Adrenergic Receptor

体外活性：Maprotiline 抑制 HEK 细胞中表达的 HERG 通道，IC50 为 5.2 μM，抑制卵母细胞中表达的 HERG 通道，IC50 为 24 μM。马普替林阻断开放通道，但对封闭通道没有显着影响。马普替林是四环抗抑郁药，它强烈抑制去甲肾上腺素的摄取，但值得注意的是它对血清素能摄取缺乏抑制。马普替林的 α-肾上腺素能阻断活性也明显低于阿米替林。马普替林以浓度和时间依赖性方式降低 Neuro-2a 细胞中的细胞活力。马普替林诱导细胞凋亡并增加 caspase-3 激活。马普替林还诱导 [Ca(2+)](i) 增加，这涉及储存在内质网中的细胞内 Ca(2+) 的动员。

全身、脑室内和足底下应用马普替林可显著抑制外周水肿，但鞘内应用马普替林未改变足部肿胀程度。应用拮抗剂不能改变马普替林的抗炎活性。 结论:马普替林具有有效的抗炎作用，这种作用与药物的外周和棘上作用有关。[5]

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研究了急性和慢性给予马普罗替林(5、10或20 mg/kg，腹腔注射)对雄性小鼠抑制回避的影响。训练前急性给予马普罗替林不影响训练潜伏期，但在5和20 mg/kg剂量的试验中，表现受损(即产生更短的潜伏期)。当训练后给药时，任何剂量的药物都没有改变测试潜伏期。慢性给药21天(训练前24小时中断)也缩短了测试中的潜伏期，但在训练中没有。一项关于马普替林对急性镇痛作用的实验(测定增加足电刺激水平时的收缩和跳跃阈值)，在规定剂量下，在幼稚动物身上进行。无镇痛作用。综上所述，结果表明急性马普替林产生顺行性遗忘，治疗21天后未出现耐受性[6]。

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免疫组织化学检测发现，马普替林可显着增加小鼠伏核和背侧纹状体中 GluR1 和 GluR2/3 亚基的表达；蛋白质印迹分析表明，海马中 GluR1 和 GluR2/3 的表达显着增加。马普替林对大鼠具有有效的抗炎作用，这种作用与药物的外周和脊髓上作用有关。训练前服用马普替林会损害学习，但训练后服用马普替林没有明显的统计学影响。

许多药物阻断延迟整流K+通道，延长心脏动作电位持续时间。在这里，我们研究了马普替林对HEK-293细胞和非洲爪蟾卵母细胞中表达的人乙醚-a-go-go相关基因(HERG) K+通道电压依赖性阻断的分子机制。0 mV下对HERG表达的HEK-293细胞和卵母细胞的IC50分别为5.2和23.7微米。马普罗替林对卵母细胞中HERG表达的阻断作用随着膜的渐进式去极化而增强，并伴随着通道激活的电压依赖性的负移。马普替林的效价通过关键芳香残基F656T的点突变降低了7倍，Y652A的点突变降低了3倍，均位于S6结构域。突变Y652A逆转了马普罗替林对HERG通道阻滞的电压依赖性。综上所述，这些结果表明HERG的电压依赖性阻断是由于药物结合位点的关键成分Y652的可及性发生了门压依赖性变化。[1]

抗抑郁药通常用于治疗各种情绪和焦虑障碍。一些研究表明，一些抗抑郁药具有抗肿瘤和细胞毒活性，但其潜在机制尚不清楚。马普替林是一种四环抗抑郁药，具有高度选择性的去甲肾上腺素再摄取能力。我们发现马普替林以浓度和时间依赖性的方式降低了神经-2a细胞的细胞活力。马普替林诱导细胞凋亡，增加caspase-3活化。马普罗替林对caspase-3的激活似乎依赖于JNK的激活和ERK的失活。马普替林还诱导[Ca(2+)](i)增加，这涉及内质网储存的细胞内Ca(2+)的动员。Ca(2+)螯合剂BAPTA/AM预处理可抑制马普罗替林诱导的ERK磷酸化，增强caspase-3活化，增加马普罗替林诱导的细胞凋亡。综上所述，马普替林通过激活jnk相关的caspase-3通路诱导神经-2a细胞凋亡。马普替林也引起了Ca(2+)-和erk依赖性的抗凋亡反应。[3]

Firstly, the anti-inflammatory effect of systemic maprotiline (12.5, 25 and 50 mg kg(-1)) was assessed using a paw edema model. Secondly, different doses of maprotiline were administrated intracerebroventricularly, intrathecally and locally before carrageenan challenge. Finally, we tried to reverse the anti-inflammatory effect of maprotiline by propranolol (10 mg kg(-1)), prazosin (4 mg kg(-1)), yohimbine (10 mg kg(-1)), naloxone (4 mg kg(-1)) and mifepristone (5 mg kg(-1)).[5]

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State-dependent learning (SDL) is a phenomenon in which the retrieval of newly acquired information is possible if the subject is in the same physiological state as during the encoding phase. SDL makes it possible to separate the effects of drugs per se on learning from the effects due to changes in drug state during the task. The present work was designed to investigate whether the antidepressants amitriptyline (30 mg/kg), maprotiline (25 mg/kg), and fluoxetine (15 mg/kg) produce SDL of the inhibitory avoidance conditioning in male and female CD1 mice. In three separate experiments, independent groups were used for each pharmacological treatment and for each sex using a 2 x 2 experimental design. The results do not show SDL in any of the drugs. In the case of amitriptilyline, the data can be attributed to a memorization deficit, while the maprotiline results are interpreted as simultaneously influenced by memorization deficit and performance facilitation due to motor impairment. Fluoxetine treatment did not produce any deteriorating effect on the conditioning. Drugs had some different effects on the performance of males and females, males showing a slightly higher deterioration than females with administration of amitriptyline and maprotiline. This study shows that these antidepressants affect the acquisition/consolidation but not the retrieval process in the inhibitory avoidance learning.[2]

Absorption, Distribution and Excretion
Slowly, but completely absorbed from the GI tract following oral administration.
Approximately 60% of a single orally administered dose is excreted in urine as conjugated metabolites within 21 days; 30% is eliminated in feces.
Maprotiline and its metabolites may be detected in the lungs, liver, brain, and kidneys; lower concentrations may be found in the adrenal glands, heart and muscle. Maprotiline is readily distributed into breast milk to similar concentrations as those in maternal blood.

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Metabolism / Metabolites
Hepatic. Maprotiline is metabolized by N-demethylation, deamination, aliphatic and aromatic hydroxylations and by formation of aromatic methoxy derivatives. It is slowly metabolized primarily to desmethylmaprotiline, a pharmacologically active metabolite. Desmethylmaprotiline may undergo further metabolism to maprotiline-N-oxide.
Maprotiline has known human metabolites that include 2-hydroxy-maprotiline, desmethylmaprotiline, and 3-hydroxy-maprotiline.
Hepatic. Maprotiline is metabolized by N-demethylation, deamination, aliphatic and aromatic hydroxylations and by formation of aromatic methoxy derivatives. It is slowly metabolized primarily to desmethylmaprotiline, a pharmacologically active metabolite. Desmethylmaprotiline may undergo further metabolism to maprotiline-N-oxide.
Route of Elimination: Approximately 60% of a single orally administered dose is excreted in urine as conjugated metabolites within 21 days; 30% is eliminated in feces.
Half Life: Average ~ 51 hours (range: 27-58 hours)

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Biological Half-Life
Average ~ 51 hours (range: 27-58 hours)

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because there is little published experience with maprotiline during breastfeeding, other agents may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Although it is structurally a tetracyclic compound, maprotiline has pharmacologic actions similar to the tricyclic antidepressants.
Follow-up for 1 to 3 years in a group of 20 breastfed infants whose mothers were taking a tricyclic antidepressant found no adverse effects on growth and development. Two small controlled studies indicate that other tricyclic antidepressants have no adverse effect on infant development.
In another study, 25 infants whose mothers took a tricyclic antidepressant during pregnancy and lactation were assessed formally between 15 to 71 months and found to have normal growth and development. One of the mothers was taking maprotiline.
◉ Effects on Lactation and Breastmilk
Maprotiline has caused increased serum prolactin levels and galactorrhea in nonpregnant, nonnursing patients. The clinical relevance of these findings in nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
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 maprotiline.
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.

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Protein Binding
88%

[1]. Eur J Pharmacol . 2006 Feb 15;531(1-3):1-8.

[2]. Behav Brain Res . 2006 Jan 6;166(1):150-8.

[3]. Toxicology . 2013 Feb 8:304:1-12.

[4]. Cancer Lett . 2009 Apr 8;276(1):14-20.

[5]. Inflamm Res . 2010 Dec;59(12):1053-9.

[6]. Behav Brain Res . 2000 Apr;109(1):1-7.

Maprotiline is a member of anthracenes.
Maprotiline is a tetracyclic antidepressant with similar pharmacological properties to tricyclic antidepressants (TCAs). Similar to TCAs, maprotiline inhibits neuronal norepinephrine reuptake, possesses some anticholinergic activity, and does not affect monoamine oxidase activity. It differs from TCAs in that it does not appear to block serotonin reuptake. Maprotiline may be used to treat depressive affective disorders, including dysthymic disorder (depressive neurosis) and major depressive disorder. Maprotiline is effective at reducing symptoms of anxiety associated with depression.
Maprotiline is a tetracyclic antidepressant with similar pharmacological properties to tricyclic antidepressants (TCAs). Similar to TCAs, maprotiline inhibits neuronal norepinephrine reuptake, possesses some anticholinergic activity, and does not affect monoamine oxidase activity. It differs from TCAs in that it does not appear to block serotonin reuptake. Maprotiline may be used to treat depressive affective disorders, including dysthymic disorder (depressive neurosis) and major depressive disorder. Maprotiline is effective at reducing symptoms of anxiety associated with depression.
A bridged-ring tetracyclic antidepressant that is both mechanistically and functionally similar to the tricyclic antidepressants, including side effects associated with its use.

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Drug Indication
For treatment of depression, including the depressed phase of bipolar depression, psychotic depression, and involutional melancholia, and may also be helpful in treating certain patients suffering severe depressive neurosis.

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Mechanism of Action
Maprotiline exerts its antidepressant action by inhibition of presynaptic uptake of catecholamines, thereby increasing their concentration at the synaptic clefts of the brain. In single doses, the effect of maprotiline on the EEG revealed a rise in the alpha-wave density, a reduction of the alpha-wave frequency and an increase in the alpha-wave amplitude. However, as with other tricyclic antidepressants, maprotiline lowers the convulsive threshold. Maprotiline acts as an antagonist at central presynaptic α₂-adrenergic inhibitory autoreceptors and hetero-receptors, an action that is postulated to result in an increase in central noradrenergic and serotonergic activity. Maprotiline is also a moderate peripheral α₁ adrenergic antagonist, which may explain the occasional orthostatic hypotension reported in association with its use. Maprotiline also inhibits the amine transporter, delaying the reuptake of noradrenaline and norepinephrine. Lastly, maprotiline is a strong inhibitor of the histamine H₁ receptor, which explains its sedative actions.

C20H24CLN

313.86

313.159

C, 76.53; H, 7.71; Cl, 11.30; N, 4.46

10347-81-6

Maprotiline-d5 hydrochloride; 1794942-12-3; Maprotiline-d3 hydrochloride; 1329496-63-0; Maprotiline; 10262-69-8; 58902-67-3 (mesylate)

4011

White to off-white solid powder

399.6ºC at 760 mmHg

230-232ºC

187.7ºC

9.8E-08mmHg at 25°C

5.404

12.03

1

1

4

21

339

0

Cl[H].N([H])(C([H])([H])[H])C([H])([H])C([H])([H])C([H])([H])C12C3=C([H])C([H])=C([H])C([H])=C3C([H])(C3=C([H])C([H])=C([H])C([H])=C13)C([H])([H])C2([H])[H]

NZDMFGKECODQRY-UHFFFAOYSA-N

InChI=1S/C20H23N.ClH/c1-21-14-6-12-20-13-11-15(16-7-2-4-9-18(16)20)17-8-3-5-10-19(17)20;/h2-5,7-10,15,21H,6,11-14H2,1H3;1H

N-methyl-3-(1-tetracyclo[6.6.2.02,7.09,14]hexadeca-2,4,6,9,11,13-hexaenyl)propan-1-amine;hydrochloride

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: ≥ 2.08 mg/mL (6.63 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 20.8 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 2 中的溶解度: ≥ 2.08 mg/mL (6.63 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 20.8 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: ≥ 2.08 mg/mL (6.63 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 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 2 mg/mL (6.37 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶 (<60°C).

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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。