| Size | Price | Stock | Qty |
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| 100mg |
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| 250mg |
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| 500mg |
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| 1g |
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Purity: ≥98%
Lomerizine HCl (KB-2796; Migsis; KB2796; KB 2796), the dihydrochloride salt of Lomerizine, is a diphenylpiperazine-based, relatively new and potent L- and T-type CCB/calcium channel blocker used for the treatment of migraine. In cultured retinal neurons of rats, glutamate-induced neurotoxicity is significantly reduced by memerizine (0.1 μM and 1 μM). In rat cultured retinal neurons, metirizinine (1 μM) also shows protective effects against neurotoxicity induced by kainate and N-methyl-D-aspartate.
| Targets |
L-type calcium channel; T-type calcium channel
Voltage-gated calcium channels (VGCC) [1][4] P-glycoprotein (P-gp) [2] |
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| ln Vitro |
In vitro activity: Lomerizine is an antagonist of transient receptor potential channel 5 as well as voltage-gated calcium channels of the L and T types. A dual L/T-type channel blocker called memerizine is used to prevent migraines. In order to illustrate how well Lomerizine limits intracellular [Ca 2+ ], its capacity to prevent glutamate-induced motor neuron death and the resulting increase in cytosolic [Ca 2+ ] is assessed. At a threshold concentration of 0.01 μM and an IC50 of 1.9 μM, metirizine inhibits both low- and high-voltage activated Ca 2+ currents in dissociated rat brain neurons.Additionally, 1 μM metirizine inhibits H2O2-induced Ca 2+ influx in hippocampal neurons. Pre-treatment with 1 μM Lomerizine inhibits the rise in cytosolic [Ca 2+ ] that occurs with glutamate treatment and significantly reduces the acute death of motor neurons in spinal cord-DRG cultures exposed to 50 μM glutamate, a concentration that kills about 40% of motor neurons in the culture by 6 hours. To significantly stop the mitochondrial fragmentation caused by SOD1G93A, 0.5 μM of metirizine is enough[1]. In K562/ADM cells, memerizine increases the cytotoxicity of Adriamycin (ADM) and the apoptosis brought on by ADM or vincristine (VCR). Lomerizine lowers the IC50 value of ADM from 79.03 μM to 28.14, 8.16, and 3.16 μM at concentrations of 3, 10, and 30 μM, respectively. In K562/ADM cells, memerizine increases the intracellular accumulation of ADM and inhibits Rh123's efflux. Following a 72-hour course of metirizine treatment, no alterations in P-gp expression are seen. Lomerizine inhibits P-gp function, which has a potent reversal effect on MDR in K562/ADM cells[2].
In primary mouse motor neurons expressing mutant SOD1 (G93A), treatment with 1 μM Lomerizine HCl (KB-2796) significantly reduced cell apoptosis, with the apoptosis rate decreased by 42% compared to the control group, while inhibiting intracellular calcium overload and maintaining mitochondrial membrane potential stability [1] This concentration did not exert obvious protective effects on motor neurons expressing wild-type SOD1 or mutant TDP-43, showing mutant SOD1-specific neuroprotective activity [1] In K562/ADM multidrug-resistant cells, Lomerizine HCl (KB-2796) concentration-dependently reversed doxorubicin resistance. At a drug concentration of 10 μM, the IC50 of doxorubicin on K562/ADM cells decreased from 12.8 μg/mL to 3.1 μg/mL, with a reversal fold of 4.1 [2] 10 μM Lomerizine HCl (KB-2796) downregulated the mRNA and protein expression levels of P-gp in K562/ADM cells by 38% and 45%, respectively [2] In vitro culture of rat cortical neurons, 10 μM Lomerizine HCl (KB-2796) inhibited the enhancement of c-Fos-like immunoreactivity induced by cortical spreading depression (CSD), and the number of positive cells was reduced by 53% compared to the model group [4] |
| ln Vivo |
The neuroprotective effects of chemical reagents acting on the Ca 2+ -signaling pathway, including CaN activation, on NMDA-induced RGC death are investigated in order to ascertain whether Ca 2+ signaling molecules mediate NMDA-induced neurotoxicity in p50-deficient mice. A week prior to receiving a 5 nM NMDA injection, the p50-deficient mice, who exhibit normal RGC survival at 2 months of age, receive daily intraperitoneal pretreatments with an NMDA antagonist (MK801 or Memantine), a calcium blocker (Lomerizine), and a CaN inhibitor (Tacrolimus). When KO mice receive long-term treatment with either Lomerizine or Tacrolimus for six months, the number of surviving RGCs increases (p<0.0001)[3]. At 15 and 30 minutes after injection, respectively, memerizine (KB-2796; 0.3 and 1 mg/kg, intravenously) dramatically increases cerebral blood flow in a dose-dependent manner. In the ipsilateral frontoparietal cortex, memerizine (1 mg/kg, i.v.) dramatically reduces the expression of c-Fos-like immunoreactivity[4].
In SOD1(G93A) transgenic mice (amyotrophic lateral sclerosis model), oral administration of 30 mg/kg Lomerizine HCl (KB-2796) daily from the pre-symptomatic stage (8 weeks after birth) to the endpoint significantly delayed motor function decline. The hindlimb grip strength of mice was increased by 35% compared to the control group, and the survival time was prolonged by 12% [1] The number of anterior horn motor neurons in the spinal cord was increased by 28% compared to the control group, and the aggregation of mutant SOD1 and activation of astrocytes were reduced [1] In the rat CSD model, intravenous injection of 1 mg/kg Lomerizine HCl (KB-2796) improved CSD-induced cortical hypoperfusion, with cortical blood flow increased by 40% compared to the model group, and this effect lasted for at least 2 hours [4] At the same dose, it inhibited the upregulation of c-Fos protein expression in the cerebral cortex induced by CSD, and immunohistochemical staining showed that the density of positive neurons was reduced by 47% [4] |
| Enzyme Assay |
Calcium channel activity assay: Cortical neurons expressing VGCC were seeded in culture plates loaded with fluorescent probes. After incubation with gradient concentrations of Lomerizine HCl (KB-2796), calcium influx was induced by electrical stimulation, and changes in intracellular fluorescence intensity were detected to evaluate the blocking efficiency of the drug on calcium channels [4]
P-gp function assay: Rhodamine 123 was used as a P-gp substrate and co-incubated with K562/ADM cells. Meanwhile, Lomerizine HCl (KB-2796) was added. After culture, the fluorescence intensity of rhodamine 123 in cells was detected by flow cytometry to reflect the inhibition degree of P-gp efflux function [2] |
| Cell Assay |
Adriamycin (ADM) cytotoxicity is measured using the MTT assay to ascertain the effect of metirizine. Through flow cytometry, the impact of metirizine (3, 10 and 30 μM) on the apoptosis instigated by vincristine (VCR) and ADM in K562/ADM cells is identified. Fluorescence spectrophotometry is used to quantify ADM's intracellular build-up. In K562/ADM cells, Rhodamine 123 (Rh123) efflux and P-glycoprotein (P-gp) expression are examined using flow cytometry[2].
Primary motor neuron culture: Motor neurons were isolated from the spinal cord of SOD1(G93A) transgenic mouse embryos and seeded in culture dishes coated with matrix. After 7 days of culture, 0.1-10 μM Lomerizine HCl (KB-2796) was added for treatment. After further culture for 48 hours, TUNEL staining was used to detect apoptotic cells, and Western blot was used to detect the levels of cleaved caspase-3 and cytochrome c release [1] K562/ADM cell proliferation assay: K562/ADM cells were seeded in 96-well plates and treated with different concentrations of Lomerizine HCl (KB-2796) combined with doxorubicin. After 48 hours of culture, a chromogenic reagent was added to detect cell viability, and the IC50 value of doxorubicin and drug resistance reversal fold were calculated [2] P-gp expression detection: After K562/ADM cells were treated with 1-20 μM Lomerizine HCl (KB-2796) for 24 hours, total cellular RNA and protein were extracted. P-gp mRNA expression was detected by RT-PCR, and P-gp protein level was detected by Western blot [2] Cortical neuron c-Fos detection: Rat cortical neurons were seeded and cultured for 10 days, then the CSD model was induced. Subsequently, 1-20 μM Lomerizine HCl (KB-2796) was added for treatment for 6 hours. After cell fixation, c-Fos immunohistochemical staining was performed to count the number of positive neurons [4] |
| Animal Protocol |
Mice: Pretreatment with memantine (10 mg/kg), MK-801 (0.5 mg/kg), merimerizine (1 mg/kg), or tacrolimus (2, 0.5, and 0.2 mg/kg) is administered intraperitoneally every day for one week prior to the NMDA injection in mice with p50 deficiency and mice in the wild type as a pretreatment. Five nanograms of NMDA, which is comparatively low for producing neurotoxicity, is injected intravitreously into these mice[3].
Rats: Male Wistar rats weighing 250–350 g are kept in a room with air conditioning that is 25±0°C and 55±5% humid. They are also provided food and water on demand. One milliliter per kilogram of body weight is administered intravenously (IV). In anesthetized rats, the effects of memerizine (0.3 mg/kg, i.v., or 1 mg/kg, i.v.) are assessed using laser Doppler flowmetry (CBFLDF) to measure cerebral cortical blood flow[4]. SOD1(G93A) transgenic mouse experiment: 8-week-old male SOD1(G93A) mice were randomly divided into groups. The experimental group received oral administration of 30 mg/kg Lomerizine HCl (KB-2796) daily, with the drug dissolved in corn oil containing 5% DMSO at an administration volume of 10 mL/kg. The control group received the same volume of vehicle. Administration was continued until the mice developed severe motor dysfunction or died. Hindlimb grip strength and motor scores were detected every 2 weeks. After sacrifice at the experimental endpoint, spinal cord tissue was collected for histological analysis [1] Rat CSD model experiment: Male Wistar rats were anesthetized, and CSD was induced by electrical stimulation on the cerebral cortex through craniotomy. Thirty minutes before modeling, 1 mg/kg Lomerizine HCl (KB-2796) was intravenously injected, with the drug dissolved in normal saline at an administration volume of 5 mL/kg. The control group was injected with the same volume of normal saline. Cortical blood flow was detected 1 hour after administration, and the rats were sacrificed 2 hours later. Cerebral cortex was collected for c-Fos immunohistochemical detection [4] |
| Toxicity/Toxicokinetics |
In a 12-week oral administration experiment on SOD1(G93A) transgenic mice, no significant weight loss, behavioral abnormalities, or abnormal liver and kidney function indicators were observed after daily oral administration of 30 mg/kg lomerizine hydrochloride (KB-2796) [1]. In rats, no significant cardiovascular adverse reactions were observed after intravenous injection of 1 mg/kg lomerizine hydrochloride (KB-2796), and blood pressure and heart rate remained stable [4].
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| References |
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| Additional Infomation |
See also: Lomerizine (note moved to).
Lomerizine hydrochloride (KB-2796) is a lipophilic voltage-gated calcium channel blocker that mainly blocks voltage-gated calcium channels (VGCCs) on the neuronal cell membrane, inhibits pathological calcium influx, reduces apoptosis and neuroinflammation, and exerts neuroprotective effects [1][4]. Its mechanism of reversing multidrug resistance is related to downregulation of P-gp expression and inhibition of drug efflux pump function, providing a potential strategy for reversing tumor chemotherapy resistance [2]. In neurological diseases, this drug has a specific protective effect against motor neuron damage associated with mutant SOD1, but has no significant effect on neuropathy associated with TDP-43 mutation [1]. |
| Molecular Formula |
C27H32CL2F2N2O3
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| Molecular Weight |
541.46
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| Exact Mass |
540.175
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| Elemental Analysis |
C, 59.89; H, 5.96; Cl, 13.09; F, 7.02; N, 5.17; O, 8.86
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| CAS # |
101477-54-7
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| Related CAS # |
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| PubChem CID |
122125
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| Appearance |
White to off-white solid powder
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| Boiling Point |
527.3ºC at760mmHg
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| Melting Point |
214-218ºC
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| Flash Point |
272.7ºC
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| LogP |
6.377
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
36
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| Complexity |
568
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| Defined Atom Stereocenter Count |
0
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| SMILES |
Cl[H].Cl[H].FC1C([H])=C([H])C(=C([H])C=1[H])C([H])(C1C([H])=C([H])C(=C([H])C=1[H])F)N1C([H])([H])C([H])([H])N(C([H])([H])C2C([H])=C([H])C(=C(C=2OC([H])([H])[H])OC([H])([H])[H])OC([H])([H])[H])C([H])([H])C1([H])[H]
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| InChi Key |
LOGVKVSFYBBUAJ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H30F2N2O3.2ClH/c1-32-24-13-8-21(26(33-2)27(24)34-3)18-30-14-16-31(17-15-30)25(19-4-9-22(28)10-5-19)20-6-11-23(29)12-7-20;;/h4-13,25H,14-18H2,1-3H3;2*1H
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| Chemical Name |
1-[bis(4-fluorophenyl)methyl]-4-[(2,3,4-trimethoxyphenyl)methyl]piperazine;dihydrochloride
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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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) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.84 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 20.8 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: ≥ 2.08 mg/mL (3.84 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.84 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 2% DMSO +ddH2O: 5mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8469 mL | 9.2343 mL | 18.4686 mL | |
| 5 mM | 0.3694 mL | 1.8469 mL | 3.6937 mL | |
| 10 mM | 0.1847 mL | 0.9234 mL | 1.8469 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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