sPLA2 ( Ki = 15 nM ); 5-HT_3A Receptor ( Ki = 3.7 nM ); 5-HT₇ Receptor ( Ki = 19 nM ); SERT ( Ki = 1.6 nM )

体外活性：Lu-AA21004 抑制重组人 CYP1A2、CYP2C9、CYP2D6 和 CYP3A4，IC50 分别为 40 μM、39 μM、9.8 μM 和 10 μM。 Lu AA21004 是一种 h5-HT1B 受体部分激动剂，基于全细胞 cAMP 的检测，EC50 为 460 nM，内在活性为 22%。 Lu AA21004 与 r5-HT7 受体结合，Ki 值为 200 nM，是 r5-HT7 受体的功能性拮抗剂，在体外全细胞 cAMP 测定中，IC50 为 2 μM。激酶测定：Vortioxetine（化合物 5m）是一种多模式血清素能药物，抑制 5-HT1A、5-HT1B、5-HT3A、5-HT7 受体和 SERT，Ki 值为 15 nM、33 nM、3.7 nM、19 nM 和 1.6分别为nM。沃替西汀对 5-HT3A 和 5-HT7 受体表现出拮抗特性，对 5-HT1B 受体表现出部分激动剂特性，对 5-HT1A 受体表现出激动特性，并对 SERT 具有有效抑制作用。细胞测定：Vortioxetine 是一种 h5-HT1B 受体部分激动剂，基于全细胞 cAMP 测定，EC50 为 460 nM，内在活性为 22%。 Vortioxetine 与 r5-HT7 受体结合的 Ki 值为 200 nM，是 r5-HT7 受体的功能性拮抗剂，在体外全细胞 cAMP 测定中 IC50 为 2 μM。

对于 Lu-AA21004，大鼠的肝脏清除率和口服生物利用度为 7.1 (L/h)/kg 和 16%。 Lu-AA21004（2.5 mg/kg、5 mg/kg 或 10 mg/kg sc）可增加清醒大鼠腹侧海马的细胞外 5-HT 水平。治疗 3 天后，Lu-AA21004（5 mg/kg 或 10 mg/kg sc）还会导致内侧前额皮质 (mPFC) 中 5-HT 基础水平显着升高。 Lu-AA21004在大鼠内侧前额叶皮层中用5mg/kg或10mg/kg治疗3天后，占据SERT的43%和57%。 Lu AA21004 剂量依赖性地占据 5-HT1B 受体，大鼠皮下给药 1 小时后 SERT 的 ED50 分别为 3.2 mg/kg 和 0.4 mg/kg。 Lu AA21004 剂量依赖性地影响大鼠的 Bezold-Jarisch 反射，抑制短暂性心动过缓，ED50 为 0.11 mg/kg。 Lu AA21004 (2.5-10.0 mg/kg sc) 增加大鼠内侧前额皮质和腹侧海马中 5-HT、DA 和 NA 的细胞外水平。 Lu AA21004（5 mg/kg sc）可增加大鼠腹侧海马中 5-HT 的细胞外水平（200%），SERT 占用率为 41%。 Lu AA21004 (7.8 mg/kg sc) 显着减少 FSL 大鼠的不动时间，但不减少 FRL 大鼠的不动时间。 Lu AA21004（8.0 mg/kg po）可增加大鼠的社交互动，并小幅但显着地增加大鼠的运动活动。 Lu AA21004 (7.9 mg/kg sc) 在大鼠条件性恐惧测定中显示出剂量依赖性抗焦虑样作用。沃替西汀 (10 mg/kg) 显着增加雄性 Sprague-Dawley 大鼠采集前 60 分钟的冻结，表明在采集和/或巩固过程中情境记忆形成增强。沃替西汀（5 mg/kg）还会导致保留期间的冻结率增加，这种效应通过事后测试达到了统计显着性。采集前的沃替西汀（2.5 mg/kg 或 5 mg/kg）显示新物体的平均探索时间分别为 29 秒和 33 秒。沃替西汀 (10 mg/kg) 显着降低大鼠的伤害感受，评估为缩爪潜伏期延长。注射后 20 分钟，5 和 10 mg/kg 的沃替西汀使乙酰胆碱水平增加至基线的 224% 和 204%。

Vortioxetine (Compound 5m) 是一种多模式血清素能药物，可抑制 SERT，抑制值分别为 1.6 nM、33 nM、3.7 nM、19 nM 以及 5-HT1A、5-HT1B 和 5-HT7 受体。 Vortioxetine 表现出强烈的 SERT 抑制作用以及对 5-HT3A 和 5-HT7 受体的拮抗作用、对 5-HT1B 受体的部分激动作用以及对 5-HT1A 受体的激动作用。
Vortioxetine/化合物5m (Lu AA21004)是先导化合物，对重组人5-HT(1A) (K(i) = 15 nM)、5-HT(1B) (K(i) = 33 nM)、5-HT(3A) (K(i) = 3.7 nM)、5-HT(7) (K(i) = 19 nM)、去甲肾上腺素能β(1) (K(i) = 46 nM)受体和SERT (K(i) = 1.6 nM)具有高亲和力。化合物5m对5-HT(3A)和5-HT(7)受体具有拮抗作用，对5-HT(1B)受体具有部分激动作用，对5-HT(1A)受体具有激动作用，对SERT具有有效抑制作用[1]。

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体外SERT和5-HT3受体占用率测定[2]
用载体、氟西汀或沃替西汀(急性给药后1小时或第14次或第21次注射后24小时)处理小鼠的大脑，快速冷冻，用低温恒温器冠状切片，然后装在载玻片上冷冻待用。切片厚度为20 μm，从距bregma正前方约1.2 mm处开始测定SERT受体占用，从距bregma正前方约2.7 mm处开始测定5-HT3受体占用(Franklin and Paxinos, 2008)。在用于放射自显影实验之前，载玻片在- 20°C下保存至少24小时。[2]

Vortioxetine 是一种 h5-HT1B 受体部分激动剂，在基于 cAMP 的全细胞测定中，EC50 为 460 nM，内在活性为 22%。在体外全细胞 cAMP 测定中，vortioxetine 与 r5-HT7 受体结合，Ki 值为 200 nM，并且是 r5-HT7 受体的功能性拮抗剂，IC50 为 2 μM。

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SERT占用率评估[2]
载玻片在含有4.5 nM [3H]-escitalopram的缓冲液(50 mM Tris-HCl, 150 mM NaCl, 5 mM KCl, pH = 7.4)中室温孵育60 min。用1 μM艾司西酞普兰检测非特异性结合。载玻片在冷缓冲液中短暂洗涤，干燥，并在Beta成像仪中暴露16小时。SERT检测的感兴趣区域(ROI)包括外侧和内侧隔膜、伏隔核和嗅结节。SERT检测的ROI示例图像可以在补充图2A中找到。

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5-HT3受体占用率的评价[2]
载玻片在由50 mM Tris和150 mM NaCl组成的缓冲液中预孵育5分钟。载玻片在空气流下干燥30-45分钟。随后，载玻片在含有1 nM [3H]LY278584的缓冲液(50 mM Tris-HCl, 150 mM NaCl, 5 mM KCl, pH = 7.4)中室温孵育60分钟。用1 μM昂丹司琼测定非特异性结合。载玻片在冷缓冲液中短暂洗涤，干燥，并在Beta成像仪中暴露24小时。5-HT3受体占用试验的ROI由海马组成。5-HT3受体占用测定的示例图像可以在补充图2B中找到。

Acute studies[2]
Three doses of vortioxetine (2.5, 5 and 10 mg/kg, free base dissolved in 10% β-cyclodextrin, oral gavage, p.o.,) were used in the OF test, the NSF test and the FST. The effects of vortioxetine were compared to the vehicle control group (10% β-cyclodextrin) and also to a fluoxetine- (18 mg/kg p.o., (David et al., 2007)) and a diazepam-treated group (1.5 mg/kg, s.c. (David et al., 2007)). All doses were corrected for the weight of the salt. All treatments were administered 1 h before testing.

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Chronic studies[2]
Two doses of vortioxetine (5 and 20 mg/kg/day, free base dissolved in 10% β-cyclodextrin, oral gavage, p.o.) were tested in mice after 14 days of administration in the NSF and 21 days of administration in the OF test, the NSF test and the FST. The mice were tested 24 h after the last dose. The effects of vortioxetine were compared to a vehicle control group (10% β-cyclodextrin) and also to a fluoxetine-treated group (18 mg/kg/day p.o.).

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Dissolved in 10% hydroxypropyl-β-cyclodextrin; 10 mg/kg; s.c. administration

Rats

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Amounts of vortioxetine in milk appear to be low. If vortioxetine is required by the mother, it is not a reason to discontinue breastfeeding. However, until more data are available, vortioxetine should be used with careful infant monitoring during breastfeeding.
◉ Effects in Breastfed Infants
Three lactating mothers were taking vortioxetine for depression, two were taking 10 mg once daily and one was taking 20 mg once daily. All mothers were exclusively breastfeeding their infants aged 1, 2 and 6 months of age. No mothers reported any unusual behavior in their infants.
A woman who was taking a vortioxetine dose of 76.1 mcg/kg daily partially breastfed her infant. She did not observe any adverse effects in her infant.
A postpartum Japanese woman with depression was taking vortioxetine 20 mg zolpidem 10 mg, duloxetine 20 mg, rebamipide 100 mg and the Asian herbal medicine Kami-kihi-tou 2.5 grams daily. She partially (over 50%) breastfed her infant for 3 months. The infant had no detectable drug-related adverse effects on routine follow-up at 1, 3, 5, 7 and 9-months postpartum.
◉ Effects on Lactation and Breastmilk
Vortioxetine has caused hyperprolactinemia and galactorrhea in some patients.
An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 37% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge. The antidepressants used by the mothers were not specified.
A retrospective cohort study of hospital electronic medical records from 2001 to 2008 compared women who had been dispensed an antidepressant during late gestation (n = 575) to those who had a psychiatric illness but did not receive an antidepressant (n = 1552) and mothers who did not have a psychiatric diagnosis (n = 30,535). Women who received an antidepressant were 37% less likely to be breastfeeding at discharge than women without a psychiatric diagnosis, but no less likely to be breastfeeding than untreated mothers with a psychiatric diagnosis. None of the mothers were taking vortioxetine.
In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, new postpartum antidepressant use was reported by 392 women and 201 reported that they continued antidepressants from pregnancy. Compared with the unexposed comparison group, late pregnancy antidepressant use was associated with a 7% reduced likelihood of breastfeeding initiation, but with no effect on breastfeeding duration or exclusivity. Compared with the unexposed comparison group, new or restarted antidepressant use was associated with a 63% reduced likelihood of predominant, and a 51% reduced likelihood of any breastfeeding at 6 months, as well as a 2.6-fold increased risk of abrupt breastfeeding discontinuation. Specific antidepressants were not mentioned.

[1]. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem. 2011 May 12;54(9):3206-21.

[2]. Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice. Neuropharmacology. 2013 May 28;73C:147-159.

[3]. A randomized trial on the acute and steady-state effects of a new antidepressant, vortioxetine (Lu AA21004), on actual driving and cognition. Clin Pharmacol Ther. 2013 Jun;93(6):493-501.

[4]. Vortioxetine (Lu AA21004) 5mg in generalized anxiety disorder: results of an 8-week randomized, double-blind, placebo-controlled clinical trial in the United States. Eur Neuropsychopharmacol. 2012 Dec;22(12):858-66.

[5]. Pharmacological effects of Lu AA21004: a novel multimodal compound for the treatment of major depressive disorder. J Pharmacol Exp Ther. 2012 Mar;340(3):666-75.

Vortioxetine hydrobromide is a hydrobromide obtained by combining vortioxetine with one molar equivalent of hydrobromic acid. Used for treatment of major depressive disorder. It has a role as an antidepressant, an anxiolytic drug, a serotonergic antagonist and a serotonergic agonist. It contains a vortioxetine(1+).
Vortioxetine Hydrobromide is a hydrobromide salt form of vortioxetine, a serotonin (5-HT) modulator and stimulator (SMS), with antidepressant activity. Vortioxetine inhibits the reuptake of serotonin and norepinephrine from the synaptic cleft and acts variably as a serotonin receptor agonist (5-HT1A), partial agonist (5-HT1B) or antagonist (5-HT3, 5-HT1D and 5-HT7). It is not clear how this agent's purported multimodal mechanism of action contributes to its antidepressant effect; however, it is presumed to increase the synaptic availability of serotonin and norepinephrine.
A piperazine derivative that acts as a serotonin reuptake inhibitor, as a 5-HT3 receptor antagonist, and 5-HT1A receptor agonist. It is used for the treatment of anxiety and depression.
See also: Vortioxetine (has active moiety).

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Drug Indication
Treatment of major depressive episodes in adults.

C18H22N2S

379.36

378.076

C, 56.99; H, 6.11; Br, 21.06; N, 7.38; S, 8.45

960203-27-4

Vortioxetine; 508233-74-7; Vortioxetine-d8 hydrobromide

56843850

White to off-white solid powder

5.216

40.57

2

3

3

22

316

0

Br.S(C1C(C)=CC(C)=CC=1)C1C(N2CCNCC2)=CC=CC=1

VNGRUFUIHGGOOM-UHFFFAOYSA-N

InChI=1S/C18H22N2S.BrH/c1-14-7-8-17(15(2)13-14)21-18-6-4-3-5-16(18)20-11-9-19-10-12-20;/h3-8,13,19H,9-12H2,1-2H3;1H

1-[2-(2,4-dimethylphenyl)sulfanylphenyl]piperazine;hydrobromide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.59 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 25.0 mg/mL澄清DMSO储备液加入到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 2 中的溶解度: ≥ 2.5 mg/mL (6.59 mM) (饱和度未知) 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), 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 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 3 中的溶解度: ≥ 2.5 mg/mL (6.59 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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配方 4 中的溶解度: 15% Captisol, pH 9: 10 mg/mL

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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。