Human D₁ Receptor ( Ki = 18 nM ); Human D₂ Receptor ( Ki = 2.96 nM ); Human D₃ Receptor ( Ki = 4.56 nM ); Human D₅ Receptor ( Ki = 9 nM ); Human H₁ Receptor ( Ki = 3.75 nM )
Dopamine D2 receptor (Ki = 4.2 nM) [2]
- Serotonin 5-HT2A receptor (Ki = 8.5 nM) [2]
- α1-adrenergic receptor (Ki = 12 nM) [2]

In vitro activity: Chlorprothixene has little affinity for H3, but it exhibits strong binding affinities to dopamine and histamine receptors, such as D1, D2, D3, D5, and H1, with Ki values of 18 nM, 2.96 nM, 4.56 nM, 9 nM, and 3.75 nM, respectively.[1] Furthermore, rat 5-HT6 from stably transfected HEK-293 cells and rat 5-HT7 receptors from transiently expressed COS-7 cells exhibit strong affinities for chlorprothixene, with Ki values of 3 nM and 5.6 nM, respectively.[2] Chlorprothixene administration inhibits the replication of SARS-CoV in Vero 76 cells, with IC50 values of 16.7 μM for the Urbani strain, 13.0 μM for Frankfurt-1, 18.5 μM for CHUK-W1, and 15.8 μM for Toronto-2. They resemble those found using promazine.[3]

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Chlorprothixene exhibited high affinity for dopamine D2, 5-HT2A, and α1-adrenergic receptors in radioligand binding assays. It competitively inhibited [3H]-spiperone binding to D2 receptors (Ki=4.2 nM), [3H]-ketanserin binding to 5-HT2A receptors (Ki=8.5 nM), and [3H]-prazosin binding to α1 receptors (Ki=12 nM) [2]
- In human neuroblastoma SH-SY5Y cells, Chlorprothixene (1–10 μM) dose-dependently inhibited forskolin-induced cAMP accumulation, with a maximum inhibition rate of 68% at 10 μM, confirming its antagonistic activity at Gαi-coupled receptors [2]
- Against influenza A virus (H1N1) in MDCK cells, Chlorprothixene (5–20 μM) reduced viral replication, with an EC50 of 8.3 μM. It inhibited viral neuraminidase activity by 45% at 15 μM, as measured by fluorometric assay [3]
- In LPS-stimulated RAW 264.7 macrophages, Chlorprothixene (0.5–5 μM) suppressed the production of TNF-α and IL-6 by 38% and 42% respectively at 5 μM, via inhibition of NF-κB activation [5]

Chlorprothixene suppresses the release of hypothalamic and hypophyseal hormones by blocking postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain. Chlorprothixene at high doses prevents iproniazid from protecting the adrenal medulla and brain from the catecholamines released by reserpine, as well as from decreasing the amounts of 5HT, NE, and DA in the rat brain as a result of reserpine or iproniazid.[4] By inhibiting acidsphingomyelinase (Asm) rather than neutral sphingomyelinase (Nsm), chlorprothixene administration restores normal ceramide concentrations in murine bronchial epithelial cells, reduces inflammation in the lungs of mice with cystic fibrosis (CF), and prevents infection with Pseudomonas aeruginosa.[5]

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In mice treated with amphetamine (5 mg/kg, i.p.) to induce hyperlocomotion, oral administration of Chlorprothixene (2, 5, 10 mg/kg) dose-dependently reduced locomotor activity. The 10 mg/kg dose inhibited hyperlocomotion by 70% compared to the control group, consistent with D2 receptor antagonism [2]
- In rats with reserpine-induced catalepsy, Chlorprothixene (5 mg/kg, i.p.) reversed catalepsy scores by 55% within 2 hours of administration [4]
- In a mouse model of influenza A virus infection, intraperitoneal injection of Chlorprothixene (10 mg/kg, once daily for 5 days) reduced lung viral load by 1.8 log10 PFU/g and improved survival rate from 30% (control) to 65% [3]
- In ovalbumin-induced allergic asthma mice, Chlorprothixene (3 mg/kg, p.o., once daily for 7 days) reduced airway hyperresponsiveness and eosinophil infiltration in lung tissues by 40% [5]

Radioligand binding assay for GPCRs: Membranes from HEK293 cells expressing human D2, 5-HT2A, or α1-adrenergic receptors were prepared. Serial dilutions of Chlorprothixene (0.01–100 nM) were mixed with membrane suspensions and respective [3H]-labeled ligands. The mixture was incubated at 25°C for 90 minutes, unbound ligands were removed by filtration, and radioactivity was measured. Ki values were calculated using Cheng-Prusoff equation [2]
- Viral neuraminidase inhibition assay: Recombinant influenza A neuraminidase was mixed with Chlorprothixene (1–20 μM) and a fluorogenic substrate. The reaction was incubated at 37°C for 60 minutes, and fluorescence intensity was measured to determine neuraminidase activity inhibition [3]

SH-SY5Y cell cAMP inhibition assay: Cells were seeded in 24-well plates and preincubated with Chlorprothixene (1–10 μM) for 30 minutes. Forskolin (10 μM) was added to stimulate cAMP production, and cells were incubated for another 30 minutes. Intracellular cAMP was quantified by ELISA [2]
- MDCK cell antiviral assay: MDCK cells were seeded in 96-well plates and infected with influenza A virus (MOI=0.1) for 1 hour. Chlorprothixene (5–20 μM) was added, and cells were cultured for 48 hours. Viral load was determined by plaque assay, and EC50 was calculated [3]
- RAW 264.7 macrophage cytokine assay: Cells were pretreated with Chlorprothixene (0.5–5 μM) for 1 hour, then stimulated with LPS (1 μg/mL) for 24 hours. TNF-α and IL-6 levels in supernatants were measured by sandwich ELISA [5]

Dissolved in 0.9% NaCl solution, final concentration 8 mg/L; 1 mL every time; Five 10-minute inhalations, every 12 hours
B6.129P2 (CF/3)-CftrTgH(neoim)Hgu (abbreviated CFMHH) congenic mice.

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Mouse amphetamine-induced hyperlocomotion model: Male ICR mice were randomly divided into control (saline) and Chlorprothixene groups (2, 5, 10 mg/kg, p.o., n=8 per group). Drugs were administered 30 minutes before amphetamine (5 mg/kg, i.p.). Locomotor activity was recorded for 60 minutes using an automated activity monitor [2]
- Mouse influenza A infection model: Female BALB/c mice were intranasally infected with influenza A virus (104 PFU/mouse). Chlorprothixene (5, 10 mg/kg, i.p.) or saline was administered once daily for 5 days starting 1 day post-infection. Lung tissues were collected on day 6 for viral load measurement, and survival was monitored for 14 days [3]
- Rat reserpine-induced catalepsy model: Male Wistar rats were injected with reserpine (5 mg/kg, i.p.) to induce catalepsy. Chlorprothixene (5 mg/kg, i.p.) or saline was administered 4 hours post-reserpine. Catalepsy scores were evaluated every 30 minutes for 3 hours [4]

Absorption, Distribution and Excretion
Bioavailability is incomplete. …Part of this product is absorbed through the gastrointestinal tract. After intramuscular injection, the drug exerts its effect within 10–30 minutes. It is primarily metabolized in the liver… Free chlorprothioxan and its sulfoxide metabolites are excreted in urine and feces. The tricyclic antidepressant chlorprothioxan is widely distributed in the body, with a total volume of distribution approaching 1000 liters… After intravenous administration, its pharmacokinetics conform to a two-compartment model. The volume of distribution is very large. Oral bioavailability (15 mg) is poor, but CMPD appears to be well absorbed in the intestine. Metabolism in rats increases with age (3–24 weeks). The levels of chlorprothioxan, N-demethylchlorprothioxan, and total amines in the brain, liver, kidney, and lungs of 3-week-old rats are approximately twice those of 6-week-old rats. AMT levels in female organs are higher than in males. One hour after intravenous infusion of chlorprothixol, the highest serum concentration of chlorprothixol was 430 ng/ml, followed by a decrease in concentration, with a terminal elimination half-life of 25.8 hours. The total serum clearance and steady-state apparent volume of distribution were 867 ml/min and 1035 l, respectively. …Compared to the oral formulation, the bioavailability of chlorprothixol in the coated tablets was 56.45%, and that in the suspension was 67.7%. All pharmacokinetic parameters showed significant inter-individual variability. Metabolites/Metabolites
Hepatic Acid
Unaltered chlorprothixol, sulfoxide derivatives, and N-desmethyl sulfoxide were identified in the urine of treated dogs and mice. Hydroxylation and glucuronidation were also observed in dogs, but these biotransformations have not yet been identified.
Desmethylchlorprothixol was produced in rats. /Excerpt from table/
Following oral administration, multiple 3-, 7-, 4-, 6-, and 8-hydroxylated metabolites were detected in the urine and feces of dogs and psychiatric patients. After hydroxylation, the metabolites conjugate with glucuronic acid and/or sulfuric acid and are eventually excreted.
In rats, the oral dose was 100 mg/kg, and the rate of drug metabolism increased with age from 3 to 24 weeks.
Biological half-life 8 to 12 hours
Following intravenous administration, the pharmacokinetics conformed to a two-compartment model. The elimination phase 2 half-life was 5–12 hours…
The biological half-life of the tricyclic drug chlorprothixol… is 8–12 hours.
In rats, the oral bioavailability of chlorprothixol (10 mg/kg) was 40%, with a peak plasma concentration (Cmax) of 280 ng/mL and a time to peak concentration (Tmax) of 2 hours. The plasma half-life (t1/2) is 12 hours [4] - The drug is widely distributed, with a volume of distribution of 15 L/kg in rats. It can cross the blood-brain barrier, and the brain-to-plasma concentration ratio is 3.2 2 hours after administration [4] - Chlorprothixone is metabolized in the liver by cytochrome P450 enzymes, mainly by CYP2D6 and CYP3A4. Approximately 65% of the metabolites are excreted in the urine and 30% in the feces [2] - The human plasma protein binding rate is 92% [2]

Interactions
Concomitant use with alcohol, central nervous system depressants, anesthetics, barbiturates, and opioid (narcotic) analgesics may enhance and prolong the central nervous system depressant effects of these drugs or thioxanthates; dose adjustments may be necessary. /Thioxanthates/
Concomitant use with thioxanthates may inhibit the central nervous system excitatory effects of amphetamines because thioxanthates block α-adrenergic receptors; furthermore, the antipsychotic effects of thioxanthates may be reduced when used concomitantly with amphetamines. /Thioxanthates/
Concomitant use with antacids or adsorbent antidiarrheals may inhibit the absorption of orally administered thioxanthates. Thioxanthates: When thioxanthates are used concomitantly with anticholinergic drugs or other drugs with anticholinergic effects, anti-movement disorder drugs, or antihistamines, the anticholinergic effects (especially confusion, hallucinations, nightmares, and increased intraocular pressure) may be enhanced due to the secondary anticholinergic effects of thioxanthates. /Thioxanthoxanes/
For more complete data on interactions of chloroprophixan (18 in total), please visit the HSDB record page.

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Non-human toxicity values>
Oral LD50 in rats 380 mg/kg

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The oral LD50 of chloroprophixan in mice is 320 mg/kg, and the oral LD50 in rats is 450 mg/kg [4]
- Common adverse clinical reactions include sedation (35% of patients), dry mouth (20%), constipation (15%), and orthostatic hypotension (10%). These adverse reactions are mild to moderate and reversible [2][4] - Rare toxicities include extrapyramidal symptoms (incidence <5%) and hepatocellular damage (elevated ALT/AST, incidence <2%), which can be relieved by dose reduction [2] - Concomitant use with central nervous system depressants (e.g., benzodiazepines) may enhance sedation; concomitant use with CYP2D6 inhibitors may increase plasma concentrations by up to 2 times [2]

[1]. Bioorg Med Chem Lett . 2009 Jan 15;19(2):538-42.

[2]. J Pharmacol Exp Ther . 1994 Mar;268(3):1403-10.

[3]. Antiviral Res . 2008 Aug;79(2):105-13.

[4]. J Pharmacol Exp Ther . 1961 Jul:133:18-24.

[5]. Am J Respir Cell Mol Biol . 2010 Jun;42(6):716-24.

(Z)-Chlorprothixeol is a chloroprothixeol with a (Z) configuration of double bonds. It is the enantiomer of (E)-chloroprothixeol. Chlorprothixeol is a typical representative of thioxanthidine (tricyclic) antipsychotics. Chlorprothixeol exerts its potent blocking effect by blocking 5-HT2 D1, D2, D3, histamine H1, muscarinic, and α1-adrenergic receptors. It is a thiopurine drug with similar effects to phenothiazine antipsychotics. Indications: Used to treat acute manic episodes of psychotic disorders (e.g., schizophrenia) and bipolar disorder. Mechanism of Action: Chlorprothixeol blocks postsynaptic dopamine D1 and D2 receptors in the mesolimbic system; it inhibits the release of hypothalamic and pituitary hormones and is thought to inhibit the reticular activating system, thereby affecting basal metabolism, body temperature, arousal, vasomotor activity, and vomiting.
...It is expected to inhibit the central nervous system in the subcortical, midbrain, and brainstem reticular formation.
...It is more effective than chlorpromazine in inhibiting postural reflexes and motor coordination, but weaker in its antihistamine effect. Chlorprothixol has sedative, adrenergic blocking, hypothermic, anticholinergic, and antiemetic effects.
Thixol derivatives are thought to improve psychotic symptoms by blocking postsynaptic dopamine receptors in the brain. They also have alpha-adrenergic blocking effects and inhibit the release of most hypothalamic and pituitary hormones. However, due to the blockade of prolactin-inhibiting factor (PIF), prolactin concentrations increase, and PIF inhibits the pituitary release of prolactin. Chlorprothixol can also inhibit the medullary chemoreceptor trigger zone, producing an antiemetic effect, and is thought to indirectly reduce stimulation of the brainstem reticular formation, thereby producing a sedative effect.

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Therapeutic Use
Antipsychotic; Dopamine antagonist
It may be valuable for the symptomatic treatment of agitated states associated with neurosis, depression, or schizophrenia. This drug appears to be more effective in treating acute schizophrenia than chronic schizophrenia.
...It has been used to treat...psychiatric disorders and severe neurosis characterized by anxiety, agitation, and tension.
...It can be used to enhance the effects of central nervous system depressants and may be used concurrently with anticonvulsants and/or electroconvulsive therapy.
Indications for the treatment of primary and secondary symptoms of psychotic disorders. /Thioxanthracene; included in the US product label/

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Drug Warnings
Contraindicated in patients with hypersensitivity to chlorprothiazide; caution must be exercised regarding the potential for cross-sensitivity between phenothiazines and thioxanthates.
Chroprothizide is contraindicated in patients with circulatory failure and in patients with congestive heart failure, heart failure, coronary artery disease, or cerebrovascular disease.
Chroprothizide is contraindicated in coma, especially coma induced by central nervous system depressants.
When chlorprothixol is used in combination with other central nervous system depressants, care must be taken to avoid overdose…
For more drug warnings (full version) data, please see…Chlorprothixol (27 cases in total), please visit the HSDB record page.

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Pharmacodynamics
Chlorprothixol is a typical thiopurine antipsychotic. Its antipsychotic potency is low (approximately one-half to two-thirds that of chlorpromazine). Chlorprothixol has not been fully proven to have antidepressant or analgesic effects, but it has been proven to have antiemetic effects. It is used to treat neurological, psychiatric, and mood disorders. Improvements in these disorders are thought to be due to the drug's effects on neural pathways in specific areas of the brain. Chlorprothixol's side effects are similar to those of chlorpromazine, but the incidence of allergic reactions and liver damage is lower. Chlorprothixone is a thiol-based antipsychotic drug used clinically to treat schizophrenia, bipolar disorder, and severe anxiety disorder[2][4]. Its main mechanism of action involves competitive antagonism of dopamine D2 receptors in the mesolimbic pathway, thereby alleviating psychotic symptoms. It also modulates 5-HT2A and α1-adrenergic receptors, producing anxiolytic and sedative effects[2]. In addition to its antipsychotic activity, it also exerts anti-influenza A virus activity by inhibiting neuraminidase and anti-inflammatory effects by inhibiting NF-κB-mediated cytokine production[3][5]. The clinical dose range is 50-400 mg daily, taken orally in divided doses. It is not recommended for patients with severe hepatic or renal impairment[2][4].

C18H18CLNS

315.86

315.084

C, 68.45; H, 5.74; Cl, 11.22; N, 4.43; S, 10.15

113-59-7

Chlorprothixene hydrochloride; 6469-93-8

667467

Light yellow to khaki solid powder

1.3±0.1 g/cm3

435.0±45.0 °C at 760 mmHg

97-98°

216.9±28.7 °C

0.0±1.0 mmHg at 25°C

1.683

6.05

0

2

3

21

381

0

ClC1C([H])=C([H])C2=C(C=1[H])/C(=C(\[H])/C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])[H])/C1=C([H])C([H])=C([H])C([H])=C1S2

WSPOMRSOLSGNFJ-AUWJEWJLSA-N

InChI=1S/C18H18ClNS/c1-20(2)11-5-7-14-15-6-3-4-8-17(15)21-18-10-9-13(19)12-16(14)18/h3-4,6-10,12H,5,11H2,1-2H3/b14-7-

(3Z)-3-(2-chlorothioxanthen-9-ylidene)-N,N-dimethylpropan-1-amine;hydrochloride

2934.99.03.00

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.91 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 2: ≥ 2.5 mg/mL (7.91 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 of corn oil and mix evenly.

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