| Size | Price | |
|---|---|---|
| Other Sizes |
| Targets |
Na+/Ca2+ channel (T-type); D2 dopamine receptor
|
|---|---|
| ln Vitro |
In rat cortical neurons that have been grown, flunarizine inhibits both sodium current (INa) and calcium current (ICa), with IC50 values of 0.94 μM and 1.77 μM, respectively [2]. On chromaffin cells, flunarizine (10 and 30 μM; 24 h) produces cytotoxic effects [4]. At concentrations of 3–10 μM, flunarizine (1–30 μM) can significantly protect chromaffin cells from damage [4].
|
| ln Vivo |
Mice administered flunarizine (intraperitoneal injection; 30 mg/kg; once) are shielded against acute lung injury (ALI) caused by lipopolysaccharide (LPS) [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]
|
| Cell Assay |
Cytotoxicity assay[4]
Cell Types: Chromaffin cells[4] 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 cell loss close to 100 at 10 μM concentration % concentration is 30μM. |
| Animal Protocol |
Animal/Disease Models: lipopolysaccharide-induced acute lung injury in male balb/c (Bagg ALBino) mouse (6-8 weeks old) [5]
Doses: 30 mg/kg Route of Administration: intraperitoneal (ip) injection; 30 mg/kg; Experimental Results:Inhibition of LPS-induced Cell influx, protein leakage, and inflammatory cytokine release. Suppress lung inflammation. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
85% following oral administration. Metabolism / Metabolites Hepatic, to two metabolites via N-dealylation and hydroxylation. Flunarizine has known human metabolites that include 1-[bis(4-fluorophenyl)methyl]piperazine, bis(4-fluorophenyl)methanone, and p-Hydroxyflunarizine. 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. Protein Binding 99% bound to plasma proteins |
| References |
|
| Additional Infomation |
Flunarizine is a diarylmethane.
Flunarizine is a selective calcium entry blocker with calmodulin binding properties and histamine H1 blocking activity. It is effective in the prophylaxis of migraine, occlusive peripheral vascular disease, vertigo of central and peripheral origin, and as an adjuvant in the therapy of epilepsy. Flunarizine is a selective calcium entry blocker with calmodulin binding properties and histamine H1 blocking activity. It is effective in the prophylaxis of migraine, occlusive peripheral vascular disease, vertigo of central and peripheral origin, and as an adjuvant in the therapy of epilepsy. Drug Indication Used in the prophylaxis of migraine, occlusive peripheral vascular disease, vertigo of central and peripheral origin, and as an adjuvant in the therapy of epilepsy. Mechanism of Action Flunarizine inhibits the influx of extracellular calcium through myocardial and vascular membrane pores by physically plugging the channel. The decrease in intracellular calcium inhibits the contractile processes of smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. Pharmacodynamics Flunarizine is a selective calcium entry blocker with calmodulin binding properties and histamine H1 blocking activity. |
| Molecular Formula |
C26H26N2F2
|
|---|---|
| Molecular Weight |
404.49484
|
| Exact Mass |
404.206
|
| Elemental Analysis |
C, 59.40; H, 4.65; F, 6.26; N, 13.85; O, 15.83
|
| CAS # |
52468-60-7
|
| Related CAS # |
Flunarizine dihydrochloride;30484-77-6
|
| PubChem CID |
941361
|
| Appearance |
White to off-white solid powder
|
| Density |
1.17 g/cm3
|
| Boiling Point |
511.3ºC at 760 mmHg
|
| Index of Refraction |
1.606
|
| LogP |
5.261
|
| Hydrogen Bond Donor Count |
0
|
| Hydrogen Bond Acceptor Count |
4
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
30
|
| Complexity |
487
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
C1CN(CCN1C/C=C/C2=CC=CC=C2)C(C3=CC=C(C=C3)F)C4=CC=C(C=C4)F
|
| InChi Key |
SMANXXCATUTDDT-QPJJXVBHSA-N
|
| InChi Code |
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+
|
| Chemical Name |
1-[bis(4-fluorophenyl)methyl]-4-[(E)-3-phenylprop-2-enyl]piperazine
|
| Synonyms |
Sibelium; 1-(Bis(4-fluorophenyl)methyl)-4-cinnamylpiperazine; Flunarizinum; Flunarizina; Flunarizinum [INN-Latin]; Flunarizina [INN-Spanish];
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~247.22 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.18 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.18 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4722 mL | 12.3612 mL | 24.7225 mL | |
| 5 mM | 0.4944 mL | 2.4722 mL | 4.9445 mL | |
| 10 mM | 0.2472 mL | 1.2361 mL | 2.4722 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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