Milnacipran (racemic) inhibits human norepinephrine transporter (NET) with IC50 = 77 nM, human serotonin transporter (SERT) with IC50 = 420 nM, and human dopamine transporter (DAT) with IC50 = 6100 nM. [1]

Milnacipran is mainly excreted in the urine as the parent and glucoronide (> 80%), and only a small fraction (< 10%) is metabolized via N-de-ethylation by the CYP3A4 enzyme. Milnacipran at high concentration can inhibit certain ligand-gated ion-channel (LGIC) receptors, including NMDA, 5-HT3A and nACh receptors, with IC50 of 58.4 μM, 185 μM, 14.3 μM.

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Milnacipran exhibited moderate potencies at NET (IC50 = 77 nM) and SERT (IC50 = 420 nM) and was weakly active at DAT (IC50 = 6100 nM) as determined in radioligand binding or functional uptake assays. [1]

Milnacipran (10 and 30 mg/kg, PO) causes a dose-related increase in the extracellular levels of 5-HT and NA in the medial prefrontal cortex of rats. Milnacipran (30 and 60 mg/kg, PO) significantly reduces the duration of both the immobility time in the forced swimming test and the freezing time in the conditioned fear stress test in rats, which are animal behavioral models for depression and anxiety, respectively. Milnacipran (<40 mg/kg i.p.) dose-dependently increases the extracellular levels of NA and 5-HT in hypothalamus of freely moving guinea pigs. Milnacipran administrated at 10 mg/kg and 40 mg/kg decreases NA metabolite MHPG levels by 57% and 47%, respectively, in hypothalamus of freely moving guinea pigs.

Recombinant ligand-gated ion channels (nACh, NMDA, GABA, and 5-HT3A) were expressed in Xenopus oocytes. Mouse cDNAs encoding α1, β2, and γ2s subunits of GABAA receptor; human cDNAs encoding 5-HT3A receptor; mouse cDNAs encoding ε1 and ξ1 subunits of NMDA receptor; and human cDNAs encoding α4 and β2 subunits of nAChR were subcloned into transcription vectors. Capped mRNA was synthesized using T3 or SP6 RNA message machine kits. Oocytes were harvested from female Xenopus laevis anesthetized on ice with 1% 3-aminobenzoic ethyl ester, manually defolliculated, and treated with 1.5 mg/ml collagenase type 1A for 30 min at room temperature in modified Barth's saline (MBS: 88 mM NaCl, 1 mM KCl, 10 mM HEPES, 2.4 mM NaHCO3, pH 7.4). Between 10 and 50 ng of cRNA was injected per oocyte. Oocytes were incubated at 20°C in MBS containing 1.8 mM Ca2+ until electrophysiological experiments.
Electrophysiological recordings were performed using a two-electrode voltage-clamp technique. Oocytes were impaled with 1-5 MΩ electrodes filled with 3 M KCl and voltage-clamped at -70 mV. Drugs were dissolved in MBS and applied by superfusion. Agonists used: 1 μM glycine + 10 μM NMDA (EC60) for NMDA receptor; 2 μM (EC30) or 6 μM (EC80) 5-HT for 5-HT3A receptor; 5 μM GABA (EC20) for GABAA receptor; 1 μM acetylcholine (EC50) for nACh receptor. Agonist applications were separated by at least 5 min drug-free superfusion (10 min for high concentrations). Competition experiments used a triple application: agonist alone (control), agonist + test drug, then agonist alone again to check recovery. Peak current amplitudes were measured digitally. Concentration-response curves were fitted to the Hill equation: I = Imax / (1 + (EC50/[agonist])^n). IC50 values and Hill coefficients were calculated. All data are expressed as mean ± SEM. [1]

10 and 30 mg/kg, PO Rats

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Milnacipran is mainly excreted in the urine as the parent drug and its glucuronide conjugate (>80% of the dose), and only a small fraction (<10%) is metabolized via N-de-ethylation by the CYP3A4 enzyme. [1]

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Milaprom levels in breast milk are very low and are not expected to have any adverse effects on breastfed infants. However, breastfeeding women should use mirtazaprom with caution, especially when breastfeeding newborns or premature infants, until more data become available.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
According to the manufacturer, galactorrhea is one of the side effects of mirtazaprom. A woman undergoing treatment for depression intentionally overdosed 950 mg of mirtazaprom. From day 5 to day 15 after the overdose, the patient noticed milk leakage from her left breast. The galactorrhea resolved spontaneously without treatment.
A study of cases of hyperprolactinemia and its symptoms (such as gynecomastia) reported by the French National Center for Drug Vigilance found that mirtazaprom did not increase the risk of hyperprolactinemia compared to other drugs.
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 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 specific 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 the third trimester (n = 575), women with mental illness but not taking antidepressants (n = 1,552), and mothers who were not diagnosed with mental illness (n = 30,535). The results showed that women who took antidepressants were 37% less likely to breastfeed at discharge than women who were not diagnosed with mental illness, but there was no significant difference in the likelihood of breastfeeding compared to mothers with untreated 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 another 201 women reported starting antidepressants during pregnancy. Compared to the control group without antidepressant exposure, antidepressant use in late pregnancy was associated with a 7% lower rate of breastfeeding initiation, but had no effect on the duration of breastfeeding or exclusive breastfeeding rates. Compared to the control group without antidepressant exposure, starting or restarting antidepressant use postpartum was associated with a 63% lower rate of primary breastfeeding at 6 months, a 51% lower rate of any feeding method, and a 2.6-fold increased risk of abrupt cessation of breastfeeding. The study did not specify the type of antidepressant.

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Milnacipran has a low potential for drug-drug interactions via CYP450 enzymes due to its minimal metabolism by CYP3A4 (less than 10% N-deethylation). No other toxicity data are reported in this paper. [1]

Bioorg Med Chem Lett.2008 Feb 15;18(4):1346-9;Psychopharmacology (Berl).2004 Sep;175(2):241-6;Psychopharmacology (Berl).2002 Jul;162(3):323-32.

Minacipran hydrochloride belongs to the acetamide class of drugs. It is a cyclopropaneformamide 5-hydroxytryptamine and norepinephrine reuptake inhibitor (SNRI) used to treat fibromyalgia. See also: Minacipran (with active fraction).

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Milnacipran is a racemic mixture of two enantiomers. It is a hydrophilic molecule (calculated logD = 1.2) compared to duloxetine (logD = 3.3). It is used as an antidepressant in Japan and France, and is in phase III clinical trials for fibromyalgia. The SERT inhibition is thought to improve depression, while NET reuptake blockade is thought to improve chronic pain. [1]

C15H22N2O.HCL

282.81

282.149

101152-94-7

Milnacipran ((1S-cis) hydrochloride);175131-60-9;Dextromilnacipran;96847-55-1;Milnacipran;92623-85-3;Milnacipran-d5 hydrochloride;2750534-79-1

163701

White to off-white solid powder

393ºC at 760 mmHg

179-181ºC

1.66E-07mmHg at 25°C

3.273

2

2

5

19

295

2

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

XNCDYJFPRPDERF-PBCQUBLHSA-N

InChI=1S/C15H22N2O.ClH/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;1H/t13-,15+;/m1./s1

(1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropane-1-carboxamide 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: ≥ 2.5 mg/mL (8.84 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 25.0 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: ≥ 2.5 mg/mL (8.84 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 25.0 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: ≥ 2.5 mg/mL (8.84 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 110 mg/mL (388.95 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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