugs.	2008 Oct	18803445
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces calcium influx through T-type calcium channel and enhances lysosomal exocytosis and insulin secretion in INS-1 cells.	2009 May-Jun	19546254
Progressive supranuclear palsy-like syndrome induced by amiodarone and flunarizine.	2009 Sep	19838530
EFNS guideline on the drug treatment of migraine--revised report of an EFNS task force.	2009 Sep	19708964
A cell protection screen reveals potent inhibitors of multiple stages of the hepatitis C virus life cycle.	2010 Feb 23	20142494
The differential diagnoses of parkinsonism: findings from a cohort of 1528 patients and a 10 years comparison in tertiary movement disorders clinics.	2010 Jun	20347518
Ameliorative effect of flunarizine in cisplatin-induced acute renal failure via mitochondrial permeability transition pore inactivation in rats.	2011 Jan	21058009

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