Synonym
F2695 hydrochloride; F2695; F 2695; F-2695; Levomilnacipran; Levomilnacipran HCl; Brand name: Fetzima.
IUPAC/Chemical Name
(1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride
InChi Key
XNCDYJFPRPDERF-NQQJLSKUSA-N
InChi Code
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+;/m0./s1
SMILES Code
O=C([C@]1(C2=CC=CC=C2)[C@H](CN)C1)N(CC)CC.Cl.
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO.
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
Biological target:
Levomilnacipran Hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor with antidepressant activity.
In vitro activity:
In CHO cells stably expressing transfected human transporters, LVM reduced the reuptake of [3H]NE and [3H]5-HT in a concentration-dependent manner (Fig. 2, top panel), with approximately two-fold higher potency at NET (IC50 = 10.5 and 19.0 nM, for [3H]NE and [3H]5-HT, respectively) (Table 4). Thus, LVM had an NE/5-HT potency ratio of 0.6. LVM did not reduce the reuptake of [3H]DA (IC50 > 100 μM), consistent with its very weak affinity for the DAT. In native tissue (rat synaptosomes), LVM inhibited [3H]NE and [3H]5-HT reuptake with an IC50 of 62.2 and 72.6 nM, respectively. LVM was much less potent in inhibiting [3H]DA reuptake (Table 4). In this manuscript, It is shown that LVM binds with high affinity to human and rat NET and SERT in vitro (but lacks affinity for DAT). Furthermore LVM otently inhibits NE and 5-HT reuptake in vitro. Overall, these data demonstrate that LVM is a selective and potent SNRI that may have potential therapeutic value in the treatment of MDD (major depressive disorder).
Reference: Drug Des Devel Ther. 2015 Jun 23;9:3199-215. https://pubmed.ncbi.nlm.nih.gov/23499664/
In vivo activity:
After oral administration of [14C]-levomilnacipran at a dose of 30 mg/kg in male monkeys, the mean maximal concentrations of levomilnacipran and N-desethyl levomilnacipran were observed at 4 hours and 6 hours, respectively (Figure 2). Levomilnacipran was the major circulating compound in plasma up to 10 hours after dosing. The average peak plasma concentration was 5,018 ng/mL for levomilnacipran and 7,209 ng Eq/mL for total radioactivity. The average extent of exposure was 40,058 h·ng/mL for levomilnacipran compared with 102,522 h·ng Eq/mL for total radioactivity, and the average half-lives were 6.3 hours and 7.9 hours for levomilnacipran and N-desethyl levomilnacipran, respectively. The mean blood-to-plasma ratio in male monkeys was 1.032 and 0.809 at 2 hours and 10 hours after administration of [14C]-levomilnacipran, respectively. Mean plasma concentrations, PK parameters, and blood-to-plasma ratios were similar in female monkeys. Further analysis of monkey urine indicated that these additional peaks corresponded to the phase II glucuronides of levomilnacipran and the phase I metabolite of N-desethyl levomilnacipran. In the 0- to 8hour monkey urine sample, two different carbamoyl glucuronides of N-desethyl levomilnacipran were identified, with corresponding retention times of 12.5 minutes and 13.8 minutes. Both metabolites had the same molecular ion (MH+ m/z 439 or sodium adduct m/z 461) corresponding to the addition of carbamic acid to N-desethyl levomilnacipran and subsequent conjugation with glucuronic acid. Levomilnacipran and/or its metabolites crossed the blood–brain barrier, and the thalamus had the highest concentration of radioactivity in the brain. Knowledge of the PKs, metabolism, and plasma protein binding of levomilnacipran may help physicians prevent adverse effects from drug–drug interactions when using levomilnacipran to treat adults with major depressive disorder.
Reference: Drug Des Devel Ther. 2015; 9: 3199–3215. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484650/
|
Solvent |
mg/mL |
mM |
comments |
| Solubility |
| DMSO |
57.0 |
201.55 |
|
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
282.81
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
1. Auclair AL, Martel JC, Assié MB, Bardin L, Heusler P, Cussac D, Marien M, Newman-Tancredi A, O'Connor JA, Depoortère R. Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety. Neuropharmacology. 2013 Jul;70:338-47. doi: 10.1016/j.neuropharm.2013.02.024. Epub 2013 Mar 13. PMID: 23499664
2. Brunner V, Maynadier B, Chen L, Roques L, Hude I, Séguier S, Barthe L, Hermann P. Disposition and metabolism of [14C]levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, in humans, monkeys, and rats. Drug Des Devel Ther. 2015 Jun 23;9:3199-215. doi: 10.2147/DDDT.S80886. PMID: 26150694; PMCID: PMC4484650.
In vitro protocol:
1. Auclair AL, Martel JC, Assié MB, Bardin L, Heusler P, Cussac D, Marien M, Newman-Tancredi A, O'Connor JA, Depoortère R. Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety. Neuropharmacology. 2013 Jul;70:338-47. doi: 10.1016/j.neuropharm.2013.02.024. Epub 2013 Mar 13. PMID: 23499664
In vivo protocol:
1. Brunner V, Maynadier B, Chen L, Roques L, Hude I, Séguier S, Barthe L, Hermann P. Disposition and metabolism of [14C]levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, in humans, monkeys, and rats. Drug Des Devel Ther. 2015 Jun 23;9:3199-215. doi: 10.2147/DDDT.S80886. PMID: 26150694; PMCID: PMC4484650.
1: Deardorff WJ, Grossberg GT. A review of the clinical efficacy, safety and tolerability of the antidepressants vilazodone, levomilnacipran and vortioxetine. Expert Opin Pharmacother. 2014 Sep 16:1-18. [Epub ahead of print] PubMed PMID: 25224953.
2: Montgomery SA, Gommoll CP, Chen C, Greenberg WM. Efficacy of levomilnacipran extended-release in major depressive disorder: pooled analysis of 5 double-blind, placebo-controlled trials. CNS Spectr. 2014 Jun 5:1-9. [Epub ahead of print] PubMed PMID: 24902007.
3: Palmer EC, Binns LN, Carey H. Levomilnacipran: A New Serotonin-Norepinephrine Reuptake Inhibitor for the Treatment of Major Depressive Disorder. Ann Pharmacother. 2014 May 8;48(8):1030-1039. [Epub ahead of print] Review. PubMed PMID: 24811398.
4: Wang ZJ, Renata H, Peck NE, Farwell CC, Coelho PS, Arnold FH. Improved cyclopropanation activity of histidine-ligated cytochrome P450 enables the enantioselective formal synthesis of levomilnacipran. Angew Chem Int Ed Engl. 2014 Jun 23;53(26):6810-3. doi: 10.1002/anie.201402809. Epub 2014 May 6. PubMed PMID: 24802161; PubMed Central PMCID: PMC4120663.
5: Chen L, Boinpally R, Greenberg WM, Wangsa J, Periclou A, Ghahramani P. Effect of hepatic impairment on the pharmacokinetics of levomilnacipran following a single oral dose of a levomilnacipran extended-release capsule in human participants. Clin Drug Investig. 2014 May;34(5):351-9. doi: 10.1007/s40261-014-0182-5. PubMed PMID: 24677141.
6: Sambunaris A, Gommoll C, Chen C, Greenberg WM. Efficacy of levomilnacipran extended-release in improving functional impairment associated with major depressive disorder: pooled analyses of five double-blind, placebo-controlled trials. Int Clin Psychopharmacol. 2014 Jul;29(4):197-205. doi: 10.1097/YIC.0000000000000033. PubMed PMID: 24667487; PubMed Central PMCID: PMC4047314.
7: Shiovitz T, Greenberg WM, Chen C, Forero G, Gommoll CP. A Randomized, Double-blind, Placebo-controlled Trial of the Efficacy and Safety of Levomilnacipran ER 40-120mg/day for Prevention of Relapse in Patients with Major Depressive Disorder. Innov Clin Neurosci. 2014 Jan;11(1-2):10-22. PubMed PMID: 24653937; PubMed Central PMCID: PMC3960779.
8: Mago R, Mahajan R, Thase ME. Levomilnacipran: a newly approved drug for treatment of major depressive disorder. Expert Rev Clin Pharmacol. 2014 Mar;7(2):137-45. doi: 10.1586/17512433.2014.889563. PubMed PMID: 24524592.
9: Levomilnacipran (Fetzima) a new SNRI for depression. Med Lett Drugs Ther. 2013 Dec 23;55(1432):101-2. PubMed PMID: 24419243.
10: Saraceni MM, Venci JV, Gandhi MA. Levomilnacipran (Fetzima): A New Serotonin-Norepinephrine Reuptake Inhibitor for the Treatment of Major Depressive Disorder. J Pharm Pract. 2013 Dec 31;27(4):389-395. [Epub ahead of print] PubMed PMID: 24381243.
