Meclizine 2HCl 1104-22-9_Histamine Receptor_GPCR & G Protein_Signaling Pathways_Products

Meclizine 2HCl (Ru Vert M; Ru-Vert-M; RuVertM; NSC28728; NSC-28728), the dihydrochloride salt of meclizine, is a potent histamine H1 receptor antagonist used to treat nausea and motion sickness, and has anti-histamine, anti-muscarinic and anti-oxidative phosphorylation properties. Meclizine also functions as an inverse agonist for hCAR and an agonist ligand for mCAR. Meclizine stimulates the binding of steroid receptor coactivator 1 to the murine receptor in vitro and increases mCAR transactivation in a dose-dependent manner.

Physicochemical Properties

Molecular Formula

C25H29CL3N2

Molecular Weight

463.87

Exact Mass

462.139

Elemental Analysis

C, 64.73; H, 6.30; Cl, 22.93; N, 6.04

CAS #

1104-22-9

Related CAS #

Meclizine-d8 dihydrochloride; 1432062-16-2; Meclizine; 569-65-3; 31884-77-2 (HCl hydrate); 36236-67-6 (HCl); 189298-48-4 (R-isomer)

PubChem CID

64713

Appearance

White to light yellow crystalline powder

Density

1.159g/cm3

Boiling Point

495.3ºC at 760mmHg

Melting Point

212 °C

Flash Point

253.3ºC

Vapour Pressure

6E-10mmHg at 25°C

LogP

7.035

Hydrogen Bond Donor Count

Hydrogen Bond Acceptor Count

Rotatable Bond Count

Heavy Atom Count

Complexity

448

Defined Atom Stereocenter Count

SMILES

CC1=CC(CN2CCN(C(C3=CC=C(Cl)C=C3)C4=CC=CC=C4)CC2)=CC=C1.Cl.Cl

InChi Key

VCTHNOIYJIXQLV-UHFFFAOYSA-N

InChi Code

InChI=1S/C25H27ClN2.2ClH/c1-20-6-5-7-21(18-20)19-27-14-16-28(17-15-27)25(22-8-3-2-4-9-22)23-10-12-24(26)13-11-23;;/h2-13,18,25H,14-17,19H2,1H3;2*1H

Chemical Name

1-[(4-chlorophenyl)-phenylmethyl]-4-[(3-methylphenyl)methyl]piperazine;dihydrochloride

Synonyms

Meclizine Hcl; Meclizine dihydrochloride monohydrate; NSC 28728; Ru Vert M; Ru-Vert-M; RuVertM; NSC28728; NSC-28728; Meclizine hydrochloride; Meclizine dihydrochloride; 1104-22-9; Bonamine; 1-((4-Chlorophenyl)(phenyl)methyl)-4-(3-methylbenzyl)piperazine dihydrochloride; Ancolan dihydrochloride; Meclizine 2HCl;

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

H₁ Receptor

ln Vitro

In vitro activity: Meclizine (Meclozine; 50 µM; 24 hours) dihydrochloride, which suppresses apoptosis based on caspase 3 and 7 cleavage, notably increases cell survival in STHdhQ111/111 cells 24 hours after serum removal. With an EC50 of 17.3 µm and a maximum efficacy of 218% increased survival over vehicle, the rescue is dose-dependent. Meclizine dihydrochloride prevents mutant (STHdhQ111/111) and wild-type (STHdhQ7/7) striatal cells from undergoing serum withdrawal-induced apoptosis when those cells express polyglutamine (polyQ)-expanded huntingtin[2].

ln Vivo

Meclizine dihydrochloride (10–100 mg/kg; intraperitoneal) shields mice from renal ischemia. In mice, kidney protection is demonstrated by pretreatment with 100 mg/kg of meclizine 17 or 24 hours before ischemia. Meclizine dihydrochloride increases glycolysis and directly inhibits the Kennedy pathway of phosphatidylethanolamine biosynthesis to lower mitochondrial oxygen consumption[4].

Enzyme Assay

The constitutive androstane receptor (CAR, NR1I3) is a key regulator of xenobiotic and endobiotic metabolism. The ligand-binding domains of murine (m) and human (h) CAR are divergent relative to other nuclear hormone receptors, resulting in species-specific differences in xenobiotic responses. Here we identify the widely used antiemetic meclizine (Antivert; Bonine) as both an agonist ligand for mCAR and an inverse agonist for hCAR. Meclizine increases mCAR transactivation in a dose-dependent manner. Like the mCAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, meclizine stimulates binding of steroid receptor coactivator 1 to the murine receptor in vitro. Meclizine administration to mice increases expression of CAR target genes in a CAR-dependent manner. In contrast, meclizine suppresses hCAR transactivation and inhibits the phenobarbital-induced expression of the CAR target genes, cytochrome p450 monooxygenase (CYP)2B10, CYP3A11, and CYP1A2, in primary hepatocytes derived from mice expressing hCAR, but not mCAR. The inhibitory effect of meclizine also suppresses acetaminophen-induced liver toxicity in humanized CAR mice. These results demonstrate that a single compound can induce opposite xenobiotic responses via orthologous receptors in rodents and humans[3].

Cell Assay

In 24-well plates, HepG2 cells are grown in DMEM supplemented with 10% calf serum that has been stripped of its charcoal. 100 ng of receptor expression vectors, 300 ng of luciferase reporter plasmids, and 100 ng of pSV2-β-galactosidase are used to transfect cells using calcium phosphate, with the latter serving as an internal transfection efficiency control. After transfection, drugs are added and cells are incubated for a further twenty-four hours. The luciferase activity of the cell lysate is measured and compared to that of β-galactosidase activity.

Animal Protocol

Drug testing in C. elegans[2]
Animals co-expressing YFP and N-terminal htt fused to CFP in touch receptor neurons were used for drug testing. Synchronized L1 larvae, obtained by hypochlorite extraction, were incubated with drugs in 96-well plates in 50 µl of the M9 medium with OP-50 bacteria and 30 mg/ml of streptomycin, at 20°C for 3 days as described previously. Three independent assays were performed and a minimum of 100 worms were tested per dose. Animals were considered as touch responsive if they reacted after light touch (backward movement). Out of three touches, two or three reactions were regarded as responsive, and 0 or 1 reaction was regarded as unresponsive. htt aggregation and axonal morphology in PLM neurons were scored using light microscopy as described previously. htt aggregation was scored using CFP fluorescence and axonal dystrophy was quantified using YFP fluorescence to detect axonal swelling. Worms were treated with DMSO or 33 µm meclizine for 3 days. Proteins were extracted using the WormBook method, separated on NUPAGE 3–8% tris-acetate gels, transferred to a membrane and the GFP-tagged 128Q-htt fragment was probed using anti-GFP antibody. Protein quantity was normalized using an anti-actin antibody.

Drug testing in D. melanogaster[2]
The UAS-Htt-Q0 and UAS-Htt-Q128 lines encoding the first 548 amino acids of human Htt containing either 0 or 128 glutamines were gifts from Troy Littleton. The elav-GAL4 driver was from the Bloomington Stock Center. The UAS-Htt-Q128 line was crossed to elav-GAL4/CyO to obtain UAS-Htt-Q128/elav-GAL4 flies. These adults showed no discernable degeneration by pseudopupil analysis upon eclosion, but the rhabdomeres underwent progressive degeneration over the following 10 days. In contrast, UAS-Htt-Q0 driven by elav-GAL4 did not show degeneration during this time. Equal numbers of newly eclosed UAS-Htt-Q128/elav-GAL4 flies were added to vials containing Carolina Biological Instant Fly food that had been freshly made up with water and meclizine or DMSO vehicle at different concentrations (100, 33, 11 or 3 μm). Flies were given fresh food and drug every 2 days and were maintained at 25°C throughout the experiment. Neurodegeneration was assessed using the pseudopupil technique at day 10 by scoring the rhabdomere number/ommatidium from at least 8 animals for each condition, with at least 40 ommatidia being scored per animal. The experiment was performed twice and scoring was conducted in a blinded manner. Western blot analysis using mouse anti-human HTT was performed using lysates from UAS-Htt-Q128/elav-GAL4 adult flies that had been fed on either 33 µm meclizine or DMSO for 10 days.

Dissolved in corn oil; 100 mg/kg; i.p. injection

Mouse

References

[1]. Safety and Efficacy in the Treatment and Prevention of Motion Sickness.

[2]. Meclizine is neuroprotective in models of Huntington's disease. Hum Mol Genet. 2011 Jan 15;20(2):294-300.

[3]. Meclizine Is an Agonist Ligand for Mouse Constitutive Androstane Receptor (CAR) and an Inverse Agonist for Human CAR. Mol Endocrinol . 2004 Oct;18(10):2402-8.

[4]. Meclizine Preconditioning Protects the Kidney Against Ischemia-Reperfusion Injury. EBioMedicine. 2015 Jul 29;2(9):1090-101.

Additional Infomation

Meclizine Hydrochloride is the hydrochloride salt form of meclizine, a synthetic piperazine with anti-emetic, sedative and histamine H1 antagonistic properties. Meclizine hydrochloride blocks the H1 histamine receptor and prevents the symptoms that are caused by histamine activity on capillaries, bronchial and gastrointestinal smooth muscles, including vasodilation, increased capillary permeability, bronchoconstriction, and spasmodic contraction of gastrointestinal smooth muscles. Meclizine hydrochloride may exert its antiemetic effects by its anticholinergic actions or due to a direct effect on the medullary chemoreceptive trigger zone.
A histamine H1 antagonist used in the treatment of motion sickness, vertigo, and nausea during pregnancy and radiation sickness.
See also: Meclizine Hydrochloride (annotation moved to).

Solubility Data

Solubility (In Vitro)

DMSO: 1~4 mg/mL (2.2~8.6 mM)

Water: <1 mg/mL

Ethanol: <1 mg/mL

Solubility (In Vivo)

Solubility in Formulation 1: 10 mg/mL (21.56 mM) in 15% Cremophor EL + 85% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
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 (5.39 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 3: ≥ 2.5 mg/mL (5.39 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 25.0 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 4: ≥ 2.5 mg/mL (5.39 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 corn oil and mix evenly.

Solubility in Formulation 5: 5% DMSO +95%Corn oil : 10mg/mL

Solubility in Formulation 6: 5 mg/mL (10.78 mM) in Cremophor EL (add these co-solvents sequentially from left to right, and one by one), clear solution; with heating and sonication.

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

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.1558 mL	10.7789 mL	21.5578 mL
	5 mM	0.4312 mL	2.1558 mL	4.3116 mL
	10 mM	0.2156 mL	1.0779 mL	2.1558 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

Meclizine 2HCl 1104-22-9

CAS No.: 1104-22-9

Physicochemical Properties

Biological Activity

Solubility Data