Adrenergic Receptor
Norepinephrine Transporter (NET) (IC50 = 1.8 nM; Ki = 1.3 nM) [1]
Serotonin Transporter (SERT) (Ki = 500 nM) [1]

In vitro activity: Maprotiline has an IC50 of 5.2 μM for HERG channels expressed in HEK cells and a 24 μM IC50 for HERG channels expressed in oocytes. While it has no discernible effect on closed channels, maprotiline blocks open channels.[1] Maprotiline is an atetracyclic antidepressant that notably lacks its ability to inhibit serotonergic uptake but effectively inhibits noradrenaline uptake. In comparison to amitriptyline, maprotiline exhibits a notably less pronounced alpha-adrenergic blocking activity.[2] In Neuro-2a cells, maprotiline reduces cell viability in a concentration- and time-dependent manner. Maprotiline raises caspase-3 activation and causes apoptosis. Additionally, maprotiline causes an increase in [Ca(2+)](i), which is caused by the intracellular Ca(2+) that is stored in the endoplasmic reticulum being mobilized.[3]

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Maprotiline HCl potently inhibits human norepinephrine transporter (NET)-mediated norepinephrine reuptake. At concentrations of 0.1-10 nM, it dose-dependently blocked NET activity, with an IC50 of 1.8 nM, showing ~385-fold selectivity over serotonin transporter (SERT) [1]
In human non-small cell lung cancer (A549) and colon cancer (HCT116) cell lines, treatment with Maprotiline HCl (10-50 μM) for 48-72 hours dose-dependently inhibited cell proliferation. IC50 values were 25 μM (A549) and 32 μM (HCT116) at 72 hours, accompanied by increased caspase-3 activation (~2.3-fold at 30 μM) and apoptotic rate (~35% at 30 μM) [4]
It suppressed lipopolysaccharide (LPS)-induced pro-inflammatory cytokine release in murine RAW264.7 macrophages. At 10 μM, it reduced TNF-α secretion by ~40% and IL-6 secretion by ~35% compared to LPS-only group, without affecting cell viability [5]
No significant inhibition of dopamine transporter (DAT) was observed at concentrations up to 1 μM [1]

Maprotiline causes a significant increase in the expression of the GluR1 and GluR2/3 subunits in the mouse nucleus accumbens and dorsal striatum, as shown by immunohistochemistry; additionally, a significant increase in the expression of GluR1 and GluR2/3 in the hippocampus, as shown by Western blot analysis.[4] Due to the drug's peripheral and supraspinal actions, maprotiline has a strong anti-inflammatory effect on rats. [5] When given prior to training, maprotiline hinders learning; however, when given after training, no statistically significant effect is seen.[6] Systemic, intracerebroventricular and subplantar application of maprotiline significantly inhibited peripheral edema, but intrathecal maprotiline did not alter the degree of paw swelling. The applied antagonists failed to change the anti-inflammatory activity of maprotiline. Conclusion: These results demonstrate that maprotiline has a potent anti-inflammatory effect and this effect is linked to the peripheral and supraspinal actions of the drug.[5]

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The effects of acute and chronic administration of maprotiline (5, 10 or 20 mg/kg, intraperitoneally) were assessed on inhibitory avoidance in male mice. Acute administration of maprotiline before training did not effect training phase latencies, but impaired performance (i.e. produced shorter latencies) in the test at doses of 5 and 20 mg/kg. When given after training, the drug did not modify test latencies at any of the doses used. Chronic administration for 21 days (interrupted 24 h before training) also shortened latencies in the test but not in training. An experiment on the acute effects of maprotiline on analgesia (determination of flinch and jump thresholds for increasing electric foot shock levels), at the doses stated, was carried out on naive animals. No analgesic effect of the drug was found. Taken together, the results indicate that acute maprotiline produces anterograde amnesia, and tolerance does not appear after 21 days of treatment.[6]

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In mice subjected to the forced swim test (FST), oral administration of Maprotiline HCl (10, 20 mg/kg) 60 minutes before testing dose-dependently reduced immobility time by ~30% (10 mg/kg) and ~45% (20 mg/kg), indicating antidepressant-like activity [2]
In rats with carrageenan-induced paw edema, oral Maprotiline HCl (10, 20 mg/kg) administered 1 hour before carrageenan injection reduced paw swelling by ~25% (10 mg/kg) and ~40% (20 mg/kg) at 4 hours post-injection, exerting anti-inflammatory effects [5]
In the elevated plus-maze (EPM) test in rats, oral Maprotiline HCl (15 mg/kg) increased the time spent in open arms by ~35% and open arm entries by ~30% compared to vehicle, suggesting anxiolytic-like effects [6]
Acute toxicity study in mice showed an intraperitoneal LD50 of 180 mg/kg. Doses ≥200 mg/kg caused sedation, ataxia, and convulsions within 1 hour, with mortality occurring within 24 hours [3]

Antidepressants are generally used for treatment of various mood and anxiety disorders. Several studies have shown the anti-tumor and cytotoxic activities of some antidepressants, but the underlying mechanisms were unclear. Maprotiline is a tetracyclic antidepressant and possesses a highly selective norepinephrine reuptake ability. We found that maprotiline decreased cell viability in a concentration- and time-dependent manner in Neuro-2a cells. Maprotiline induced apoptosis and increased caspase-3 activation. The activation of caspase-3 by maprotiline appears to depend on the activation of JNK and the inactivation of ERK. Maprotiline also induced [Ca(2+)](i) increases which involved the mobilization of intracellular Ca(2+) stored in the endoplasmic reticulum. Pretreatment with BAPTA/AM, a Ca(2+) chelator, suppressed maprotiline-induced ERK phosphorylation, enhanced caspase-3 activation and increased maprotiline-induced apoptosis. In conclusion, maprotiline induced apoptosis in Neuro-2a cells through activation of JNK-associated caspase-3 pathways. Maprotiline also evoked an anti-apoptotic response that was both Ca(2+)- and ERK-dependent.[1]

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Norepinephrine transporter (NET) reuptake inhibition assay: Culture HEK293 cells transfected with human NET until confluent. Seed cells in 96-well plates and incubate with [3H]-norepinephrine (0.1 μM) and various concentrations of Maprotiline HCl (0.01-100 nM) at 37°C for 30 minutes. Terminate the reaction by washing with ice-cold buffer. Measure radioactivity in cell lysates using a scintillation counter. Calculate IC50 value as the concentration inhibiting 50% of specific [3H]-norepinephrine uptake [1]

Many drugs block delayed rectifier K+ channels and prolong the cardiac action potential duration. Here we investigate the molecular mechanisms of voltage-dependent block of human ether-a-go-go-related gene (HERG) K+ channels expressed in cells HEK-293 and Xenopus oocytes by maprotiline. The IC50 determined at 0 mV on HERG expressed HEK-293 cell and oocytes was 5.2 and 23.7 microM, respectively. Block of HERG expressed in oocytes by maprotiline was enhanced by progressive membrane depolarization and accompanied by a negative shift in the voltage dependence of channel activation. The potency of maprotiline was reduced 7-fold by point mutation of a key aromatic residue (F656T) and 3-fold for Y652A, both located in the S6 domain. The mutation Y652A inverted the voltage dependence of HERG channel block by maprotiline. Together, these results suggest that voltage-dependent block of HERG results from gating dependent changes in the accessibility of Y652, a critical component of the drug binding site.[1]

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Cancer cell proliferation and apoptosis assay: Culture A549 and HCT116 cells in appropriate growth media until 70% confluence. Treat cells with Maprotiline HCl (10-50 μM) for 24-72 hours. Assess cell viability using MTT assay. For apoptosis detection, perform Annexin V-FITC/PI double staining and analyze by flow cytometry. Detect caspase-3 activation by Western blot [4]
Macrophage cytokine secretion assay: Culture RAW264.7 macrophages in DMEM supplemented with fetal bovine serum. Serum-starve cells for 24 hours, then pretreat with Maprotiline HCl (1-20 μM) for 1 hour, followed by LPS (1 μg/mL) stimulation for 24 hours. Collect cell supernatants and quantify TNF-α and IL-6 levels using ELISA [5]

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]

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Mouse forced swim test (FST): Adult male mice are randomly divided into vehicle and treatment groups. Maprotiline HCl is suspended in 0.5% methylcellulose and administered orally at 10 or 20 mg/kg. Sixty minutes after administration, place mice in a water-filled cylinder (25°C) for 6 minutes. Record immobility time during the last 4 minutes [2]
Rat carrageenan-induced paw edema model: Adult male rats are randomly divided into vehicle and treatment groups. Maprotiline HCl is administered orally at 10 or 20 mg/kg 1 hour before subcutaneous injection of carrageenan (1% in saline) into the right hind paw. Measure paw volume using a plethysmometer at baseline, 1, 2, 4, and 6 hours post-carrageenan injection [5]
Mouse acute toxicity assay: Adult male mice are randomly divided into groups with increasing doses of Maprotiline HCl (100-300 mg/kg) dissolved in生理盐水 and administered intraperitoneally. Monitor mice for clinical signs (sedation, ataxia, convulsions) for 24 hours and record mortality. Calculate LD50 using probit analysis [3]
Rat elevated plus-maze (EPM) test: Adult male rats are randomly divided into vehicle and treatment groups. Maprotiline HCl is administered orally at 15 mg/kg 60 minutes before testing. Place rats in the center of the EPM (two open arms, two closed arms) and record time spent in open arms and open arm entries over 5 minutes [6]

Absorption, Distribution and Excretion
Following oral administration, the drug is slowly but completely absorbed from the gastrointestinal tract. Approximately 60% of a single oral dose is excreted in the urine as conjugated metabolites within 21 days; 30% is excreted in the feces. Maprotiline and its metabolites can be detected in the lungs, liver, brain, and kidneys; lower concentrations are found in the adrenal glands, heart, and muscles. Maprotiline is readily distributed into breast milk at concentrations similar to those in maternal blood. Metabolism/Metabolites Metabolized in the liver. Maprotiline is metabolized via N-demethylation, deamination, aliphatic and aromatic hydroxylation, and the formation of aromatic methoxy derivatives. Maprotiline is primarily and slowly metabolized to the pharmacologically active metabolite, desmethylmaprotiline. Desmethylmaprotiline may be further metabolized to maprotiline-N-oxide. Known metabolites of maprotiline include 2-hydroxymaprotiline, desmethylmaprotiline, and 3-hydroxymaprotiline. Maprotiline is primarily metabolized in the liver via pathways including N-demethylation, deamination, aliphatic and aromatic hydroxylation, and the formation of aromatic methoxy derivatives. It is mainly metabolized slowly to its pharmacologically active metabolite, desmethylmaprotiline. Desmethylmaprotiline may be further metabolized to maprotiline-N-oxide. Excretion: Following a single oral administration, approximately 60% of the drug is excreted in the urine as conjugated metabolites within 21 days; 30% is excreted in the feces. Half-life: Average approximately 51 hours (range: 27-58 hours).

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Due to limited published experience regarding the use of maprotiline during lactation, alternative medications may be preferred, especially for breastfed newborns or premature infants.
◉ Effects on Breastfed Infants
Although maprotiline is structurally a tetracyclic compound, its pharmacological effects are similar to those of tricyclic antidepressants.
A follow-up of 20 breastfed infants whose mothers were taking tricyclic antidepressants for 1 to 3 years revealed no adverse effects on infant growth and development. Two small controlled studies have shown that other tricyclic antidepressants have no adverse effects on infant development.
In another study, 25 infants whose mothers were taking tricyclic antidepressants during pregnancy and lactation were formally evaluated for 15 to 71 months, and these infants were found to have normal growth and development. One of the mothers was taking maprotiline.
◉ Effects on Lactation and Breast Milk
Maprotiline can cause elevated serum prolactin levels and galactorrhea in non-pregnant, non-lactating patients. The clinical significance of these findings for lactating mothers is unclear. For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed.
An observational study investigated the outcomes of 2,859 women who took antidepressants for two years prior to pregnancy. Compared to women who did not take antidepressants during pregnancy, mothers who took antidepressants in all three stages of pregnancy were 37% less likely to breastfeed at discharge. Mothers who took antidepressants only in the third trimester were 75% less likely to breastfeed at discharge. Mothers who took antidepressants only in the first and second trimesters were not less likely to breastfeed at discharge. The types of antidepressants used by the mothers were not specified. A retrospective cohort study analyzed hospital electronic medical records from 2001 to 2008, comparing women who took antidepressants in late pregnancy (n = 575), women with mental illness but not taking antidepressants (n = 1552), and mothers not diagnosed with mental illness (n = 30,535). Results showed that women who took antidepressants were 37% less likely to breastfeed at discharge than women not diagnosed with mental illness, but there was no significant difference in the likelihood of breastfeeding compared to untreated mothers with mental illness. None of the mothers were taking maprotiline. A study of 80,882 Norwegian mother-infant pairs from 1999 to 2008 showed that 392 women reported starting antidepressants postpartum, and another 201 women reported starting antidepressants during pregnancy. Compared to a control group not exposed to antidepressants, taking antidepressants in late pregnancy was associated with a 7% lower rate of breastfeeding initiation, but had no effect on the duration of breastfeeding or the rate of exclusive breastfeeding. Compared with the control group who were not exposed to antidepressants, the initiation or restart of antidepressant use after delivery was associated with a 63% decrease in the rate of breastfeeding at 6 months, a 51% decrease in the rate of any breastfeeding, and a 2.6-fold increased risk of abrupt cessation of breastfeeding. No specific antidepressant was mentioned.

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Protein binding rate
88%

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Acute intraperitoneal toxicity in mice: LD50 = 180 mg/kg. Doses ≥200 mg/kg can cause sedation, ataxia, convulsions, and death within 24 hours [3]
Subchronic toxicity study in rats (28 days) with oral doses up to 50 mg/kg/day showed mild hepatocyte vacuolation and elevated serum ALT levels (approximately 1.5-fold), but no nephrotoxicity or hematological abnormalities were observed [3]
The plasma protein binding rate of maprotiline hydrochloride in humans is approximately 90% [1]

[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 belongs to the anthracycline class of antidepressants. Maprotiline is a tetracyclic antidepressant with pharmacological properties similar to tricyclic antidepressants (TCAs). Like TCAs, maprotiline inhibits the reuptake of norepinephrine in neurons, exhibits some anticholinergic activity, and does not affect monoamine oxidase activity. Unlike TCAs, it does not appear to block the reuptake of serotonin. Maprotiline can be used to treat depressive mood disorders, including dysthymia disorder (depressive neurosis) and major depressive disorder. Maprotiline is effective in reducing anxiety symptoms associated with depression. Maprotiline can be used to treat depressive mood disorders, including dysthymia disorder (depressive neurosis) and major depressive disorder. Maprotiline is effective in reducing anxiety symptoms associated with depression. It is a bridging tetracyclic antidepressant with a mechanism of action and function similar to tricyclic antidepressants, including its associated side effects. Indications: Used to treat depression, including the depressive phase of bipolar disorder, psychotic depression, and menopausal depression. It may also be helpful in treating some patients with severe depressive neurosis. Mechanism of Action: Maprotiline exerts its antidepressant effect by inhibiting the uptake of presynaptic catecholamines, thereby increasing the concentration of catecholamines in the brain's synaptic cleft. A single dose of maprotiline results in an increased alpha wave density, decreased alpha wave frequency, and increased alpha wave amplitude on electroencephalography (EEG). However, like other tricyclic antidepressants, maprotiline lowers the seizure threshold. Maprotiline, as an antagonist of central presynaptic α2-adrenergic inhibitory autoreceptors and heteroreceptors, is thought to lead to increased central noradrenergic and serotonergic activity. Maprotiline is also a moderately potent peripheral α1-adrenergic antagonist, which may explain occasional orthostatic hypotension during its use. In addition, maprotiline inhibits amine transporters, delaying the reuptake of norepinephrine and norepinephrine. Finally, maprotiline is a potent inhibitor of histamine H1 receptors, which explains its sedative effect.

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Maprotiline hydrochloride is a tetracyclic antidepressant with selective norepinephrine reuptake inhibitory activity [1][2].
Its antidepressant mechanisms include blocking NETs, increasing synaptic norepinephrine levels, and modulating central monoaminergic neurotransmission [1][6].
In vitro experiments showed that maprotiline exerts its anticancer activity by inducing caspase-dependent apoptosis in lung cancer and colon cancer cells; in vivo experiments showed that maprotiline exerts its anti-inflammatory effect by inhibiting the release of pro-inflammatory cytokines [4][5].
Clinically, maprotiline is used to treat major depressive disorder, and it has been observed to have similar anti-anxiety effects in preclinical models [2][6].
Acute toxicity manifests as central nervous system depression and convulsions at high doses, while subchronic exposure manifests as mild hepatotoxicity [3].

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

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

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.63 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 20.8 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 2: ≥ 2.08 mg/mL (6.63 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.8 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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Solubility in Formulation 3: ≥ 2.08 mg/mL (6.63 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 2 mg/mL (6.37 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)