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 是一种多巴胺受体拮抗剂，对多巴胺 D2、D3 和 D1 受体的 Kis 分别为 1.4 nM、2.5 nM 和 588 nM；还对 α1-肾上腺素受体和 5-HT1A 具有亲和力，Kis 分别为 39 nM 和 310 nM[1]。 Pimozide 是 STAT3 的抑制剂。 Pimozide (0-15 μM) 可抑制 U2OS 细胞的增殖，24、48 和 72 h 时的 IC50 值分别为 22.16 ± 2.54、17.49 ± 1.14 和 13.78 ± 0.34 μM。 Pimozide (10 μM) 抑制骨肉瘤细胞的集落和球体形成能力。 Pimozide (15 μM) 诱导 G0/G1 期细胞周期停滞，抑制细胞外信号调节激酶 (Erk) 信号传导以抑制细胞活力，并通过抑制骨肉瘤细胞中抗氧化酶基因过氧化氢酶的表达来产生 ROS [2]。 Pimozide 是 STAT5 的抑制剂。 Pimozide 降低内源性 STAT5 靶基因的表达，并降低 STAT5 酪氨酸磷酸化[3]。

通过 WST-8 比色测定评估细胞增殖。将人骨肉瘤细胞以每孔 2,500 个细胞的密度铺在 96 孔板中，并接受不同浓度的匹莫齐特处理不同的时间间隔（24 小时、48 小时和 72 小时）。在指定时间后将 WST-8 溶液添加到每个孔中。在 37°C 下再孵育 4 小时后，使用多孔板读数器在 450 nm 处测量吸光度 [2]。

Absorption, Distribution and Excretion
Greater than 50% absorption after oral administration. Serum peak appears 6-8 hours post ingestion.

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Metabolism / Metabolites
Notable first-pass metabolism in the liver, primarily by N-dealkylation via the cytochrome P450 isoenzymes CYP3A and CYP1A2 (and possibly CYP2D6). The activity of the two major metabolites has not been determined.
Pimozide has known human metabolites that include 1,3- dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one (DHPBI).
Notable first-pass metabolism in the liver, primarily by N-dealkylation via the cytochrome P450 isoenzymes CYP3A and CYP1A2 (and possibly CYP2D6). The activity of the two major metabolites has not been determined.
Half Life: 29 ± 10 hours (single-dose study of healthy volunteers).

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Biological Half-Life
29 ± 10 hours (single-dose study of healthy volunteers).

Toxicity Summary
The ability of pimozide to suppress motor and phonic tics in Tourette's Disorder is thought to be primarily a function of its dopaminergic blocking activity. Pimozide binds and inhibits the dopamine D2 receptor in the CNS. It also appears to block voltage-operated calcium channels and acts as an antagonist at opiate receptors (OP2).

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Hepatotoxicity
Liver test abnormalities have not been reported to occur in of patients on pimozide, but the degree and duration of monitoring done in initial studies were not clear. Instances of clinically apparent acute liver injury have not been reported due to pimozide, and thus must be rare if they occur at all.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because there is no published experience with pimozide during breastfeeding, other drugs are preferred.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Pimozide can cause hyperprolactinemia. The hyperprolactinemia is caused by the drug's dopamine-blocking action in the tuberoinfundibular pathway.

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Toxicity Data
LD50: 1100 mg/kg (Oral, Rat) (A308)
LD50: 228 mg/kg (Oral, Mouse) (A308)

[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

Pimozide can cause developmental toxicity and female reproductive toxicity according to state or federal government labeling requirements.
Pimozide is a member of the class of benzimidazoles that is 1,3-dihydro-2H-benzimidazol-2-one in which one of the nitrogens is substituted by a piperidin-4-yl group, which in turn is substituted on the nitrogen by a 4,4-bis(p-fluorophenyl)butyl group. It has a role as a H1-receptor antagonist, a serotonergic antagonist, a first generation antipsychotic, an antidyskinesia agent and a dopaminergic antagonist. It is a member of benzimidazoles, an organofluorine compound and a heteroarylpiperidine.
A diphenylbutylpiperidine that is effective as an antipsychotic agent and as an alternative to haloperidol for the suppression of vocal and motor tics in patients with Tourette syndrome. Although the precise mechanism of action is unknown, blockade of postsynaptic dopamine receptors has been postulated. (From AMA Drug Evaluations Annual, 1994, p403)
Pimozide is a Typical Antipsychotic.
Pimozide is a conventional antipsychotic used largely in the therapy of Tourette syndrome. Pimozide therapy has not been associated with serum aminotransferase elevations nor with cases of clinically apparent acute liver injury.
Pimozide is a diphenylbutylpiperidine derivative and a dopamine antagonist with antipsychotic property. Pimozide selectively inhibits type 2 dopaminergic receptors in the central nervous system (CNS), thereby decreasing dopamine neurotransmission and reducing the occurrence of motor and vocal tics and delusions of parasitosis. In addition, this agent antagonizes alpha-adrenergic and 5-HT2 receptors.
A diphenylbutylpiperidine that is effective as an antipsychotic agent and as an alternative to haloperidol for the suppression of vocal and motor tics in patients with Tourette syndrome. Although the precise mechanism of action is unknown, blockade of postsynaptic dopamine receptors has been postulated. (From AMA Drug Evaluations Annual, 1994, p403)
A diphenylbutylpiperidine that is effective as an antipsychotic agent and as an alternative to HALOPERIDOL for the suppression of vocal and motor tics in patients with Tourette syndrome. Although the precise mechanism of action is unknown, blockade of postsynaptic dopamine receptors has been postulated. (From AMA Drug Evaluations Annual, 1994, p403)

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Drug Indication
Used for the suppression of motor and phonic tics in patients with Tourette's Disorder who have failed to respond satisfactorily to standard treatment.

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Mechanism of Action
The ability of pimozide to suppress motor and phonic tics in Tourette's Disorder is thought to be primarily a function of its dopaminergic blocking activity. Pimozide binds and inhibits the dopamine D2 receptor in the CNS.

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Pharmacodynamics
Pimozide is an orally active antipsychotic drug product which shares with other antipsychotics the ability to blockade 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 both pimozide's therapeutic and untoward effects. In addition, pimozide, in common with other antipsychotic drugs, has various effects on other central nervous system receptor systems which are not fully characterized. Pimozide also has less potential for inducing sedation and hypotension as it has more specific dopamine receptor blocking activity than other neuroleptic agents (and is therefore a suitable alternative to haloperidol).

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

41.03

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

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.42 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

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配方 2 中的溶解度: ≥ 1.67 mg/mL (3.62 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 16.7 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 3 中的溶解度: 1.67 mg/mL (3.62 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
例如，若需制备1 mL的工作液，可将 100 μL 16.7 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。