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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
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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].
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| 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] |
| 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]
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| 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. |
| 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. |
| ADME/Pharmacokinetics |
Absorption
85% following oral administration. Metabolism / Metabolites Hepatic, to two metabolites via N-dealylation and hydroxylation. Flunarizine has known human metabolites that include p-Hydroxyflunarizine, 1-[bis(4-fluorophenyl)methyl]piperazine, and bis(4-fluorophenyl)methanone. Biological Half-Life: 18 days |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation Flunarizine is not approved for marketing in the United States by the U.S. Food and Drug Administration, but is available in other countries. No information is available on the use of flunarizine during breastfeeding. Because of its long half-life of 19 days in children, expert opinion recommends that flunarizine not be used in migraine prophylaxis in nursing mothers. An alternate drug is preferred, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. women TDLo oral 73 mg/kg/1Y-I BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY); BEHAVIORAL: TREMOR Italian Journal of Neurological Sciences., 10(89), 1989 [PMID:2925349] man 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] women TDLo oral 18 mg/kg/90D-I BEHAVIORAL: TREMOR Neurology., 37(881), 1987 [PMID:3574697] Protein Binding 99% bound to plasma proteins |
| 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)-alpha,alpha-diphenyl-2-pyrrolidinemethanol is a diarylmethane.
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| 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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