H₁ Receptor
Histamine H1 receptor (H1R) (human H1R, Ki=0.85 nM; rat H1R, Ki=1.1 nM) [1]
Mouse Constitutive Androstane Receptor (mCAR) (agonist, EC50=3.2 μM) [3]
Human Constitutive Androstane Receptor (hCAR) (inverse agonist, Ki=4.7 μM) [3]

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].

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Primary rat striatal neurons expressing mutant huntingtin (mHTT) were treated with Meclizine 2HCl (1 μM-20 μM) for 48 hours. The drug reduced mHTT aggregate formation by 58% at 10 μM, inhibited caspase-3 activation (by 45%), and increased cell viability from 42% (control) to 76% (10 μM), exerting neuroprotective effects [2]
- HEK293 cells transfected with mCAR or hCAR reporter gene constructs were treated with Meclizine 2HCl (0.1 μM-50 μM). It activated mCAR-mediated luciferase activity in a concentration-dependent manner (EC50=3.2 μM) but inhibited hCAR basal activity (Ki=4.7 μM), confirming species-specific CAR modulation [3]
- Human renal proximal tubular epithelial cells (HK-2) subjected to hypoxia-reoxygenation (H/R) injury were pre-treated with Meclizine 2HCl (5 μM-50 μM). At 20 μM, it reduced intracellular reactive oxygen species (ROS) levels by 62%, inhibited Bax/Bcl-2 ratio (by 55%), and increased cell viability by 38% compared to H/R alone [4]
- Isolated guinea pig ileum segments pre-contracted with histamine (1 μM) were treated with Meclizine 2HCl (0.1 μM-10 μM). It induced concentration-dependent relaxation (IC50=1.5 μM) via competitive H1R antagonism [1]

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].

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Motion sickness model in rats: Oral administration of Meclizine 2HCl (25 mg/kg, 50 mg/kg) 1 hour before rotational stimulation (10 rpm for 30 minutes) reduced motion-induced emetic-like behaviors (retching, freezing) by 65% and 82% respectively. The effect lasted for 6-8 hours post-administration [1]
- Huntington's disease (HD) model in R6/2 transgenic mice: Oral gavage of Meclizine 2HCl (30 mg/kg/day) from 4 to 10 weeks of age improved motor function (rotarod performance increased by 40%) and reduced striatal neuron loss by 35% compared to vehicle. It also decreased cerebral mHTT aggregate burden by 48% [2]
- Mouse renal ischemia-reperfusion (I/R) injury model: Intraperitoneal injection of Meclizine 2HCl (10 mg/kg) 24 hours before ischemia and again at reperfusion reduced serum creatinine (by 42%) and blood urea nitrogen (BUN) (by 38%) at 24 hours post-reperfusion. Histological analysis showed reduced tubular necrosis (by 52%) and inflammatory cell infiltration [4]
- Clinical trial for motion sickness prevention: Adult subjects administered oral Meclizine 2HCl (25 mg or 50 mg) 1 hour before sea travel had a 78% and 89% reduction in motion sickness symptoms (nausea, vomiting, dizziness) compared to placebo. No severe adverse events were reported [1]

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].

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H1R binding assay: Prepare membrane fractions from human H1R-expressing HEK293 cells or rat brain tissue. Incubate membranes with [3H]-mepyramine (0.5 nM) and various concentrations of Meclizine 2HCl (0.01 nM-100 nM) at 25°C for 60 minutes. Separate bound and free ligand by vacuum filtration through glass fiber filters. Measure radioactivity with a liquid scintillation counter and calculate Ki values using the Cheng-Prusoff equation [1]
- CAR receptor reporter assay: Transfect HEK293 cells with mCAR/hCAR expression plasmids and luciferase reporter plasmids (driven by CAR-responsive promoter). Incubate transfected cells with Meclizine 2HCl (0.1 μM-50 μM) for 24 hours. Lyse cells and measure luciferase activity using a luminometer to assess agonist (mCAR) or inverse agonist (hCAR) activity [3]

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.

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Striatal neuron neuroprotection assay: Isolate primary striatal neurons from E14-E16 rat embryos and culture for 7 days. Transfect neurons with mHTT-expressing plasmid, then treat with Meclizine 2HCl (1 μM-20 μM) for 48 hours. Detect mHTT aggregates via immunofluorescence, caspase-3 activation via Western blot, and cell viability via MTT assay [2]
- HK-2 cell H/R injury assay: Seed HK-2 cells in 96-well plates (viability) or 6-well plates (ROS/apoptosis) and incubate until 80% confluent. Subject cells to hypoxia (1% O2) for 6 hours, then reoxygenate (21% O2) for 24 hours. Pre-treat with Meclizine 2HCl (5 μM-50 μM) 1 hour before hypoxia. Measure cell viability via CCK-8 assay, intracellular ROS via DCFH-DA probe, and Bax/Bcl-2 protein levels via Western blot [4]
- Guinea pig ileum relaxation assay: Isolate guinea pig ileum segments, mount in organ baths with oxygenated Krebs-Ringer solution (37°C, 95% O2/5% CO2), and equilibrate for 60 minutes. Pre-contract with histamine (1 μM), then add Meclizine 2HCl (0.1 μM-10 μM) cumulatively and record tension changes [1]

Dissolved in corn oil; 100 mg/kg; i.p. injection
\nMouse \nDrug testing in C. elegans[2]
\nAnimals 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.

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\nDrug testing in D. melanogaster[2]
\nThe 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.

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\nMotion sickness rat model: Male Sprague-Dawley rats (200-250 g) were acclimated for 5 days. Meclizine 2HCl was dissolved in 0.5% carboxymethylcellulose sodium and administered via oral gavage (25 mg/kg, 50 mg/kg) 1 hour before exposure to rotational stimulation (10 rpm, 30 minutes). Record emetic-like behaviors (retching, freezing) during and 1 hour post-stimulation [1]
\n- HD R6/2 mouse model: Female R6/2 transgenic mice (4 weeks old) were randomly divided into vehicle and treatment groups. Meclizine 2HCl (30 mg/kg/day) was administered via oral gavage once daily from 4 to 10 weeks of age. Rotarod test was performed weekly to assess motor function. At 10 weeks, mice were euthanized, and brain tissues were collected for immunohistochemical detection of mHTT aggregates and neuron counting [2]
\n- Renal I/R injury mouse model: Male C57BL/6 mice (20-25 g) were anesthetized with isoflurane. The left renal artery was clamped for 45 minutes to induce ischemia, then reperfused. Meclizine 2HCl (10 mg/kg) was injected intraperitoneally 24 hours before ischemia and immediately after reperfusion. Serum creatinine and BUN were measured at 24 hours post-reperfusion; left kidneys were harvested for histological analysis [4]

Absorption: The oral bioavailability in the human body is 70-75%; the peak plasma concentration (Cmax) is reached 2-3 hours after oral administration (25 mg dose: Cmax = 85 ng/mL) [1] - Distribution: The volume of distribution (Vd) in the human body is 11-13 L/kg; it is widely distributed in tissues, with a brain/plasma concentration ratio of 0.7 [1] - Metabolism: It is mainly metabolized in the liver by cytochrome P450 (CYP) 3A4 and 2D6 into inactive metabolites [1] - Excretion: 60% of the dose is excreted in feces (40% as metabolites, 20% as the original drug), and 35% is excreted in urine (mainly as metabolites). The elimination half-life (t1/2) in humans is 10-12 hours [1]
- Plasma protein binding rate: Meclozazine hydrochloride has a plasma protein binding rate of 88-92% in human plasma [1]

Acute toxicity: LD50 in rats and mice >2000 mg/kg (oral); no deaths or serious clinical symptoms (convulsions, respiratory depression) have been reported [1]
- Chronic toxicity: No significant hepatotoxicity or hematologic abnormalities were observed in rats after oral administration of meclozazole hydrochloride (100 mg/kg/day) for 6 consecutive months [1]
- Clinical side effects: Mild sedation (15-20% of patients), dry mouth (8-10%) and dizziness (5-7%) were common, especially at higher doses. No significant cardiotoxicity or genotoxicity was observed at therapeutic doses [1]
- Drug interactions: Co-administration with CYP3A4 inhibitors (e.g., ketoconazole) can increase plasma meclozazole concentration by 30-35%; no significant interaction with central nervous system depressants (additive sedation may occur) [1]

[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.

Meclizine hydrochloride is the hydrochloride salt form of mecclorazine, a synthetic piperazine drug with antiemetic, sedative, and histamine H1 receptor antagonistic effects. Mecclorazine hydrochloride blocks H1 histamine receptors, thereby preventing symptoms caused by histamine acting on capillary, bronchial, and gastrointestinal smooth muscle, including vasodilation, increased capillary permeability, bronchoconstriction, and gastrointestinal smooth muscle spasms. The antiemetic effect of mecclorazine hydrochloride may be achieved through its anticholinergic action or direct action on the medullary chemoreceptor trigger zone. It is a histamine H1 receptor antagonist used to treat motion sickness, vertigo, nausea during pregnancy, and radiation sickness. See also: Mecclorazine hydrochloride (note moved to). Mecclorazine hydrochloride is a first-generation histamine H1 receptor antagonist with a variety of pharmacological activities, including anti-motion sickness, neuroprotective, and renal protective effects [1,2,4].
The core mechanism of its treatment of motion sickness is competitive antagonism of H1 receptors in the vestibular system, thereby blocking histamine-mediated nausea and vomiting[1].
In a Huntington's disease model, it exerts neuroprotective effects by reducing mHTT aggregation and inhibiting neuronal apoptosis[2]. The drug modulates CAR in a species-specific manner: as an agonist for mouse CAR and as an inverse agonist for human CAR, which may affect the metabolism of exogenous substances[3].
Indications include prevention and treatment of motion sickness (nausea, vomiting, dizziness) and vertigo associated with inner ear diseases[1].
Its sedative effect is attributed to its moderate blood-brain barrier penetration, which distinguishes it from second-generation H1 receptor antagonists that do not have sedative effects[1].

C25H29CL3N2

463.87

462.139

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

1104-22-9

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

64713

White to light yellow crystalline powder

1.159g/cm3

495.3ºC at 760mmHg

212 °C

253.3ºC

6E-10mmHg at 25°C

7.035

2

2

5

30

448

0

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

VCTHNOIYJIXQLV-UHFFFAOYSA-N

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

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

2934.99.9001

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.

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

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.

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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.

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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.

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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.

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

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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.

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