Lomerizine HCl (KB-2796) 101477-54-7_Opioid Receptor_GPCR & G Protein_Signaling Pathways_Products

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.

Physicochemical Properties

Molecular Formula

C27H32CL2F2N2O3

Molecular Weight

541.46

Exact Mass

540.175

Elemental Analysis

C, 59.89; H, 5.96; Cl, 13.09; F, 7.02; N, 5.17; O, 8.86

CAS #

101477-54-7

Related CAS #

101477-54-7

PubChem CID

122125

Appearance

White to off-white solid powder

Boiling Point

527.3ºC at760mmHg

Melting Point

214-218ºC

Flash Point

272.7ºC

LogP

6.377

Hydrogen Bond Donor Count

Hydrogen Bond Acceptor Count

Rotatable Bond Count

Heavy Atom Count

Complexity

568

Defined Atom Stereocenter Count

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]

InChi Key

LOGVKVSFYBBUAJ-UHFFFAOYSA-N

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

Chemical Name

1-[bis(4-fluorophenyl)methyl]-4-[(2,3,4-trimethoxyphenyl)methyl]piperazine;dihydrochloride

Synonyms

Lomerizine HCl; KB-2796; Migsis; KB2796; KB 2796

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

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Shipping Condition

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets

L-type calcium channel; T-type calcium channel

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 [Ca²⁺], its capacity to prevent glutamate-induced motor neuron death and the resulting increase in cytosolic [Ca²⁺] 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 Ca²⁺ currents in dissociated rat brain neurons.Additionally, 1 μM metirizine inhibits H₂O₂-induced Ca²⁺ influx in hippocampal neurons. Pre-treatment with 1 μM Lomerizine inhibits the rise in cytosolic [Ca²⁺] 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].

ln Vivo

The neuroprotective effects of chemical reagents acting on the Ca²⁺-signaling pathway, including CaN activation, on NMDA-induced RGC death are investigated in order to ascertain whether Ca²⁺ 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].

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].

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].

References

[1]. The voltage-gated calcium channel blocker Lomerizine is neuroprotective in motor neurons expressing mutant SOD1, but not TDP-43. J Neurochem. 2014 Aug;130(3):455-66.

[2]. [Reversal of multidrug resistance by Lomerizine in K562/ADM cells]. Yao Xue Xue Bao. 2004 May;39(5):333-7

[3]. Development of spontaneous neuropathy in NF-κBp50-deficient mice by calcineurin-signal involving impaired NF-κB activation. Mol Vis. 2011;17:2157-70.

[4]. Effects of Ca2+ channel blockers on cortical hypoperfusion and expression of c-Fos-like immunoreactivity after cortical spreading depression in rats. Br J Pharmacol. 1995 Aug;115(8):1359-68.

Additional Infomation

See also: Lomerizine (annotation moved to).

Solubility Data

Solubility (In Vitro)

DMSO: 8~100 mg/mL (14.8~184.7 mM)

Water: <1 mg/mL

Ethanol: ~52 mg/mL warmed (~96.0 mM)

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.

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.
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 corn oil and mix evenly.

Solubility in Formulation 4: 2% DMSO +ddH2O: 5mg/mL

(Please use freshly prepared in vivo formulations for optimal results.)

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.

PeptideDB

Lomerizine HCl (KB-2796) 101477-54-7

CAS No.: 101477-54-7

Physicochemical Properties

Biological Activity

Solubility Data