Chlorcyclizine targets histamine H1 receptors with a Ki of 9 nM. It also inhibits HCV entry with an EC₅₀ of 44 nM in Huh7.5.1 cells, demonstrating efficacy against HCV genotypes 1b and 2a. It has shown dual pharmacology as both an antihistamine and an HCV entry inhibitor.

In vitro, chlorcyclizine inhibits HCV entry in Huh7.5.1 cells with an EC₅₀ of 44 nM. It acts as a histamine H1 receptor antagonist in receptor binding assays with a Ki of 9 nM. It bridges high-potency (hydroxyzine, 1.9 nM) and low-potency (meclizine, 250 nM) controls for graded dose-response profiling.

Rats in pregnancy that were given chlorcyclizine at doses of 30, 60, and 90 mg/kg at the delicate stage of palate development lived until their planned sacrifice on gestation day (GD) 17 or 21. Rats given 60 or 90 mg/kg of chlorcyclizine experienced 7% and 7% body weight loss, respectively, between doses, as well as temporary unfavorable clinical symptoms (rhinorrhea, red perioral material, urogenital staining, and loose stools). 11%. Rats given 30 mg/kg of chlorcyclizine during gestation did not acquire weight at the anticipated dose intervals, but they did not exhibit any negative clinical symptoms. Testing facility-based historical control database (16 studies, n = 380). Rats that are pregnant usually gain between 12 and 15 weeks of body weight [1].
In vivo, pregnant rats administered 30, 60, or 90 mg/kg chlorcyclizine during gestation days 11-14 survived until scheduled sacrifice on gestation days 17 or 21. It has demonstrated efficacy against HCV in human hepatocyte chimeric mouse models.

H1 receptor binding affinity is determined using radioligand displacement assays with [³H]-mepyramine in mammalian brain membrane preparations. Competition binding curves are generated, and Ki values are calculated. HCV entry inhibition is assessed using HCV pseudoparticle (HCVpp) or cell culture-derived HCV (HCVcc) infection assays.

Huh7.5.1 hepatoma cells are cultured and infected with HCVpp or HCVcc in the presence of chlorcyclizine at various concentrations. Infection is quantified by measuring reporter gene expression (e.g., luciferase) or viral protein levels. EC₅₀ values are calculated from dose-response curves.

In vivo efficacy against HCV is evaluated in human hepatocyte chimeric mouse models. Mice are engrafted with human hepatocytes, infected with HCV, and treated with chlorcyclizine orally or intraperitoneally. Viral load is measured in serum by RT-qPCR. Teratogenicity studies are conducted in pregnant rats at 30-90 mg/kg during gestation.

Absorption, Distribution and Excretion
It is readily absorbed after oral administration and widely distributed throughout the body. It is metabolized via N-demethylation to desmethylcyclorhizine and also via N-oxidation. It is primarily excreted slowly in the urine; measurable desmethylcyclorhizine can still be detected in urine for up to 3 weeks after discontinuation of long-term oral administration. Approximately 0.5% of a single dose is excreted in the urine as N-oxide. In four subjects, after a single oral dose of 2 mg/kg, the mean peak plasma concentrations of the parent drug and desmethylcyclorhizine reached approximately 0.05 mg/L and 0.03 mg/L, respectively, within 5 hours. After oral administration of 50 mg three times daily for 6 consecutive days, the plasma concentration of desmethylcyclorhizine on day 1 after discontinuation ranged from 0.05 to 0.11 mg/L, and on day 10 after discontinuation, the plasma concentration ranged from 0.02 to 0.04 mg/L [Kuntzman et al., 1973].
...Rats and humans treated with clocyclizine excreted clocyclizine N-oxide in their urine. Benzo[a]hydroxypiperazine and its N-dealkylated products were distributed in all tissues of rats and transferred to the fetus.
...Nerocyclizine remained in the human body for at least 20 days after discontinuation of clocyclizine treatment. Because clocyclizine is mainly distributed in tissues, especially the lungs, its plasma concentration is very low.
Long-term administration of clocyclizine stimulated autometabolism in dogs: On days 1-7, a daily oral dose of 10 mg/kg resulted in a plasma concentration of clocyclizine of 4.5 ± 1.7 mg/L, while the concentration of norclocyclizine was trace. /Excerpt from table/
Long-term administration of clocyclizine stimulated autometabolism in dogs: After 63 days of daily oral administration of 15 mg/kg, the plasma concentration of clocyclizine was trace, while the concentration of norclocyclizine was 8.3 ± 2.0 mg/L. /Excerpt from Table/
For more complete data on the absorption, distribution, and excretion of chlorocyclorhizides (6 in total), please visit the HSDB record page.

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Metabolism/Metabolites
High concentrations of N-demethylated metabolites are found in the liver, lungs, kidneys, and spleen.
Prolonged administration of chlorocyclorhizides to rats resulted in the presence of drug metabolites in their tissues, which are substituted ethylenediamines formed by repeated oxidative N-dealkylation cleavage of the piperazine ring. Accumulation of N-(p-chlorobenzoyl)ethylenediamine was found in rats treated with chlorocyclorhizides.
Oxidative dealkylation is the main metabolic pathway for benzoylpiperazine drugs…chlorocyclorhizides are converted to…norchlorocyclorhizides…chlorocyclorhizides N-oxide is not located on the metabolic pathway connecting chlorocyclorhizides and norchlorocyclorhizides, but chlorocyclorhizides N-oxide is excreted in the urine of rats and humans treated with chlorocyclorhizides.
Nosylchlorocyclorhizides are produced in rats. /From Table/

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Biological Half-Life
Approximately 12 hours.
Chlorcyclizine has a distinct metabolic pathway involving N-oxide formation. As a piperazine antihistamine, it is orally bioavailable. It undergoes hepatic metabolism and is excreted primarily in urine. Specific pharmacokinetic parameters (half-life, Cmax, bioavailability) are less extensively documented.

Protein Binding
Approximately 85% to 90%. Interactions Some reviews briefly mention that antihistamines can interfere with anticoagulation therapy; however, no literature is provided, and there are no case reports of antihistamine-induced anticoagulation problems. /Antihistamines/ The teratogenicity of clocycline in mice… can be reduced by prior treatment with SKF 525A/prodifen/ or phenobarbital, and must involve more than one biotransformation. Procarbamine A (1 ug/ml) induces slow-onset and sustained contractions in isolated guinea pig ileum. This response is insensitive to atropine (1 μmol/L) and tetrodotoxin (1 μmol/L), but can be significantly inhibited by H1 histamine receptor antagonists, including mepiquat (10 nmol/L), clocycline (10 nmol/L), and diphenhydramine (0.1 μmol/L). This article describes a method for determining whether topical application of clocyclizine hydrochloride (I) in combination with 0.5% hydrocortisone acetate (Mantadil; II) cream can demonstrate antihistamine activity. Thirty subjects participated in the study, using 5% hydrocortisone cream, II cream, and a placebo cream, respectively. Results showed that component I in the combination treatment reduced wheal and erythema reactions in the subjects. /clocyclizine hydrochloride/
Chlorcyclizine is generally well-tolerated as an antihistamine, with common side effects including sedation, dry mouth, and drowsiness (characteristic of first-generation antihistamines). At high doses, it may cause teratogenic effects, as suggested by animal studies. It has been used clinically as an antihistamine and antiemetic.

[1]. Effects of the histamine H1 antagonist Chlorcyclizine on rat fetal palate development. Birth Defects Res B Dev Reprod Toxicol. 2010 Dec;89(6):474-84.

1-[(4-chlorophenyl)-phenylmethyl]-4-methylpiperazine is a diarylmethane. Chlorcyclizine is a first-generation phenylpiperazine antihistamine used to treat urticaria, rhinitis, pruritus, and other allergic symptoms. Chlorcyclizine also has certain local anesthetic, anticholinergic, and antiserotonergic properties and can be used as an antiemetic. See also: Chlorcyclizine hydrochloride (in salt form). Mechanism of Action: Antihistamines act as pharmacological antagonists of histamine at most histamine receptor sites, but not by preventing histamine release. Chlorcyclizine has hepatic microsomal enzyme-inducing properties…due to enzyme induction, it shortens the duration of action of some barbiturates. H1 receptor antagonists inhibit most of the smooth muscle response to histamine. The antagonistic effect of histamine on the contraction of respiratory smooth muscle is readily confirmed in vitro. ...In the vascular system, H1 receptor antagonists inhibit both the vasoconstrictive effects of histamine and, to some extent, the more rapid vasodilation mediated by H1 receptors on endothelial cells. Residual vasodilation reflects the involvement of H2 receptors on smooth muscle and can only be inhibited by concurrent administration of H2 receptor antagonists. The effects of histamine antagonists on histamine-induced systemic blood pressure changes parallel these vascular effects. /H1 Receptor Antagonists/
H1 receptor antagonists potently block the effects of histamine, thereby reducing increased capillary permeability and the formation of edema and wheals. /H1 Receptor Antagonists/
All H1 receptor antagonists...bind to H1 receptors in the central nervous system...H1 receptor antagonists can both excite and inhibit the central nervous system. /H1 Receptor Antagonists/
For more complete data on the mechanisms of action of chlorcyclophosphamides (6 in total), please visit the HSDB record page.

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Therapeutic Uses
Histamine H1 Receptor Antagonists
Antichrists with mild sedative effects, long-lasting action, and a low incidence of toxic side effects. Chlorcycloclazine hydrochloride has mild anticholinergic and antispasmodic effects and can enhance the effects of adrenaline. It also has some local anesthetic effects.

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Drug Warnings
While the side effects of H1 receptor antagonists are rarely serious and usually disappear with continued treatment, sometimes the side effects can be so bothersome that discontinuation of the drug is necessary. /H1 Receptor Antagonists/
The most common side effect of all H1 receptor antagonists, except for terfenadine or astemizole, is sedation. …Concomitant use with alcohol or other central nervous system depressants can have an additive effect, impairing motor skills. Other adverse reactions related to central nervous system effects include dizziness, tinnitus, fatigue, incoordination, exhaustion, blurred vision, diplopia, euphoria, nervousness, insomnia, and tremor. /H1 receptor antagonists/
...Common side effects involve the gastrointestinal tract, including loss of appetite, nausea, vomiting, upper abdominal discomfort, and constipation or diarrhea. ...Other side effects are apparently caused by the anticholinergic effects of some older generation drugs, including dry mouth and dry respiratory tract, sometimes causing cough, urinary retention or frequency, and difficulty urinating. ...Older generation drugs may also cause palpitations, low blood pressure, headache, chest tightness, and numbness and weakness in the hands. /H1 receptor antagonists/
Oral H1 receptor antagonists can cause drug allergies, but allergies are more common with topical application. Allergic dermatitis is not uncommon; other hypersensitivity reactions include drug heat and photosensitivity reactions. /H1 receptor antagonists/
Chlorcyclizine is a first-generation antihistamine marketed under various brand names for allergic conditions. More recently, it has been identified as a potent HCV entry inhibitor and studied for repurposing in HCV treatment. Its dual pharmacology makes it a valuable tool compound for both histamine receptor and antiviral research.

C18H21CLN2

300.83

300.139

82-93-9

Chlorcyclizine hydrochloride;14362-31-3

2710

Oil

137-145ºC at 0.1-0.15 MM HG

3.552

0

2

3

21

300

0

ClC1C=CC(C(N2CCN(C)CC2)C2C=CC=CC=2)=CC=1

WFNAKBGANONZEQ-UHFFFAOYSA-N

InChI=1S/C18H21ClN2/c1-20-11-13-21(14-12-20)18(15-5-3-2-4-6-15)16-7-9-17(19)10-8-16/h2-10,18H,11-14H2,1H3

1-((4-chlorophenyl)(phenyl)methyl)-4-methylpiperazine

Chlorcyclizine ChlorcyclizineDi-Paralene, Trihistan,Mantadil, Pruresidine, Chlorcyclizine free base

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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