IC50: 3.4 μM (alpha-adrenergic receptor)
Dextromilnacipran targets the serotonin transporter (SERT) and norepinephrine transporter (NET) as a reuptake inhibitor, thereby increasing the synaptic availability of these monoamine neurotransmitters. It also targets the human alpha-adrenergic receptor as an antagonist, with an IC50 of 3.4 μM. The compound's primary mechanism involves inhibition of 5-HT and NE reuptake, which is characteristic of serotonin-norepinephrine reuptake inhibitors (SNRIs) used in the treatment of depression. As the 1R,2S enantiomer, it exhibits different pharmacological properties compared to its more active counterpart, levomilnacipran.

In vitro studies demonstrate that Dextromilnacipran is a selective serotonin and norepinephrine reuptake inhibitor. It also exhibits antagonist activity at the human alpha-adrenergic receptor with an IC50 of 3.4 μM. As an enantiomer of milnacipran, it shows reduced pharmacological activity compared to the racemic mixture and the 1S,2R enantiomer (levomilnacipran). The compound's ability to inhibit monoamine reuptake makes it a useful tool for studying neurotransmitter systems involved in mood regulation. Its alpha-adrenergic receptor antagonism may contribute to additional pharmacological effects.

In vivo studies have been conducted primarily in the context of milnacipran research, as Dextromilnacipran is an enantiomer of this approved drug. Milnacipran, the racemic mixture containing both enantiomers, is approved for the treatment of fibromyalgia and has been studied for major depressive disorder. The (1R,2S) enantiomer is pharmacologically less active than the (1S,2R) enantiomer (levomilnacipran). Levomilnacipran is approved as an extended-release formulation (Fetzima) for major depressive disorder. In vivo studies have shown that levomilnacipran has higher efficacy and a better safety profile compared to the racemate. Dextromilnacipran itself is primarily a research tool for enantiomer-specific studies.

For serotonin/norepinephrine reuptake inhibition assays, membrane preparations from cells expressing human recombinant SERT or NET are incubated with radiolabeled substrates (e.g., [3H]-5-HT or [3H]-NE) and varying concentrations of Dextromilnacipran. Non-specific uptake is determined using excess unlabeled reference inhibitors. Following incubation at 37°C for a specified period, uptake is terminated by rapid filtration or centrifugation. Radioactivity retained on filters or in cell pellets is counted by liquid scintillation. IC50 values are calculated from competition curves using nonlinear regression. For receptor binding assays, similar membrane preparations are used with appropriate radioligands. Assays are performed in triplicate with vehicle and positive controls.

For in vitro cellular assays, cell lines expressing serotonin or norepinephrine transporters (e.g., HEK293 cells transfected with SERT or NET) are cultured in appropriate media under standard conditions (37°C, 5% CO2). Dextromilnacipran is dissolved in DMSO and diluted in culture medium to desired concentrations. Cells are seeded in multi-well plates and pre-incubated with test compound for a specified duration. Monoamine uptake is measured by adding radiolabeled substrates and quantifying intracellular radioactivity after washing. Alternatively, neurotransmitter levels in the supernatant can be measured by HPLC or LC-MS. Each concentration is tested in replicate wells with vehicle controls and known reference inhibitors as positive controls.

For in vivo animal studies, Dextromilnacipran or its racemic mixture milnacipran is typically formulated in suitable vehicles (e.g., saline or DMSO/PEG mixtures) and administered via oral gavage, intraperitoneal (i.p.) injection, or subcutaneous (s.c.) injection. Dosing regimens vary by study objective. For behavioral studies in depression models (e.g., forced swim test, tail suspension test), animals are treated with compound and behavioral responses are recorded. For pharmacokinetic studies, blood and brain tissue samples are collected at predetermined time points post-administration, and drug concentrations are quantified by LC-MS/MS. All procedures follow institutional animal care and use committee guidelines.

Absorption, Distribution and Excretion
When taken once daily at doses of 25 mg to 300 mg (2.5 times the maximum recommended dose of levamisole), the steady-state concentration of levamisole is dose-dependent. After a daily dose of 120 mg levamisole, the mean Cmax was 341 ng/mL, and the mean steady-state AUC was 5196 ng·h/mL. The relative bioavailability of oral levamisole extended-release capsules was 92% compared to oral solution. The median time to peak concentration (Tmax) after oral administration of levamisole was 6 to 8 hours. Food had no significant effect on levamisole concentration. Levomilacristor and its metabolites are primarily excreted via the kidneys. After oral administration of 14C-levamisole solution, approximately 58% of the dose is excreted unchanged in the urine. N-Desethyllevonergic Levomilnacipran is the major metabolite excreted in urine, accounting for approximately 18% of the dose. Other identifiable metabolites excreted in urine include Levomilnacipran glucoside (4%), desethyllevonergic Levomilnacipran glucoside (3%), p-hydroxylevonergic Levomilnacipran glucoside (1%), and p-hydroxylevonergic Levomilnacipran (1%). Levomilnacipran has a wide distribution, with an apparent volume of distribution of 387 to 473 liters. After oral administration, the mean apparent total clearance of Levomilnacipran is 21–29 liters per hour. Metabolites/Metabolites: Levomilnacipran is deethylated to desethyllevonergic Levomilnacipran (or N-desethyllevonergic Levomilnacipran), and hydroxylated to p-hydroxylevonergic Levomilnacipran. These metabolites are pharmacologically inactive. Both oxidative metabolites can be further glucuronidated. Deethylation is primarily catalyzed by CYP3A4, with smaller contributions from CYP2C8, 2C19, 2D6, and 2J2.

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Biological Half-Life
The apparent terminal elimination half-life of the sustained-release levamisole is approximately 12 hours.

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Pharmacokinetic properties of Dextromilnacipran are derived from studies on milnacipran and its enantiomers. The compound has a molecular weight of 246.35 and formula C15H22N2O. It is a liquid at room temperature with a CAS number of 96847-55-1. Solubility: DMSO 50 mg/mL (202.96 mM) with sonication and warming. Storage: powder at -20°C for 3 years; in solvent at -80°C for 6 months or -20°C for 1 month. The compound is hygroscopic. As an SNRI, it is expected to have moderate oral bioavailability and blood-brain barrier penetration, though specific parameters for the individual enantiomer are limited.

Effects During Pregnancy and Lactation
◉ Overview of Lactation Use
No studies have been conducted on levomilacrimate in lactating women. However, the racemic form of levomilacrimate is present in low concentrations in breast milk and is not expected to have any adverse effects on breastfed infants. Lactating women should use levomilacrimate with caution, especially when breastfeeding newborns or premature infants, until more data become available. Breastfed infants should be monitored for restlessness, irritability, feeding difficulties, and poor weight gain.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No specific published information found regarding levomilacrimate as of the revision date.
An observational study investigated the outcomes of 2,859 women who took antidepressants in the two years prior to pregnancy. Compared to women who did not take antidepressants during pregnancy, mothers who took antidepressants throughout all three stages of pregnancy were 37% less likely to breastfeed at discharge. Mothers who took antidepressants only in late pregnancy were 75% less likely to breastfeed at discharge. Mothers who took antidepressants only in early and mid-pregnancy were not less likely to breastfeed at discharge. The study did not specify the type of antidepressants 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 mirtazapine. 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, antidepressant use 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, starting or restarting 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. Levomilnacipran binds to plasma proteins at concentrations ranging from 10 to 1000 ng/mL, with a binding rate of 22%.

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According to available safety information, Dextromilnacipran is intended for research use only and is a controlled substance. Standard laboratory safety precautions should be followed when handling this compound, including the use of appropriate personal protective equipment (gloves, lab coat, safety goggles). The compound should be handled in a well-ventilated area. Avoid dust formation and inhalation. In case of skin contact, wash with plenty of soap and water. In case of eye contact, rinse cautiously with water for several minutes. As a reuptake inhibitor, it may affect neurotransmitter systems and should be handled with care. No clinical toxicity data are available for this enantiomer alone.

[1]. Pierre Sokoloff. Levomilnacipran drug for functional rehabilitation after an acute neurological stroke. WO2013014263A1.

Levomilnacipran belongs to the acetamide class of compounds. Levomilnacipran is a selective serotonin and norepinephrine reuptake inhibitor (SNRI), although its inhibitory effect on norepinephrine reuptake is stronger than its inhibitory effect on serotonin reuptake. Levomilnacipran is the more active 1S,2R-enantiomer of the racemic [mirnacitabine]. After administration, Levomilnacipran and its stereoisomers do not interconvert in the human body. Levomilnacipran was first approved by the U.S. Food and Drug Administration (FDA) on July 25, 2013, for the treatment of major depressive disorder in adults. Although Levomilnacipran had previously been studied in Europe and proposed as a potential treatment for stroke, the European Medicines Agency (EMA) ultimately decided not to approve it for this purpose. Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor. Levomilevulin's mechanism of action is as a norepinephrine reuptake inhibitor and a serotonin reuptake inhibitor. The (1S,2R)-isomer of mirtazapine is used to treat major depressive disorder. See also: Levomilevulin hydrochloride (active ingredient); mirtazapine (note moved to). Drug Indications Levomilevulin is a serotonin and norepinephrine reuptake inhibitor indicated for the treatment of major depressive disorder (MDD) in adults. Stroke Treatment Mechanism of Action Levomilevulin is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI). The exact mechanism of levomilevulin's antidepressant effect is not fully understood, but it is generally believed to involve enhancing the effects of serotonin and norepinephrine in the central nervous system by inhibiting the reuptake of serotonin and norepinephrine transporters. Similar to mirtazapine, levamisole has a stronger inhibitory effect on norepinephrine transporter than on serotonin transporter: its inhibitory selectivity for norepinephrine reuptake is more than 15 times higher than its inhibitory selectivity for serotonin reuptake.

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Dextromilnacipran ((1R,2S)-milnacipran; F2696) is an enantiomer of milnacipran, a serotonin and norepinephrine reuptake inhibitor. It is pharmacologically less active than the racemic mixture and levomilnacipran. Levomilnacipran (1S,2R) is approved as Fetzima for major depressive disorder. Dextromilnacipran also acts as a human alpha-adrenergic receptor antagonist with an IC50 of 3.4 μM. The compound is used in research to study depression and mood disorders. It has no reported clinical development or regulatory approvals as a single agent. For research use only.

C15H22N2O

246.35

246.173

96847-55-1

Milnacipran hydrochloride;101152-94-7;Milnacipran;92623-85-3

6917779

Colorless to light yellow liquid

1.077

393ºC at 760 mmHg

179°C

2.471

1

2

5

18

295

2

CCN(CC)C(=O)[C@@]1(C[C@@H]1CN)C2=CC=CC=C2

GJJFMKBJSRMPLA-HIFRSBDPSA-N

InChI=1S/C15H22N2O/c1-3-17(4-2)14(18)15(10-13(15)11-16)12-8-6-5-7-9-12/h5-9,13H,3-4,10-11,16H2,1-2H3/t13-,15+/m1/s1

(1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropane-1-carboxamide

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.)