Dopamine D2 receptor ( Ki = 1.4 nM ); Dopamine D3 receptor ( Ki = 2.5 nM ); Dopamine D1 receptor ( Ki = 588 nM ); α1-adrenoceptor ( Ki = 39 nM ); STAT3; STAT5
Pimozide targets dopamine D2 receptors with high affinity (Ki = 1.4 nM). It also binds to dopamine D3 receptors (Ki = 2.5 nM) and dopamine D1 receptors (Ki = 588 nM). It has affinity at α1-adrenoceptor (Ki = 39 nM). It binds with high affinity to the 5-HT7 receptor (Ki = 0.5 nM). It also inhibits STAT3 and STAT5.

Pimozide functions as an antagonist of dopamine receptors, exhibiting 1.4 nM, 2.5 nM, and 588 nM for dopamine D2, D3, and D1 receptors, respectively. It also demonstrates affinity for α1-adrenoceptors and 5-HT1A, with corresponding Kis values of 39 nM and 310 nM[1]. Pimozide inhibits STAT3 in an action. The proliferation of U2OS cells is inhibited by pimozide (0-15 μM), with IC50 values of 22.16 ± 2.54, 17.49 ± 1.14, and 13.78 ± 0.34 μM at 24, 48, and 72 hours, respectively. Osteosarcoma cells' capacity to form colonies and spheres is inhibited by pimozide (10 μM). Pimozide (15 μM) inhibits the expression of the antioxidant enzyme gene catalase in osteosarcoma cells, causing ROS generation, and induces cell cycle arrest in the G0/G1 phase[2]. It also suppresses extracellular signal-regulated kinase (Erk) signaling to limit cell viability. Pimozide inhibits STAT5 in an action. Pimozide lowers STAT5 tyrosine phosphorylation and the expression of endogenous STAT5 target genes[3].

Pimozide is an orally active antipsychotic drug. It is used for the treatment of Tourette's disorder in patients who have failed to respond satisfactorily to standard treatment. It is also used for the treatment of schizophrenia and other psychiatric disorders.

Pimozide is evaluated in cell-free receptor binding assays to determine its affinity for dopamine, serotonin, and adrenergic receptors. Radioligand binding displacement assays are performed using membrane preparations expressing these receptors. Ki values are determined to quantify the potency of receptor antagonism.

The WST-8 colorimetric assay is used to evaluate cell proliferation. In 96-well plates, 2,500 human osteosarcoma cells are plated per well. The cells are then treated with varying concentrations of pimozide for varying lengths of time (24, 48, and 72 hours). After the designated amount of time, the WST-8 solution is added to each well. Using a multi-well plate reader, the absorbance is determined at 450 nm following an additional 4 hours of incubation at 37°C[2]./td>
Pimozide is assessed in cell-based assays to measure its antagonist activity at dopamine receptors and its effects on STAT3/5 signaling. Cells expressing dopamine receptors are treated with Pimozide, and receptor activity is measured by assessing downstream signaling pathways. STAT3/5 phosphorylation is assessed by Western blot analysis.

Pimozide is administered orally in animal models to evaluate its antipsychotic and anti-Tourette effects. It has been studied in models of schizophrenia and Tourette syndrome. Efficacy is assessed using behavioral tests and physiological measurements.

Absorption, Distribution and Excretion
The oral absorption rate is greater than 50%. Peak serum levels occur 6–8 hours after administration. Metabolism/Metabolites It undergoes significant first-pass metabolism primarily in the liver, mainly via N-dealkylation by cytochrome P450 isoenzymes CYP3A and CYP1A2 (and possibly CYP2D6). The activities of the two major metabolites have not been determined. Known metabolites of pimozide include 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one (DHPBI). It undergoes significant first-pass metabolism primarily in the liver, mainly via N-dealkylation by cytochrome P450 isoenzymes CYP3A and CYP1A2 (and possibly CYP2D6). The activities of the two major metabolites have not been determined. Half-life: 29 ± 10 hours (single-dose study in healthy volunteers).

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Biological half-life
29±10 hours (single-dose study in healthy volunteers).
Pimozide has a molecular weight of 461.55 and a molecular formula of C28H29F2N3O. It has a CAS number of 2062-78-4. The compound is soluble in DMSO. It should be stored under recommended conditions.

Toxicity Summary
Pimozide's ability to inhibit motor and vocal tics in Tourette syndrome is thought to be primarily related to its dopaminergic blocking activity. Pimozide binds to and inhibits the activity of dopamine D2 receptors in the central nervous system. It also appears to block voltage-gated calcium channels and act as an antagonist of opioid receptors (OP2). Hepatotoxicity
No reports of liver dysfunction have been received in patients taking pimozide, but the extent and duration of such cases monitored in earlier studies are unclear. There are no reported cases of clinically significant acute liver injury caused by pimozide, and if it occurs, it is certainly very rare. Probability Score: E (Unlikely to cause clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Since there is no published experience with the use of pimozide during lactation, alternative medications are recommended. ◉ Effects on Breastfed Infants As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
Pimozide can cause hyperprolactinemia. This drug leads to hyperprolactinemia by blocking dopamine action in the tuberous infundibulum pathway.

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Toxicity Data
LD50: 1100 mg/kg (oral, rat) (A308)
LD50: 228 mg/kg (oral, mouse) (A308)
Pimozide is a therapeutic agent used for the treatment of Tourette syndrome and schizophrenia. It has significant side effects, including cardiac effects. It is available by prescription only.

[1]. Adrenoceptors and dopamine receptors are not involved in the discriminative stimulus effect of the 5-HT1A receptor agonist flesinoxan. Eur J Pharmacol. 1994 Apr 21;256(2):141-7.

[2]. The STAT3 inhibitor pimozide impedes cell proliferation and induces ROS generation in human osteosarcoma by suppressing catalase expression. Am J Transl Res. 2017 Aug 15;9(8):3853-3866. eCollection 2017.

[3]. The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors. Blood. 2011 Mar 24; 117(12): 3421-3429

According to state or federal labeling requirements, pimozide may cause developmental toxicity and female reproductive toxicity. Pimozide belongs to the benzimidazole class of drugs, with the chemical name 1,3-dihydro-2H-benzimidazole-2-one, in which one nitrogen atom is replaced by a piperidine-4-yl group, and the nitrogen atom on the piperidine-4-yl group is in turn replaced by a 4,4-bis(p-fluorophenyl)butyl group. It has various pharmacological effects, including H1 receptor antagonist, serotonergic antagonist, first-generation antipsychotic, anti-movement disorder drug, and dopaminergic antagonist. It belongs to the benzimidazole class, organofluorine compounds, and heteroarylpiperidine class of drugs. Diphenylbutylpiperidine is a potent antipsychotic drug and can also be used as an alternative to haloperidol to suppress vocal and motor tics in patients with Tourette syndrome. Although its exact mechanism of action is unclear, it is speculated to work by blocking postsynaptic dopamine receptors. (Excerpt from JAMA Drug Evaluation Yearbook, 1994, p. 403)
Pimozide is a typical antipsychotic drug.
Pimozide is a traditional antipsychotic drug primarily used to treat Tourette syndrome. Pimozide treatment is not associated with elevated serum transaminases or clinically apparent acute liver injury.
Pimozide is a diphenylbutylpiperidine derivative and a dopamine antagonist with antipsychotic properties. Pimozide selectively inhibits type II dopamine receptors in the central nervous system (CNS), thereby reducing dopamine neurotransmission and alleviating motor tics, vocal tics, and parasitic delusions. In addition, the drug also antagonizes α-adrenergic receptors and 5-HT2 receptors.
A diphenylbutylpiperidine drug, it can be used as an antipsychotic and can be used as an alternative to haloperidol for the treatment of vocal and motor tics in patients with Tourette syndrome. Although its exact mechanism of action is unclear, it is speculated to work by blocking postsynaptic dopamine receptors. (Excerpt from JAMA Drug Evaluation Annals, 1994, p. 403)
A diphenylbutylpiperidine drug, used as an antipsychotic and as an alternative to haloperidol for the treatment of vocal and motor tics in patients with Tourette syndrome. Although its exact mechanism of action is unclear, it is speculated to work by blocking postsynaptic dopamine receptors. (Excerpt from JAMA Drug Evaluation Annals, 1994, p. 403)
Indications

For the suppression of motor and vocal tics in patients with Tourette syndrome who do not respond well to standard treatment.
Mechanism of Action

The ability of pimozide to suppress motor and vocal tics in Tourette syndrome is thought to be primarily related to its dopaminergic blocking activity. Pimozide binds to and inhibits the activity of dopamine D2 receptors in the central nervous system.

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Pharmacodynamics
Pimozide is an orally effective antipsychotic that, like other antipsychotics, blocks dopaminergic receptors on neurons in the central nervous system. However, receptor blockade is often accompanied by a series of secondary alterations in central dopamine metabolism and function, which may contribute to the therapeutic effects and adverse reactions of pimozide. Furthermore, like other antipsychotics, pimozide has multiple effects on other central nervous system receptor systems, but these effects are not fully elucidated. Compared to other antipsychotics, pimozide has more specific dopamine receptor blocking activity, thus reducing the likelihood of sedation and hypotension (making it a suitable alternative to haloperidol).
Pimozide is a diphenylbutylpiperidine derivative. It is also known as Orap. It is a dopamine D2-receptor antagonist. It is a therapeutic agent.

C28H29F2N3O

461.55

461.227

C, 72.86; H, 6.33; F, 8.23; N, 9.10; O, 3.47

2062-78-4

Pimozide-d4-1; Pimozide-d4; 1803193-57-8; Pimozide-d5 N-Oxide; 1794795-40-6

16362

White solid powder

1.2±0.1 g/cm3

649.0±65.0 °C at 760 mmHg

214-218 °C
214 - 218 °C

346.3±34.3 °C

0.0±2.0 mmHg at 25°C

1.623

6.06

1

4

7

34

632

0

O=C1NC2=CC=CC=C2N1C3CCN(CCCC(C4=CC=C(F)C=C4)C5=CC=C(F)C=C5)CC3

YVUQSNJEYSNKRX-UHFFFAOYSA-N

InChI=1S/C28H29F2N3O/c29-22-11-7-20(8-12-22)25(21-9-13-23(30)14-10-21)4-3-17-32-18-15-24(16-19-32)33-27-6-2-1-5-26(27)31-28(33)34/h1-2,5-14,24-25H,3-4,15-19H2,(H,31,34)

3-[1-[4,4-bis(4-fluorophenyl)butyl]piperidin-4-yl]-1H-benzimidazol-2-one

R6238; NSC 170984; NSC170984; R-6238; NSC-170984; R 6238

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)

DMSO: 16.7~90 mg/mL (36.1~195 mM)
H2O: < 0.1 mg/mL

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.42 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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Solubility in Formulation 2: ≥ 1.67 mg/mL (3.62 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 16.7 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: 1.67 mg/mL (3.62 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 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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 (Please use freshly prepared in vivo formulations for optimal results.)