Mianserin targets multiple neurotransmitter receptors to exert its pharmacological effects. It is a H1 receptor inverse agonist. Mianserin blocks alpha-adrenergic, histamine H1, and some types of serotonin receptors. It is a weak inhibitor of norepinephrine reuptake and strongly stimulates the release of norepinephrine. The compound's mechanism of therapeutic action is not well understood, although it apparently blocks alpha-adrenergic, histamine H1, and some types of serotonin receptors. Mianserin is a tetracyclic antidepressant that has antihistaminic and hypnosedative, but almost no anticholinergic, effect. By modulating neurotransmitter systems, particularly by antagonizing receptors for serotonin, histamine, and alpha-adrenergic receptors, mianserin helps to improve mood. The compound's multi-receptor profile contributes to its antidepressant, anxiolytic, antiemetic, hypnotic, and antihistamine effects.

In vitro, mianserin demonstrates significant activity at various neurotransmitter receptors. The compound is a H1 receptor inverse agonist. It blocks alpha-adrenergic, histamine H1, and some types of serotonin receptors. Mianserin is a weak inhibitor of norepinephrine reuptake and strongly stimulates the release of norepinephrine. In receptor binding assays, mianserin shows affinity for H1, 5-HT2, and alpha-adrenergic receptors. The compound's effects on neurotransmitter release and reuptake can be studied in synaptosomal preparations or in cell cultures. Mianserin's ability to modulate serotonin, histamine, and noradrenergic signaling contributes to its antidepressant and anxiolytic effects. The compound's lack of significant anticholinergic activity distinguishes it from many other antidepressants.

In vivo, mianserin demonstrates antidepressant and anxiolytic activity in various animal models. The compound is effective in the treatment of depression and anxiety. Mianserin has antidepressant, anxiolytic, antiemetic, hypnotic, and antihistamine effects. In behavioral models of depression, such as the forced swim test or tail suspension test, mianserin shows antidepressant-like effects. The compound's effects on sleep architecture have also been studied, given its hypnotic properties. Mianserin's ability to modulate neurotransmitter systems in the brain contributes to its therapeutic effects. In humans, mianserin is used for the treatment of major depressive disorder and has therapeutic activity similar to amitriptyline. The compound is used throughout Europe and elsewhere but is not approved for marketing in the United States.

In vitro receptor binding assays for mianserin employ radioligand displacement techniques using membrane preparations from tissues or cells expressing various neurotransmitter receptors. For H1 receptor binding, membranes from cells expressing the H1 receptor or from brain tissue are used. The assay involves incubating mianserin at varying concentrations with the membrane preparation and a fixed concentration of a radiolabeled H1 antagonist, such as [³H]-mepyramine. For 5-HT2 receptor binding, [³H]-ketanserin or similar radioligands are used. For alpha-adrenergic receptor binding, [³H]-prazosin or [³H]-rauwolscine are used. Following incubation, bound and free radioligand are separated by rapid filtration, and radioactivity is measured. Non-specific binding is determined in the presence of a high concentration of an unlabeled competitor. Binding affinity (Ki) values are calculated from competition curves using nonlinear regression analysis.

In vitro cellular assays for mianserin typically employ cell lines expressing neurotransmitter receptors or primary neuronal cultures. For studies investigating the compound's effects on neurotransmitter release, synaptosomal preparations or cultured neurons are treated with mianserin, and neurotransmitter release is measured using HPLC or radioimmunoassay. For studies investigating receptor antagonism, cells expressing H1, 5-HT2, or alpha-adrenergic receptors are treated with mianserin in the presence or absence of receptor agonists, and downstream signaling such as calcium flux or cAMP accumulation is measured. The compound's effects on cell viability and proliferation can be assessed using standard cytotoxicity assays. Mianserin's effects on neuronal differentiation or function can be studied in various neuronal cell models.

In vivo animal experiments for mianserin employ various models of depression, anxiety, and other behavioral disorders. For antidepressant studies, rodents are administered mianserin orally or intraperitoneally, and behavioral tests such as the forced swim test, tail suspension test, or open field test are performed. For anxiety studies, the elevated plus maze or light-dark box tests are used. For studies investigating the compound's effects on sleep, electroencephalography (EEG) recordings are performed. For studies investigating the compound's effects on neurotransmitter systems, brain tissue is collected for neurochemical analysis. Dosing regimens vary depending on the experimental objectives, with acute studies using single doses and chronic studies using repeated daily administration.

Absorption, Distribution and Excretion
Oral Absorption: This study investigated the pharmacokinetics of mianserin hydrochloride in six healthy male subjects. Subjects received the following three routes of administration: intravenous injection (5 mg mianserin hydrochloride infused at a constant rate over 1 hour), oral administration (60 mg as two 30 mg tablets), and oral administration (60 mg as an oral solution). A one-month washout period was allowed between each route of administration. Blood samples were collected at predetermined time points within 120 hours after administration. Plasma concentrations of mianserin were measured, and pharmacokinetic analysis was performed. Data from intravenous administration were adequately described using a three-compartment model, and data from oral administration were adequately described using a two-compartment model. Both models employed first-order transfer and elimination rate constants. The mean plasma clearance of mianserin was 19 ± 2 L/hr (mean ± standard error), with a kinetic volume of distribution of 444 ± 250 L, a steady-state volume of distribution of 242 ± 171 L, and an elimination half-life of 33 ± 5 h. The absolute bioavailability (by extent of absorption) of the solution was 22 ± 3%, and that of the tablets was 20 ± 3%. The mean peak concentration of the solution was 79 ± 11 ng/mL, and that of the tablets was 54 ± 5 ng/mL; the mean time to peak concentration was 1.1 ± 0.2 h for the solution and 1.4 ± 0.2 h for the tablets. The mean absorption half-life of the solution was 0.43 ± 0.13 h, and that of the tablets was 0.39 ± 0.11 h. We investigated the pharmacokinetics of mianserin after a single 60 mg dose in 8 hospitalized patients with depression. Significant differences in plasma drug concentrations were observed among the patients. The mean peak plasma concentration (± standard error) was 114 ± 26 ng/ml, with a time to peak concentration ranging from 1 to 3 hours. The decline in mianserin plasma concentration was biphasic. The mean elimination half-life was 21.6 ± 3.1 hours, ranging from 10.7 to 40.8 hours. The estimated first-pass loss ranged from 26% to 48% (mean 37%), lower than previously reported for tricyclic antidepressants. The mean apparent volume of distribution (15.7 ± 2.2 L/kg; 9.7 to 28.8 L/kg) was similar to that of imipramine but slightly lower than that of maprotiline. The apparent systemic clearance ranged from 0.33 to 0.81 L/hr/kg (mean ± standard error, 0.52 ± 0.05 L/hr/kg), comparable to that of maprotiline. Our results indicate that the pharmacokinetics of mianserin are similar in most respects to those of tertiary amine tricyclic antidepressants (e.g., imipramine) and tetracyclic antidepressants (e.g., maprotiline). Metabolism/Metabolites: Hepatic metabolism. The metabolism of mianserin has been investigated in women, rabbits, and rats. In female urine, unmetabolized mianserin, 8-hydroxymianserin, and mianserin-2-oxide were isolated and identified. These two metabolites accounted for more than 60% of the total urinary radioactivity; bound and unbound mianserin accounted for approximately 35%. In rabbits, mianserin is primarily metabolized to 8-hydroxymianserin and an unidentified 8-hydroxymianserin ester; only about 2.4% is unmetabolized mianserin. A small amount of 2-formyldesmethylmianserin was isolated. In rats, the major metabolite is 8-hydroxydesmethylmianserin. Rats primarily metabolize mianserin to 8-hydroxy compounds, with a small amount metabolized to demethylated metabolites. The authors conclude that mianserin is metabolized mainly through three pathways: 8-hydroxylation, demethylation, and 2-oxide formation. Mianserin hydrochloride/
To determine the steady-state plasma concentrations of mianserin and its main active metabolite, demethylmianserin, and to analyze the influence of various clinical factors on these plasma concentrations, we measured the steady-state plasma concentrations of mianserin and demethylmianserin in 76 patients aged 20 to 70 years with depression. These patients took 30 mg/day of mianserin at bedtime for 3 weeks, with the dose increased to 60 mg/day if necessary. The results showed significant individual variability in the steady-state plasma concentrations of these compounds; only 43% of patients had plasma concentrations of mianserin plus demethylmianserin within the therapeutic range. With increasing age, the plasma concentration of mianserin significantly increased, while the plasma concentration of mianserin plus demethylmianserin remained constant. Sex, smoking, and concomitant use of benzodiazepines do not affect drug metabolism. There is no evidence that the kinetics of these compounds change non-linearly with increasing dose. Known metabolites of mianserin include 8-hydroxymianserin, demethylmianserin, and mianserin N-oxide. Biochemical half-life: 10–17 hours. The pharmacokinetics of mianserin hydrochloride were determined in 8 healthy volunteers (mean age 27 years) and 14 elderly patients (mean age 76 years). Volunteers were administered via intravenous infusion (0.011 mg/kg/min, over 15 minutes) and oral administration (single dose 30 mg). Elderly patients received a single oral dose of 40–60 mg. The terminal elimination half-life was significantly prolonged in elderly patients. The terminal elimination half-life in younger subjects was 9.6 ± 1.9 (standard deviation) hours. The half-life in elderly patients was 27 ± 13.1 (standard deviation) hours. The apparent oral clearance was significantly reduced in elderly patients. The half-life was 87.1 ± 32 (standard deviation) hours in younger patients and 38.1 ± 14.8 (standard deviation) hours in elderly patients. These pharmacokinetic differences may have an important influence on the sedative effect of mirtazapine.
The pharmacokinetic properties of mianserin have been characterized in humans and animal models. Mianserin is readily absorbed from the gastrointestinal tract, but its bioavailability is reduced to about 70% by extensive first-pass metabolism in the liver. The decline of mianserin levels in plasma is biphasic, with a mean elimination half-life of 21.6 ± 3.1 hours and a range of 10.7 to 40.8 hours. The estimated first-pass loss ranges from 26% to 48% (mean, 37%) and is lower than that reported for tertiary amine tricyclic antidepressants. Mianserin has been found to have a biphasic plasma half-life with the duration of the terminal phase ranging from 6 to 39 hours. With advancing age, the plasma concentrations of mianserin increase significantly. The compound's absolute bioavailability is approximately 20% for tablets. Mianserin is metabolized primarily in the liver.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Mianserin has not yet received marketing approval from the U.S. Food and Drug Administration (FDA), but it is available in other countries. Limited information suggests that even with daily doses up to 60 mg, low concentrations in breast milk are not expected to have any adverse effects on breastfed infants, especially those older than 2 months. Close monitoring is recommended when using mianserin during lactation until more data become available.
◉ Effects on Breastfed Infants
As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
An observational study investigated the outcomes of 2,859 women who took antidepressants within 2 years prior to pregnancy. Compared to women who did not take antidepressants during pregnancy, mothers who took antidepressants during 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 type of antidepressant used by the mothers. 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). Women treated with antidepressants 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 untreated mothers diagnosed with mental illness. None of the mothers took micranthin. A study of 80,882 Norwegian mother-infant pairs between 1999 and 2008 showed that 392 women reported starting antidepressants postpartum, and 201 women reported starting antidepressants during pregnancy. Compared to a control group unexposed to antidepressants, use of 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 a control group unexposed to antidepressants, recent use or re-initiation of antidepressants 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. Specific antidepressants used were not mentioned.

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Protein binding
90%

The toxicity profile of mianserin is consistent with that of tetracyclic antidepressants. Common adverse effects include drowsiness, sedation, and dry mouth. Mianserin may cause hematological problems, including agranulocytosis, which is a rare but serious adverse effect. The compound has almost no anticholinergic effect, which distinguishes it from tricyclic antidepressants. Mianserin may cause weight gain and dizziness. The compound should be used with caution in patients with a history of epilepsy, liver disease, or cardiovascular disease. Mianserin is not approved for marketing in the United States. The compound's safety in pregnancy and lactation has not been established, and its use should be guided by clinical judgment.

[1]. The atypical antidepressant mianserin exhibits agonist activity at κ-opioid receptors. Br J Pharmacol. 2012 Nov;167(6):1329-41.

[2]. Roeder T. High-affinity antagonists of the locust neuronal octopamine receptor. Eur J Pharmacol. 1990 Nov 27;191(2):221-4.

Mianserin is a dibenzo[c,f]pyrazino[1,2-a]azazepine, a dibenzo[c,f]-hexahydrodibenzo[c,f]pyrazino[1,2-a]azazepine, with a methyl group substituted at the N-2 position. It is closely related to the tetracyclic antidepressant mirtazapine (which has now largely replaced it) and is an atypical antidepressant widely used in Europe and elsewhere to treat depression. It has various pharmacological effects, including antidepressant, histamine agonist, sedative, alpha-adrenergic antagonist, adrenergic reuptake inhibitor, serotonergic antagonist, H1 receptor antagonist, EC 3.4.21.26 (prolyl oligopeptidase) inhibitor, and anti-aging effects. It is a tetracyclic compound with antidepressant activity. Mianserin was once sold globally, but has been replaced by mirtazapine in most markets. Mianserin is a tetracyclic antidepressant with antidepressant activity. It may cause drowsiness and blood problems. Its therapeutic mechanism is not fully understood, but it is speculated that it blocks alpha-adrenergic receptors, histamine H1 receptors, and certain types of serotonin receptors.

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Indications
For the treatment of depression.

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Mechanism of Action
The therapeutic mechanism of mirtracerin is not fully understood, but it is speculated that it blocks alpha-adrenergic receptors, histamine H1 receptors, and certain types of serotonin receptors.
Miracleline
The therapeutic mechanism of mirtracerin is not fully understood, but it is speculated that it blocks alpha-adrenergic receptors, histamine H1 receptors, and certain types of serotonin receptors.

Mianserin is a tetracyclic antidepressant that has antihistaminic and hypnosedative, but almost no anticholinergic, effect. It is a weak inhibitor of norepinephrine reuptake and strongly stimulates the release of norepinephrine. Mianserin is a H1 receptor inverse agonist. It is used for the treatment of depression and anxiety, with therapeutic activity similar to amitriptyline. Mianserin has antidepressant, anxiolytic, antiemetic, hypnotic, and antihistamine effects. It is closely related to mirtazapine and is used in the treatment of depression throughout Europe and elsewhere. However, mianserin is not approved for marketing in the United States. The compound's mechanism of action involves blocking alpha-adrenergic, histamine H1, and some types of serotonin receptors. The mean elimination half-life of mianserin is 21.6 ± 3.1 hours.

C18H20N2

264.3648

264.163

24219-97-4

Mianserin hydrochloride;21535-47-7

4184

Typically exists as solid at room temperature

1.18g/cm3

411.3ºC at 760mmHg

186.1ºC

3.086

0

2

0

20

342

0

CN(CC1)CC2N1C3=CC=CC=C3CC4=CC=CC=C24

UEQUQVLFIPOEMF-UHFFFAOYSA-N

InChI=1S/C18H20N2/c1-19-10-11-20-17-9-5-3-7-15(17)12-14-6-2-4-8-16(14)18(20)13-19/h2-9,18H,10-13H2,1H3

5-methyl-2,5-diazatetracyclo[13.4.0.02,7.08,13]nonadeca-1(19),8,10,12,15,17-hexaene

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.)