Tetracyclic antidepressant; Adrenergic Receptor

Apoptosis is induced and HCC cells become more sensitive to sorafenib (2 μM) when exposed to maprotiline (10 μM) [2]. In HepG2 and Huh7 cells, maprotiline (0, 10 or 20 μM, 72 hours) suppresses the phosphorylation of SREBP2 by acting on the ERK pathway [2]. In HCC cells, maprotiline may regulate cholesterol production by targeting CRABP1 [2]. Test for cell invasion [2]

Neuropathic pain can be effectively reduced by combining the synthetic cannabinoid WIN 55,212-2 with maprotiline (3, 10, or 30 mg/kg; i.p.) [1]. Low toxicity to organs, immune system, and hematopoiesis is observed with maprotiline (0, 20, or 40 mg/kg); intraperitoneally; twice weekly; 3 weeks [2]. By blocking cholesterol production and interacting with CRABP1, maprotiline (0, 20, or 40 mg/kg; i.p.; twice weekly; 3 weeks) suppresses the development and metastasis of HCC cells [2].

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

Cell invasion test [2]
Cell Types: human liver cancer cell lines Huh7 and HepG2
Tested Concentrations: 0, 10, 20 μM
Incubation Duration: 24 hrs (hours)
Experimental Results: Inhibition of liver cancer cell migration and epithelial-mesenchymal transition (EMT).

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Cell viability assay [2]
Cell Types: human liver cancer cell lines Huh7 and HepG2
Tested Concentrations: 0, 10, 20 μM
Incubation Duration: 0, 24, 48, 72, 96, 120 hrs (hours)
Experimental Results: Triggered cell apoptosis and inhibited cell viability Huh7 and HepG2 cells in a dose- and time-dependent manner.

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Western Blot Analysis [2]
Cell Types: Human liver cancer cell lines Huh7 and HepG2
Tested Concentrations: 0, 10, 20 μM
Incubation Duration: 72 hrs (hours)
Experimental Results: Inhibition of cholesterol biosynthesis in liver cancer cells.

Animal/Disease Models: Male Balb-c mouse (25-30 g) [1]
Doses: 3, 10, 30 mg/kg
Route of Administration: intraperitoneal (ip) injection; assessment 30 minutes after treatment
Experimental Results: Pain-related behaviors in neuropathic mice weaken.

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Animal/Disease Models: Nude mice (BALB/C nu/nu, 4-6 weeks old, female) [2]
Doses: 40 mg/kg
Route of Administration: intraperitoneal (ip) injection; twice a week; 3-week
Experimental Results: diminished serum and tumor cholesterol levels, inhibited the growth of Huh7-derived tumor xenografts without obvious toxic effects.

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)

Toxicity Summary
Maprotiline exerts its antidepressant effect by inhibiting the uptake of presynaptic catecholamines, thereby increasing the concentration of catecholamines in the brain synaptic cleft. Following a single dose, maprotiline's effects on the electroencephalogram (EEG) include increased alpha wave density, decreased alpha wave frequency, and increased alpha wave amplitude. However, like other tricyclic antidepressants, maprotiline lowers the seizure threshold. As an antagonist of central presynaptic alpha2-adrenergic inhibitory autoreceptors and heteroreceptors, this effect is thought to lead to increased central noradrenergic and serotonergic activity. Maprotiline is also a moderately potent peripheral alpha1-adrenergic antagonist, which may explain occasional reports of orthostatic hypotension during its use. Maprotiline also 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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Use of the drug 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 when breastfeeding 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 study following 20 infants breastfed by mothers taking tricyclic antidepressants for 1 to 3 years found no adverse effects on their 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 took tricyclic antidepressants during pregnancy and lactation underwent formal evaluation at 15 to 71 months of age and 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. Prolactin levels in established lactating mothers 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 study did not specify the types of antidepressants used by the mothers. A retrospective cohort study analyzed hospital electronic medical records from 2001 to 2008, comparing women taking 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). Women receiving antidepressant treatment were 37% less likely to breastfeed at discharge than women not diagnosed with mental illness, but there was no difference in the likelihood of breastfeeding compared to mothers not diagnosed with mental illness but not receiving treatment. 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 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 likelihood of initiating breastfeeding, but had no effect on the duration of breastfeeding or the rate of exclusive breastfeeding. Compared to the control group who had not been exposed to antidepressants, recent use or restart of antidepressant use was associated with a 63% lower likelihood of primary breastfeeding at 6 months, a 51% lower likelihood 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%Toxicity data
LD50: 900 mg/kg (oral, rat) (A308)
LD50: 90 mg/kg (oral, human) (A308)

[1]. Gunduz O, et al. Analysis of the anti-allodynic effects of combination of a synthetic cannabinoid and a selective noradrenaline re-uptake inhibitor in nerve injury-induced neuropathic mice. Eur J Pain. 2016 Mar. 20(3):465-71.
[2]. Zheng C, et al. Maprotiline Suppresses Cholesterol Biosynthesis and Hepatocellular Carcinoma Progression Through Direct Targeting of CRABP1. Front Pharmacol. 2021 May 20. 12:689767.

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 (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 use-related side effects. Indications: For the treatment of 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, 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. Furthermore, maprotiline inhibits amine transporters, delaying the reuptake of norepinephrine and amine agonists. Finally, maprotiline is a potent inhibitor of histamine H1 receptors, explaining its sedative effect.

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Pharmacodynamics
Maprotiline is a tetracyclic antidepressant. While its primary therapeutic use is for depression, studies have also shown it to have a sedative effect on anxiety symptoms often associated with depression. A sleep study showed that maprotiline prolonged REM sleep in patients with depression compared to imipramine, which shortens REM sleep. Maprotiline is a potent inhibitor of norepinephrine reuptake in the brain and peripheral tissues, but notably, it has a weaker inhibitory effect on serotonin reuptake. Furthermore, it possesses potent antihistamine activity (which may explain its sedative effect) and relatively weak anticholinergic activity. Compared to amitriptyline, maprotiline also exhibits lower alpha-adrenergic blocking activity.

C20H23N

277.40332

277.183

C, 86.59; H, 8.36; N, 5.05

10262-69-8

Maprotiline hydrochloride;10347-81-6

4011

Typically exists as solid at room temperature

1.08 g/cm3

399.6ºC at 760 mmHg

187.7ºC

1.35E-06mmHg at 25°C

1.599

4.602

1

1

4

21

339

0

CNCCCC12CCC(C3=CC=CC=C31)C4=CC=CC=C42

QSLMDECMDJKHMQ-UHFFFAOYSA-N

InChI=1S/C20H23N/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

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

maprotiline; 10262-69-8; Maprotylina [Polish]; Maprotylina; Maprotilinum [INN-Latin]; Maprotilina [INN-Spanish]; 9,10-Ethanoanthracene-9(10H)-propanamine, N-methyl-; 276-Ba;

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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