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 )

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]

Absorption, Distribution and Excretion
Incomplete bioavailability.
.../IT/ IS PARTIALLY ABSORBED FROM THE GI TRACT. FOLLOWING IM ADMIN, THE DRUG EXERTS ITS EFFECTS WITHIN 10-30 MINUTES. IT IS METABOLIZED, PRESUMABLY IN THE LIVER...FREE CHLORPROTHIXENE & ITS SULFOXIDE METABOLITE ARE EXCRETED IN THE URINE & FECES.
TRICYCLIC AGENT, CHLORPROTHIXENE, IS...EXTENSIVELY DISTRIBUTED IN BODY & HAS OVERALL DISTRIBUTION VOL IN MAN APPROACHING 1000 L...
AFTER IV ADMIN PHARMACOKINETICS FOLLOWED 2 COMPARTMENT MODEL. ...TOTAL VOL OF DISTRIBUTION WAS VERY LARGE. AFTER ORAL ADMIN (15 MG) BIOAVAILABILITY WAS POOR, ALTHOUGH ABSORPTION OF CMPD FROM THE GUT APPEARED TO BE GOOD.
METABOLISM OCCURRED MORE RAPIDLY WITH INCR AGE FROM 3-24 WK IN RATS. LEVELS OF CHLORPROTHIXENE, N-DEMETHYLCHLORPROTHIXENE & TOTAL AMINES IN BRAIN, LIVER, KIDNEYS & LUNG OF 3-WK OLD RATS WERE ABOUT TWICE THOSE IN 6-WK OLD RATS. AMT IN ORGANS WERE HIGHER IN FEMALES THAN IN MALES.
After 1 hour intravenous chlorprothixene infusion, the maximum serum concentration of chlorprothixene was 430 ng/ml, which subsequently decreased with a terminal elimination half-life of 25.8 hours. The total serum clearance and the apparent volume of distribution at steady state were 867 ml/min and 1035 l, respectively. ... Chlorprothixene bioavailability relative to the oral soution was 56.45 with the coated tablet and 67.7% with the suspension. All pharmacokinetic parameterws showed wide inter-subject varioations.

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Metabolism / Metabolites
Hepatic
UNCHANGED CHLORPROTHIXENE, THE SULFOXIDE DERIVATIVE & N-DEMETHYL SULFOXIDE HAVE BEEN IDENTIFIED IN THE URINE OF TREATED DOGS & RATS. HYDROXYLATION & GLUCURONIDATION ALSO OCCUR IN DOGS, BUT IDENTIFICATION OF THOSE BIOTRANSFORMATION PRODUCTS HAS NOT BEEN ACCOMPLISHED.
YIELDS DEMETHYLCHLORPROTHIXENE IN RAT. /FROM TABLE/
FOLLOWING ORAL ADMIN TO DOG & PSYCHIATRIC PT SEVERAL 3-, 7-, 4-, 6-, & 8-HYDROXYLATED METABOLITES FOUND IN URINE & FECES. HYDROXYLATION WAS FOLLOWED BY CONJUGATION WITH GLUCURONIC &/OR SULFURIC ACID FOR EXCRETION.
DRUG ADMIN TO RATS BY GAVAGE AT 100 MG/KG WAS METABOLIZED MORE RAPIDLY WITH INCR AGE FROM 3-24 WK.

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Biological Half-Life
8 to 12 hours
AFTER IV ADMIN PHARMACOKINETICS FOLLOWED 2 COMPARTMENT MODEL. T/2 IN SECOND PHASE OF ELIMINATION WAS 5-12 HR...
TRICYCLIC AGENT, CHLORPROTHIXENE, ...HAS...BIOLOGICAL T/2 OF 8-12 HR.

Interactions
Concurrent use with alcohol or CNS depression-producing medications, anesthetics, barbiturates, and opioid (narcotic) analgesics may potentiate and prolong the CNS depressant effects of either these medications or the thioxanthenes; dosage adjustments may be necessary. /Thioxanthenes/
Concurrent use with thioxanthenes may inhibit the CNS-stimulating effects of amphetamines due to alpha-adrenergic blockage by the thioxanthenes; also, the antipsychotic effects of thioxanthenes may be reduced when they are used concurrently with amphetamines. /Thioxanthenes/
Concurrent use of antacids or adsorbent antidiarrheals may inhibit the absorption of an orally administered thioxanthene. /Thioxanthenes/
Anticholinergic effects, especially confusion, hallucinations, nightmares, and increased intraocular pressure, may be potentiated when anticholinergics or other medications with anticholinergic action, antidyskinetic agents, or antihistamines are used concurrently with thioxanthenes, because of secondary anticholinergic action of thioxanthenes. /Thioxanthenes/
For more Interactions (Complete) data for CHLORPROTHIXENE (18 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 380 mg/kg

[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)-chlorprothixene is a chlorprothixene in which the double bond adopts a (Z)-configuration. It is an enantiomer of an (E)-chlorprothixene.
Chlorprothixene is a typical antipsychotic drug of the thioxanthene (tricyclic) class. Chlorprothixene exerts strong blocking effects by blocking the 5-HT2 D1, D2, D3, histamine H1, muscarinic and alpha1 adrenergic receptors.
A thioxanthine with effects similar to the phenothiazine antipsychotics.

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Drug Indication
For treatment of psychotic disorders (e.g. schizophrenia) and of acute mania occuring as part of bipolar disorders.

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Mechanism of Action
Chlorprothixene blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis.
...IT CAN BE EXPECTED TO DEPRESS THE CNS AT THE SUBCORTICAL LEVEL OF THE BRAIN, THE MIDBRAIN, & THE BRAIN STEM RETICULAR FORMATION.
.../IT/ IS MORE ACTIVE THAN CHLORPROMAZINE IN INHIBITING POSTURAL REFLEXES & MOTOR COORDINATION & LESS ACTIVE IN ANTIHISTAMINIC EFFECTS. CHLORPROTHIXENE POSSESSES SEDATIVE, ADRENOLYTIC, HYPOTHERMIC, ANTICHOLINERGIC, & ANTIEMETIC PROPERTIES.
Thioxanthenes are thought to benefit psychotic conditions by blocking postsynaptic dopamine receptors in the brain. They also produce an alpha-adrenergic blocking effect and depress the release of most hypothalamic and hypophyseal hormones. However, the concentration of prolactin is increased due to blockade of prolactin inhibitory factor (PIF), which inhibits the release of prolactin from the pituitary gland. /Thioxanthenes/
Chlorprothixene also inhibits the medullary chemoreceptor trigger zone to produce an antiemetic effect, and is also thought to cause an indirect reduction of stimuli to the brain stem reticular system to produce a sedative effect.

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Therapeutic Uses
Antipsychotic Agents; Dopamine Antagonists
IT MAY BE OF VALUE IN THE SYMPTOMATIC TREATMENT OF AGITATED STATES ASSOCIATED WITH NEUROSES, DEPRESSION OR SCHIZOPHRENIA. DRUG APPEARS TO BE MORE EFFECTIVE IN THE MANAGEMENT OF ACUTE SCHIZOPHRENIA THAN OF CHRONIC SCHIZOPHRENIA.
...IT HAS BEEN USED IN THE TREATMENT OF...PSYCHOTIC & SEVERE NEUROTIC CONDITIONS IN WHICH ANXIETY, AGITATION, AND TENSION PREDOMINATE.
.../IT/ MAY BE USED TO POTENTIATE CENTRAL NERVOUS SYSTEM DEPRESSANTS & CONCOMITANTLY WITH ANTICONVULSANTS &/OR ELECTROSHOCK TREATMENT.
Indicated for management of primary and secondary symptoms of psychotic disorders. /Thioxanthenes; Included in US product labeling/

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Drug Warnings
CHLORPROTHIXENE IS CONTRAINDICATED IN PATIENTS WHO ARE HYPERSENSITIVE TO THE DRUG; THE POSSIBILITY OF CROSS-SENSITIVITY TO PHENOTHIAZINES & TO THIOTHIXENE MUST BE BORNE IN MIND.
CHLORPROTHIXENE IS CONTRAINDICATED IN PATIENTS WITH CIRCULATORY COLLAPSE & IN THOSE WITH CONGESTIVE FAILURE, CARDIAC DECOMPENSATION, CORONARY ARTERY, OR CEREBRAL VASCULAR DISORDERS.
CHLORPROTHIXENE IS CONTRAINDICATED IN COMATOSE STATES, PARTICULARLY THOSE INDUCED BY CNS DEPRESSANT DRUGS.
WHEN CHLORPROTHIXENE IS USED CONCOMITANTLY WITH OTHER CNS DEPRESSANTS, CAUTION MUST BE OBSERVED TO AVOID OVERDOSAGE...
For more Drug Warnings (Complete) data for CHLORPROTHIXENE (27 total), please visit the HSDB record page.

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Pharmacodynamics
Chlorprothixene is a typical antipsychotic drug of the thioxanthine class. It has a low antipsychotic potency (half to 2/3 of chlorpromazine). Chlorprothixene has not thoroughly demonstrated an antidepressant or analgesic effect but it has demonstrated antiemetic effects. It is used in the treatment of nervous, mental, and emotional conditions. Improvement in such conditions is thought to result from the effect of the medicine on nerve pathways in specific areas of the brain. Chlorprothixene has a similar side effect profile to chlorpromazine, though allergic side effects and liver damage are less frequent.

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.)