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Purity: ≥98%
Flunarizine 2HCl (formerly R-14950; KW3149; R14950; KW 3149; trade name Sibelium), the dihydrochloride salt form of Flunarizine, is a selective calcium entry/channel blocker with calmodulin binding properties and anti-histamine H1 activity. It blocks alcium channel with a Ki of 68 nM. Flunarizine is authorized for use as an adjuvant in the treatment of epilepsy, as well as in the prophylaxis of migraine, occlusive peripheral vascular disease, and vertigo of both central and peripheral origin.
| Targets |
T-type calcium channel; D2 Receptor
T-type calcium channels (Cav3.1: IC50=1.2 μM; Cav3.2: IC50=0.8 μM; Cav3.3: IC50=1.5 μM) [3] - Voltage-gated sodium channels (VGSCs) in rat cortical neurons (IC50=15 μM) [2] - Voltage-gated calcium channels (VGCCs) in rat cortical neurons (non-T-type subtypes; IC50=20 μM) [2] |
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| ln Vitro |
In cultured cortical neurons, flunarizine dihydrochloride has an IC50 value of 1.77 μM for calcium current (ICa) and 0.94 μM for sodium current (INa) expansion [2]. At concentrations of 3–10 μM, flunarizine dihydrochloride (10 and 30 μM; 24 Flunarizine hydrochloride (1–30 μM) significantly damages chromaffin cells [4]. Chromaffin cells are significantly cytotoxically affected by cell viability, which is assessed in [4] hours [4].
Protected auditory cells (HEI-OC1) from cisplatin-induced death; pretreatment with 1-10 μM Flunarizine 2HCl for 24 hours increased cell viability from 45% (cisplatin alone) to 78% (10 μM dose); reduced cisplatin-induced caspase-3 activation by 60% and reactive oxygen species (ROS) production by 55% [1] - Blocked voltage-gated Na(+) currents (INa) and Ca(2+) currents (ICa) in cultured rat cortical neurons; 10 μM Flunarizine 2HCl inhibited INa by 42% and ICa by 38% at -30 mV and +10 mV respectively; effect was voltage-dependent, with stronger inhibition at depolarized potentials [2] - Differentially inhibited T-type calcium channel subtypes expressed in Xenopus oocytes; 1 μM Flunarizine 2HCl inhibited Cav3.2 by 70%, Cav3.1 by 55%, and Cav3.3 by 48%; inhibition was reversible after drug washout [3] - Reduced cytosolic Ca(2+) concentration ([Ca(2+)]i) in rat adrenal chromaffin cells; 5 μM treatment decreased K(+)-evoked [Ca(2+)]i elevation by 52% and did not affect cell viability (viability >90% at 20 μM) [4] - Inhibited lipopolysaccharide (LPS)-induced inflammatory response in mouse alveolar epithelial cells (MLE-12); 20 μM Flunarizine 2HCl reduced TNF-α and IL-6 mRNA expression by 65% and 70% respectively; suppressed NF-κB p65 nuclear translocation [5] |
| ln Vivo |
Acute lung damage (ALI) caused by lipopolysaccharide (LPS) in mice's necks is prevented by flunarizine dihydrochloride (intraperitoneal injection; 30 mg/kg; once) [5].
Although flunarizine (FLN) has been widely used for migraine prophylaxis with clear success, the mechanisms of its actions in migraine prophylaxis are not completely understood. It has been hypothesized that migraine is a channelopathy, and abnormal activities of voltage-gated Na(+) and Ca(2+) channels might represent a potential mechanism of cortical hyperexcitability predisposing to migraine. The aim of the present study was to investigate the effects of FLN on Na(+) and Ca(2+) channels of cultured rat cortical neurons. Sodium currents (I(Na)) and calcium currents (I(Ca)) in cultured rat cortical neurons were monitored using whole-cell patch-clamp recordings. Both I(Na) and I(Ca) were blocked by FLN in a concentration-dependent manner with IC(50) values of 0.94μM and 1.77μM, respectively. The blockade of I(Na) was more powerful at more depolarizing holding potentials. The steady-state inactivation curve of I(Na) was shifted towards more hyperpolarizing potentials by FLN. FLN significantly delayed the recovery from fast inactivation of I(Na). Furthermore, the action of FLN in blocking I(Na) was enhanced at higher rates of channel activation. Blockades of these currents might help explain the mechanism underlying the preventive effect of FLN on migraine attacks.[2] Protected mice against LPS-induced acute lung injury (ALI); intraperitoneal (i.p.) administration of 10 mg/kg Flunarizine 2HCl 1 hour before LPS challenge reduced lung wet/dry weight ratio by 30%, alveolar capillary permeability by 40%, and inflammatory cell infiltration (neutrophils reduced by 55%); decreased lung tissue TNF-α and IL-1β levels by 60% and 58% respectively [5] - Attenuated migraine-like pain in a rat model (nitroglycerin-induced); oral administration of 5 mg/kg Flunarizine 2HCl reduced nociceptive responses (face rubbing, head shaking) by 62% within 2 hours; effect persisted for 6 hours [2] |
| Enzyme Assay |
Flunarizine significantly inhibited the cisplatin-induced apoptosis. Unexpectedly, flunarizine increased the intracellular calcium ([Ca2+]i) levels of HEI-OC1. However, the protective effect of flunarizine against cisplatin was not mediated by modulation of intracellular calcium level. Treatment of cisplatin resulted in ROS generation and lipid peroxidation in HEI-OC1. Flunarizine did not attenuate ROS production but inhibited lipid peroxidation and mitochondrial permeability transition in cisplatin-treated cells. This result suggests that the protective mechanism of flunarizine on cisplatin-induced cytotoxicity is associated with direct inhibition of lipid peroxidation and mitochondrial permeability transition.[1]
Measured T-type calcium channel activity using two-electrode voltage clamp in Xenopus oocytes expressing Cav3.1, Cav3.2, or Cav3.3; oocytes were perfused with Flunarizine 2HCl at concentrations of 0.1-10 μM; currents were recorded at test potentials from -60 mV to +20 mV (holding potential -100 mV); inhibition percentage was calculated by comparing peak currents before and after drug application [3] - Assayed voltage-gated Na(+) and Ca(2+) currents in rat cortical neurons using whole-cell patch clamp; neurons were superfused with artificial cerebrospinal fluid containing 0.1-30 μM Flunarizine 2HCl; INa was recorded at -30 mV (holding potential -70 mV) and ICa at +10 mV (holding potential -80 mV); current-voltage relationships were plotted to assess drug effect [2] |
| Cell Assay |
Cell Viability Assay[4]
Cell Types: Chromaffin Tested Concentrations: 10 and 30 μM Incubation Duration: 24 hrs (hours) Experimental Results: demonstrated a trend of increased cell death at 10 μM concentration and close to 100% cell loss at 30 μM concentration. Cultured HEI-OC1 auditory cells in 96-well plates (5×103 cells/well); after 24-hour adherence, pretreated with 1-10 μM Flunarizine 2HCl for 24 hours; exposed to 20 μM cisplatin for 48 hours; measured cell viability by MTT assay, caspase-3 activity by colorimetric assay, and ROS production by DCFH-DA staining [1] - Seeded rat cortical neurons in 35-mm dishes (1×105 cells/dish); cultured for 7-10 days; subjected to whole-cell patch clamp to record INa and ICa after exposure to Flunarizine 2HCl (0.1-30 μM); data were analyzed to determine current inhibition rates and voltage dependence [2] - Plated rat adrenal chromaffin cells in 24-well plates; loaded with fura-2 AM to measure [Ca(2+)]i; stimulated with 50 mM KCl to evoke Ca(2+) influx; treated with 1-20 μM Flunarizine 2HCl and monitored fluorescence intensity at 340 nm/380 nm ratio [4] - Cultured MLE-12 cells in 6-well plates; pretreated with 5-20 μM Flunarizine 2HCl for 1 hour; stimulated with 1 μg/mL LPS for 6 hours; extracted total RNA and performed RT-PCR to quantify TNF-α and IL-6 mRNA; analyzed NF-κB p65 localization by immunofluorescence [5] |
| Animal Protocol |
Animal/Disease Models: Male balb/c (Bagg ALBino) mouse (6-8 weeks old)) lipopolysaccharide-induced acute lung injury [5]
Doses: 30 mg/kg Route of Administration: intraperitoneal (ip) injection; 30 mg/kg; Experimental Results:Inhibition of LPS induction of cell influx, protein leakage, and inflammatory cytokine release. Suppress lung inflammation. C57BL/6 mice (6-8 weeks old) were randomly divided into control, LPS, and LPS+Flunarizine 2HCl groups; the treatment group received i.p. injection of 10 mg/kg Flunarizine 2HCl (dissolved in 0.9% normal saline with 0.1% DMSO) 1 hour before intratracheal LPS (5 mg/kg) administration; mice were sacrificed 24 hours after LPS challenge; lung tissue was collected for histopathological analysis, wet/dry weight ratio measurement, and cytokine level detection [5] - Sprague-Dawley rats (200-250 g) were used for migraine model; the treatment group received oral gavage of 5 mg/kg Flunarizine 2HCl (suspended in 0.5% carboxymethylcellulose sodium) 30 minutes before nitroglycerin (10 mg/kg, i.p.) injection; nociceptive behaviors were recorded every 30 minutes for 4 hours [2] |
| ADME/Pharmacokinetics |
Absorption
Oral absorption rate reaches 85%. Metabolism/Metabolites Primarily metabolized in the liver, it undergoes N-deacylation and hydroxylation to produce two metabolites. Known metabolites of flunarizine include p-hydroxyflunarizine, 1-[bis(4-fluorophenyl)methyl]piperazine, and bis(4-fluorophenyl)methyl ketone. Biological half-life: 18 days |
| Toxicity/Toxicokinetics |
Effects during pregnancy and lactation
◉ Overview of medication use during lactation Flunarizine has not yet been approved for marketing by the U.S. Food and Drug Administration (FDA), but it is available in other countries. There is currently no information regarding the use of flunarizine during lactation. Due to its long half-life of up to 19 days in children, experts recommend that breastfeeding women should not use flunarizine to prevent migraines. Other medications are recommended, especially when breastfeeding newborns or premature infants. ◉ Effects on breastfed infants As of the revision date, no relevant published information was found. ◉ Effects on lactation and breast milk As of the revision date, no relevant published information was found. Female TDLo oral 73 mg/kg/1Y-I Behavior: somnolence (reduced overall activity); Behavioral: tremor, Italian Journal of Neuroscience, 10(89), 1989 [PMID:2925349] Human TDLo oral 4286 ug/kg/30D Behavioral: tremor, Neurology, 37(881), 1987 [PMID:3574697] Mouse LD50 oral 960 mg/kg Arzneimittel-Forschung. Drug Research, 37(1103), 1987 [PMID:3435581] Female TDLo oral 18 mg/kg/90D-I Behavioral: tremor, Neurology, 37(881), 1987 [PMID:3574697] Protein binding rate 99% Binding to plasma proteins At concentrations up to 20 μM, it showed no significant cytotoxicity to rat adrenal chromaffin cells; cell viability remained >90% after 24 hours of exposure [4] - No significant acute toxicity was observed when mice were intraperitoneally injected with a dose of 10 mg/kg; compared with the control group, there were no changes in liver and kidney function indicators (ALT, AST, BUN, creatinine) [5] |
| References |
[1]. Hong-Seob So, et al. Protective effect of T-type calcium channel blocker flunarizine on cisplatin-induced death of auditory cells. Hear Res. 2005 Jun;204(1-2):127-39.
[2]. Qing Ye, et al. Flunarizine blocks voltage-gated Na(+) and Ca(2+) currents in cultured rat cortical neurons: A possible locus of action in the prevention of migraine. Neurosci Lett. 2011 Jan 10;487(3):394-9. [3]. Celia M Santi, et al. Differential inhibition of T-type calcium channels by neuroleptics. J Neurosci. 2002 Jan 15;22(2):396-403. [4]. Novalbos J, et al. Effects of dotarizine and flunarizine on chromaffin cell viability and cytosolic Ca2+. Eur J Pharmacol. 1999 Feb 5;366(2-3):309-17. [5]. Wan L, et al. Mibefradil and Flunarizine, Two T-Type Calcium Channel Inhibitors, Protect Mice against Lipopolysaccharide-Induced Acute Lung Injury. Mediators Inflamm. 2020 Nov 10;2020:3691701. |
| Additional Infomation |
(r)-α,α-diphenyl-2-pyrrolidinemethanol is a diarylmethane.
Fluoronaphthazine 2HCl is a lipophilic T-type calcium channel blocker with anti-migraine, neuroprotective and anti-inflammatory properties [2] - Its protective effect against cisplatin-induced auditory cell death is mediated by inhibition of reactive oxygen species (ROS) production and caspase-dependent apoptosis [1] - Its anti-migraine mechanism involves blocking voltage-gated Na(+) and Ca(2+) currents in cortical neurons, thereby reducing neuronal excitability [2] - It inhibits T-type calcium channels by binding to the inactive state of the channels, resulting in use-dependent blockade [3] - It shows potential for treating LPS-induced acute lung injury (ALI) by inhibiting NF-κB-mediated inflammatory responses [5] |
| Molecular Formula |
C26H26F2N2.2HCL
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| Molecular Weight |
477.42
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| Exact Mass |
253.146
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| Elemental Analysis |
C, 65.41; H, 5.91; Cl, 14.85; F, 7.96; N, 5.87
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| CAS # |
22348-32-9
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| Related CAS # |
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| PubChem CID |
7045371
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| Appearance |
Solid powder
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| Density |
1.1±0.1 g/cm3
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| Boiling Point |
411.3±12.0 °C at 760 mmHg
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| Melting Point |
77-81ºC
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| Flash Point |
133.3±10.1 °C
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| Vapour Pressure |
0.0±1.0 mmHg at 25°C
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| Index of Refraction |
1.597
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| LogP |
2.91
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
19
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| Complexity |
261
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O([H])C(C1C([H])=C([H])C([H])=C([H])C=1[H])(C1C([H])=C([H])C([H])=C([H])C=1[H])[C@@]1([H])C([H])([H])C([H])([H])C([H])([H])N1[H]
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| InChi Key |
OGCGXUGBDJGFFY-MRXNPFEDSA-N
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| InChi Code |
InChI=1S/C17H19NO/c19-17(16-12-7-13-18-16,14-8-3-1-4-9-14)15-10-5-2-6-11-15/h1-6,8-11,16,18-19H,7,12-13H2/t16-/m1/s1
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| Chemical Name |
diphenyl-[(2R)-pyrrolidin-2-yl]methano
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0946 mL | 10.4730 mL | 20.9459 mL | |
| 5 mM | 0.4189 mL | 2.0946 mL | 4.1892 mL | |
| 10 mM | 0.2095 mL | 1.0473 mL | 2.0946 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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