5-HT1A Receptor (Ki = 0.12 nM); 5-HT2A Receptor (Ki = 0.47 nM); D2L Receptor (Ki = 0.3 nM); human noradrenergic α1B (Ki = 0.17 nM); human noradrenergic α2C (Ki = 0.59 nM)

在 PC12 细胞中，breexpipromaze（0-1.0 μM，4 天）剂量依赖性地促进 NGF 诱导的神经突生长 [1]。

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布瑞哌唑（7-{4-[4-（1-苯并噻吩-4-基）哌嗪-1-基]丁氧基}喹啉-2（1H）-酮）是一种新型血清素多巴胺活性调节剂，旨在为不同的精神疾病提供有效和可耐受的治疗，包括精神分裂症和MDD的辅助治疗。在这项研究中，我们研究了在给予N-甲基-d-天冬氨酸（NMDA）受体拮抗剂MK-801（地佐西平）后，布瑞哌唑是否可以改善小鼠的社会认知缺陷（社会认知缺陷之一）。地佐西平（0.1mg/kg）给药后，小鼠的社会认知能力明显受损。布瑞哌唑（0.01、0.03、0.1mg/kg，口服）显著改善了地佐西平诱导的社会认知缺陷，而没有镇静或减少探索行为。此外，单独使用布瑞哌唑对未经治疗的对照组小鼠的社会认知没有影响。相比之下，利培酮（0.03mg/kg，口服）和奥氮平（0.03mg/kg）均未改变地佐西平诱导的社会认知缺陷。最后，选择性5-羟色胺5-HT1A拮抗剂WAY-100635拮抗了布瑞哌唑对地佐西平诱导的社会认知缺陷的影响。这些结果表明，布瑞哌唑可以通过激活5-HT1A受体来改善地佐西平诱导的小鼠社会识别缺陷。因此，布瑞哌唑可能对精神疾病患者的社会认知缺陷有益[1]。

布瑞哌唑（7-{4-[4-（1-苯并噻吩-4-基）哌嗪-1-基]丁氧基}喹啉-2（1H）-酮）是一种新型血清素多巴胺活性调节剂，旨在为不同的精神疾病提供有效和可耐受的治疗，包括精神分裂症和MDD的辅助治疗。在这项研究中，我们研究了在给予N-甲基-d-天冬氨酸（NMDA）受体拮抗剂MK-801（地佐西平）后，布瑞哌唑是否可以改善小鼠的社会认知缺陷（社会认知缺陷之一）。地佐西平（0.1mg/kg）给药后，小鼠的社会认知能力明显受损。布瑞哌唑（0.01、0.03、0.1mg/kg，口服）显著改善了地佐西平诱导的社会认知缺陷，而没有镇静或减少探索行为。此外，单独使用布瑞哌唑对未经治疗的对照组小鼠的社会认知没有影响。相比之下，利培酮（0.03mg/kg，口服）和奥氮平（0.03mg/kg）均未改变地佐西平诱导的社会认知缺陷。最后，选择性5-羟色胺5-HT1A拮抗剂WAY-100635拮抗了布瑞哌唑对地佐西平诱导的社会认知缺陷的影响。这些结果表明，布瑞哌唑可以通过激活5-HT1A受体来改善地佐西平诱导的小鼠社会识别缺陷。因此，布瑞哌唑可能对精神疾病患者的社会认知缺陷有益[2]。

细胞培养和神经突起生长的定量[1]
PC12细胞在37°C、5%CO2的Dulbecco改良Eagle培养基（DMEM）中培养，补充5%热灭活胎牛血清（FBS）、10%热灭活马血清和1%青霉素-链霉素。每周更换两到三次介质。将PC12细胞铺在涂有聚-d-赖氨酸/层粘连蛋白的24孔组织培养板上。细胞以相对较低的密度（0.25×104个细胞/cm2）在含有0.5%FBS、1%青霉素-链霉素的DMEM培养基中铺板。如先前报道的那样，使用含有最低水平血清（0.5%FBS）的培养基（Nishimura等人，2008，Ishima等人，2008；Ishima等，2012；Minase等人，2010；Hashimoto和Ishima，2010；桥本和石岛，2011；Itoh等人，2011；石岛和桥本，2012）。之前，我们研究了诱导PC12细胞神经突起生长所需的NGF的最佳浓度，发现NGF（2.5、5、10、20、40 ng/ml）以浓度依赖的方式增加了神经突起生长的细胞数量（Nishimura等人，2008）。在这项研究中，使用2.5 ng/ml的NGF来研究布瑞哌唑对神经突起生长的增强作用。接种后24小时，将培养基替换为含有0.5%FBS和1%青霉素-链霉素的DMEM培养基，并添加NGF（2.5 ng/ml），添加或不添加布瑞哌唑（0.001、0.01、0.1或1.0μM），WAY-100635（5-HT1A受体拮抗剂；10μM）、雷氯匹定（多巴胺D2受体拮抗剂）；DOI（5-HT2A受体激动剂；0.1、1.0或10μM；100μM）、氟西汀（5-羟色胺转运体抑制剂：1.0μM）或帕罗西汀（5-羟色胺转运蛋白抑制剂：1.0µM）。 在与NGF（2.5 ng/ml）一起孵育四天后，在有或没有特定药物的情况下，用连接到相机的倒置显微镜对相差照明下拍摄的活细胞数字化图像进行形态计量分析。每个孔拍摄三个区域的图像，平均每个区域有100个细胞。通过目视检查视野来计数分化的细胞；仅计数具有至少一个长度等于细胞体直径的神经突起的细胞，然后将其表示为场中总细胞的百分比。计数是以盲法进行的。

Animal/Disease Models: Male C57BL/6NCrSlc mice, dizozepine (0.1 mg/kg)-induced social cognitive deficits [2]. 0.01, 0.03 and 0.1 mg/kg.
Route of Administration: Take once orally.
Experimental Results: Significant improvement of social cognitive deficits caused by dizocycline without sedation or reduction in exploratory behavior.

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Brexpiprazole, risperidone, olanzapine and WAY-100,635 were dissolved in 5% (w/v) gum Arabic and administered orally (p.o.), at 10 ml/kg, 1 h prior to sociability testing. Male C57BL/6NCrSlc mice aged between 4 and 5 weeks old were selected as stranger mice, while animals between 8 and 10 weeks old were used for this study.

Absorption, Distribution and Excretion
After a single-dose administration, the Tmax was four hours and the absolute oral bioavailability was 95%. Brexpiprazole steady-state concentrations were attained within 10 to 12 days of dosing. After single and multiple once-daily dose administration, the Cmax and AUC increased dose-proportionally. A high-fat meal did not significantly affect the Cmax or AUC of brexpiprazole.
Following a single oral dose of radiolabeled brexpiprazole, approximately 25% and 46% of radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged brexpiprazole was excreted in the urine, and approximately 14% of the oral dose was recovered unchanged in the feces.
The volume of distribution of brexpiprazole following intravenous administration is 1.56 ± 0.42 L/kg, indicating extravascular distribution.
Apparent oral clearance of brexpiprazole after once-daily administration is 19.8 (±11.4) mL/h/kg.

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Metabolism / Metabolites
According to _in vitro_ studies, brexpiprazole is mainly metabolized by CYP3A4 and CYP2D6. Brexpiprazole and its major metabolite, DM-3411, were the predominant drug moieties in the systemic circulation following single and multiple dose administration. At steady-state, DM-3411 represented 23% to 48% of brexpiprazole exposure (AUC) in plasma. DM-3411 is considered not to be pharmacologically active.

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Biological Half-Life
After multiple once-daily administrations, the terminal elimination half-lives of brexpiprazole and its major metabolite, DM-3411, were 91 hours and 86 hours, respectively.

Hepatotoxicity
Liver test abnormalities were reported to occur in ~1% of patients on long term therapy with brexpiprazole, but similar rates occurred in patients on placebo or with comparator agents. There have been no published reports of clinically apparent acute liver injury due to brexpiprazole and only rare instances have been reported with the much more frequently used aripiprazole. Thus, liver injury due to brexpiprazole must be rare, if it occurs 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
No information is available on the excretion of brexpiprazole in breastmilk. A single case report implicated brexpiprazole as a cause of decreased lactation. A review of case reports found lactation disorders and breast secretion reported as side effects, but details are lacking. Until more data are available, an alternate drug may be preferred.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
A woman was taking brexpiprazole 2 mg daily during the third trimester of pregnancy for bipolar disorder. Her newborn infant was hospitalized in the NICU for hypoxic ischemic encephalopathy for 18 days. While her infant was in the NICU, she reduced her brexpiprazole dose to 2 mg every 2 days because of a shortage of medication. The mother, who had successfully breastfed 2 previous infants, pumped milk 10 times daily and was able to pump 120 mL daily by one week postpartum. After her infant was discharged, she increased the dose back to 2 mg daily. At a follow-up clinic visit, she could only pump 30 mL daily. She then stopped brexpiprazole and began a short course of metoclopramide. Within 10 days of stopping brexpiprazole, her milk supply increased, and she could almost exclusively breastfeed her infant who gained weight normally. Her serum prolactin level also increased to normal.
A review of case reports of adverse reactions reported in the US Food and Drug Administration’s Adverse Event Reporting System from 2015 to 2023 found 6 reports of “lactation disorder” and 10 cases of “breast discharge” reported with brexpiprazole. Other details were lacking.

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Protein Binding
_In vitro_, brexpiprazole was 99% bound to plasma proteins, mainly serum albumin and α1-acid glycoprotein.

[1]. Potentiation of neurite outgrowth by brexpiprazole, a novel serotonin-dopamine activity modulator: a role for serotonin 5-HT1A and 5-HT2A receptors. Eur Neuropsychopharmacol. 2015 Apr;25(4):505-11.

[2]. Improvement of dizocilpine-induced social recognition deficits in mice by brexpiprazole, a novel serotonin-dopamine activity modulator. Eur Neuropsychopharmacol. 2015 Mar;25(3):356-64.

Brexpiprazole is a N-arylpiperazine.
Brexpiprazole is an atypical antipsychotic and a novel D2 dopamine and serotonin 1A partial agonist called serotonin-dopamine activity modulator (SDAM). It has a high affinity for serotonin, dopamine and alpha (α)-adrenergic receptors. Although it is structurally similar to [aripiprazole], brexpiprazole has different binding affinities for dopamine and serotonin receptors. Compared to aripiprazole, brexpiprazole has less potential for partial agonist-mediated adverse effects such as extrapyramidal symptoms, which is attributed to lower intrinsic activity at the D2 receptor. It also displays stronger antagonism at the 5-HT1A and 5-HT2A receptors. Brexpiprazole was first approved by the FDA on July 10, 2015. Currently approved for the treatment of depression, schizophrenia, and agitation associated with dementia due to Alzheimer’s disease, brexpiprazole has also been investigated in other psychiatric disorders, such as post-traumatic stress disorder.
Brexpiprazole is an Atypical Antipsychotic.
Brexpiprazole is an atypical antipsychotic used in the treatment of schizophrenia and major depressive disorders. Brexpiprazole has been associated with a low rate of serum aminotransferase elevations during therapy but has not been linked to instances of clinically apparent acute liver injury.

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Drug Indication
Brexpiprazole is indicated as adjunctive therapy to antidepressants for the treatment of major depressive disorder in adults. It is also indicated for the treatment of schizophrenia in patients 13 years of age and older. Brexpiprazole is also indicated for the treatment of agitation associated with dementia due to Alzheimer’s disease; however, it is not indicated as an as-needed (“prn”) treatment for this condition.
Treatment of schizophrenia.
Treatment of schizophrenia

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Mechanism of Action
Although the exact mechanism of action of brexpiprazole in psychiatric disorders has not been fully elucidated, the efficacy of brexpiprazole may be attributed to combined partial agonist activity at 5-HT_1A and dopamine D2 receptors, and antagonist activity at 5-HT_2A receptors. Brexpiprazole binds to these receptors with subnanomolar affinities. These therapeutic targets have been implicated in psychiatric conditions such as schizophrenia and depression. Partial D2 receptor agonism allows the drug to stimulate D2 receptors under low dopamine conditions, while attenuating their activation when dopamine levels are high. Partial agonism at 5-HT_1A receptors may be tied to improved memory function and cognitive performance. Antagonism at α-adrenergic receptors has also been implicated in schizophrenia and depression.

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Pharmacodynamics
Brexpiprazole is an atypical antipsychotic agent used to ameliorate the symptoms of psychiatric conditions, such as cognitive deficits and affective symptoms. Brexpiprazole has affinity (expressed as Ki) for multiple monoaminergic receptors including serotonin 5-HT_1A (0.12 nM), 5-HT_2A (0.47 nM), 5-HT_2B (1.9 nM), 5-HT₇ (3.7 nM), dopamine D2 (0.30 nM), D3 (1.1 nM), and noradrenergic α_1A (3.8 nM), α_1B (0.17 nM), α_1D (2.6 nM), and α_2C (0.59 nM) receptors. Brexpiprazole acts as a partial agonist at the 5-HT_1A, D2, and D3 receptors and as an antagonist at 5-HT_2A, 5-HT_2B, 5-HT₇, α_1A, α_1B, α_1D, and α_2C receptors. Brexpiprazole also exhibits affinity for histamine H1 receptor (19 nM) and for muscarinic M1 receptor (67% inhibition at 10 µM).

C25H27N3O2S

433.5658

433.182

C, 69.26; H, 6.28; N, 9.69; O, 7.38; S, 7.39

913611-97-9

Brexpiprazole-d8-1;1427049-19-1;Brexpiprazole hydrochloride;913612-38-1;Brexpiprazole-d8;1427049-21-5

11978813

Typically exists as White to off-white solid at room temperature

1.2±0.1 g/cm3

675.2±55.0 °C at 760 mmHg

362.1±31.5 °C

0.0±2.1 mmHg at 25°C

1.646

5.82

77.07

1

5

7

31

636

0

O=C1NC2C(=CC=C(C=2)OCCCCN2CCN(C3C4=C(SC=C4)C=CC=3)CC2)C=C1

ZKIAIYBUSXZPLP-UHFFFAOYSA-N

InChI=1S/C25H27N3O2S/c29-25-9-7-19-6-8-20(18-22(19)26-25)30-16-2-1-11-27-12-14-28(15-13-27)23-4-3-5-24-21(23)10-17-31-24/h3-10,17-18H,1-2,11-16H2,(H,26,29)

7-[4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy]-1H-quinolin-2-one

BREXPIPRAZOLE; 913611-97-9; Rexulti; OPC-34712; 7-(4-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)quinolin-2(1H)-one; OPC 34712; Rxulti; UNII-2J3YBM1K8C;

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 : ~25 mg/mL (~57.66 mM)

配方 1 中的溶解度: 2.5 mg/mL (5.77 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), 悬浮液；超声助溶。
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 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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配方 2 中的溶解度: ≥ 2.5 mg/mL (5.77 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 储备液添加到 900 μL 玉米油中并混合均匀。

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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;
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7、 以上所有助溶剂都可在 Invivochem.cn网站购买。