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Dextromilnacipran

HCID 11622909
NotesReactions
Basic informationOverviewNames & identifiersPropertiesChemistry & industryRelated reactionsCompound notes
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Basic information

CAS
136090-84-1
Standard SMILES
CCN(CC)C(=O)C1(c2ccccc2)CC1CN
InChIKey
GJJFMKBJSRMPLA-UHFFFAOYSA-N
Molecular formula
C15H22N2O
Average molar mass
246.35 g/mol
Monoisotopic mass
246.17321333

Overview

Milnacipran is a member of acetamides.

Names & identifiers

Preferred name
Dextromilnacipran
IUPAC
2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropane-1-carboxamide

Names & synonyms

(+-)-MilnacipranDextromilnacipran2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropane-1-carboxamide136090-84-1Milnacipran Impurity 46L-Milnacipran HydrochlorideSCHEMBL114034CHEMBL259209GTPL7436DTXSID90861127CHEBI:135005BDBM50490618
Show more names
EBC-26308AKOS026750554DB04896TS-08444DS-015843AB01563301_01EN300-26869031BRD-A15202882-003-02-7

Database identifiers

CAS
136090-84-1、92623-85-3
PubChem CID
11622909
DTXSID
DTXSID90861127
ChEMBL
CHEMBL259209
ChEBI
CHEBI:135005
EC Number
603-943-1

Properties

Computed structural properties

XLogP
1.4
Topological polar surface area
46.3 Ų
Hydrogen bond donors
1
Hydrogen bond acceptors
2
Rotatable bonds
5
Heavy atoms
18
Formal charge
0
Complexity
295

Experimental & physicochemical properties

Melting Point179°C

Chemistry & industry

Pharmacology

Protein BindingThe protein binding determined for racemic milnacipran is 13%. Conversely, the plasma protein binding documented for levomilnacipran is 22% over a concentration range of 10 to 1000 ng/mL.
Pharmacodynamics · 1 item

When utilized to treat fibromyalgia, the effect of milnacipran on the QTcF interval in patients was measured in a double-blind placebo-and positive-controlled parallel study in 88 healthy subjects using three to six times the recommended therapeutic dose for fibromyalgia at 600 mg/day. After baseline and placebo adjustment, the maximum mean QTcF change was 8 ms - an increase that is generally not considered to be clinically significant. Conversely, when used for treating major depressive disorder (MDD), non-clinical studies have shown that levomilnacipran binds with high affinity to the norepinephrine (NE) and serotonin (5-HT) transporters (Ki = 71-91 nM and 11 nM respectively at human transporters). Levomilnacipran inhibits the uptake of both NE and 5-HT in vitro and in vivo; preferentially inhibiting reuptake of NE over 5-HT by approximately 2-fold. Levomilnacipran does not directly affect the uptake of dopamine or other neurotransmitters. Levomilnacipran has no significant affinity for serotonergic (5-HT1-7), α- and β-adrenergic, muscarinic (M1-5), histamine (H1-4), dopamine (D1-5), opiate, benzodiazepine, and γ-aminobutyric acid (GABA) receptors in vitro. Levomilnacipran has no significant affinity for Ca++, K+, Na+, and Cl– channels and does not inhibit the activity of human monoamine oxidases (MAO-A and MAO-B) or acetylcholinesterase. Moreover, in ECG studies with levomilnacipran used to treat MDD, although no clinically significant changes in QTcF interval (QTcF=QT/RR0.33) were noted, it appears that the agent can cause increases in heart rate and blood pressure. In particular, it appears that the maximum therapeutic dose of levomilnacipran at 120 mg/day is capable of causing a maximum mean difference in heart rate from placebo of 20.2 bpm and a mean difference in systolic and diastolic blood pressure from placebo ranging from 3.8 to 7.2 mmHg and 6.1 to 8.1 mmHg, respectively. Alternatively, a supratherapeutic dose of 300 mg/day is capable of causing a maximum mean difference in heart rate from placebo of 22.1 bpm and a mean difference in systolic and diastolic blood pressure from placebo ranging from 5.4 to 7.9 mmHg and 7.9 to 10.6 mmHg, respectively.

Mechanism of Action · 1 item

Related reactions

1 records
New reaction record
HRID 1515391 reaction equation
HRID 1515391As productuspto-grants-2012_07

Compound notes

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On this pageBasic informationOverviewNames & identifiersPropertiesChemistry & industryRelated reactionsCompound notes

The dual ability for milnacipran to inhibit the reuptake of both serotonin (5HT) and norepinephrine (NE) facilitates its treatment of both fibromyalgia and major depressive disorder (MDD). In particular, it is generally believed that 5HT and NE participate in the modulation of endogenous analgesic mechanisms by way of the descending inhibitory pain pathways in the brain and spinal cord. Although the specific mechanism of action remains unclear, some studies have proposed that low levels of 5HT may be associated with increased sensitivity to pain - a condition that could subsequently be improved by milnacipran's capacity to enhance the presence of 5HT by inhibiting its reuptake via serotonin transporters at synaptic clefts. Furthermore, in the CNS it is also generally believed that NE released from descending pathways can mitigate pain sensations via eliciting inhibitory effects on alpha-2A-adrenoceptors on central terminals of primary afferent nociceptors, by direct alpha-2-adrenergic action on pain-relay neurons, and by alpha-1-adrenoceptor-mediated activation of inhibitory interneurons. Such NE pain mitigation is consequently also enhanced by milnacipran's ability to enhance the presence of NE by inhibiting its reuptake via norepinephrine transporters at synaptic clefts. Concurrently, milnacipran's capacity to inhibit the reuptake of both 5HT and NE also facilitates its treatment of MDD. Given the monoamine hypothesis' assertion that decreased 5HT can be associated with anxiety, obsessions, compulsions, and decreased NE can result in lowered alertness, energy, attention, and general interest in life, it is proposed that milnacipran's basic activities as a serotonin and norepinephrine reuptake inhibitor could assist in treating such symptoms of MDD by increasing the presence of both 5HT and NE in the body by inhibiting their reuptake.

Biological Half-Life · 1 item

The terminal elimination half-life documented for racemic milnacipran is approximately 6-8 hours, where d-milnacipran has a longer elimination half-life of 8-10 hours compared to that of the l-enantionmer at 4-6 hours. Alternatively, the terminal elimination half-life determined specifically for levomilnacipran formulations is about 12 hours.

Metabolism/Metabolites · 1 item

It has been determined that levomilnacipran undergoes desethylation and hydroxylation to generate desethyl levomilnacipran and p-hydroxy-levomilnacipran, respectively. Both oxidative metabolites undergo further conjugation with glucuronide to form the conjugate milnacipran carbamoyl-O-glucuronide. The desethylation is catalyzed primarily by CYP3A4 with minor contribution by CYP2C8, 2C19, 2D6, and 2J2. Additionally, it is the general understanding that there is no interconversion between the enantiomers of milnacipran in the body.

Absorption, Distribution and Excretion · 4 items

Racemic milnacipram demonstrates an absolute bioavailability of about 85-90% following oral administration. Maximum concentrations of the racemic agent are reached within 2-4 hours after oral dosing, and steady-state levels are obtained by 36-48 hours. Conversely, the relative bioavailability of levomilnacipram has been documented as 92%. The median time to peak concentration Tmax for levomilnacipram is about 6-8 hours after oral administration. After daily dosing of levomilnacipram 120 mg, the mean Cmax value is 341 ng/mL, and the mean steady-state AUC value is 5196 ng.h/mL. In general, the administration of either racemic milnacipram or levomilnacipram with food does not affect the medication's oral bioavailability.

Levomilnacipran and its metabolites are eliminated primarily by renal excretion. Following oral administration of 14C-levomilnacipran solution, approximately 58% of the dose is excreted in urine as unchanged levomilnacipran. N-desethyl levomilnacipran is the major metabolite excreted in the urine and accounted for approximately 18% of the dose. Other identifiable metabolites excreted in the urine are levomilnacipran glucuronide (4%), desethyl levomilnacipran glucuronide (3%), p-hydroxy levomilnacipran glucuronide (1%), and p-hydroxy levomilnacipran (1%).

The mean volume of distribution recorded for racemic milnacipran following a single intravenous dose to healthy subjects was approximately 400 L. Alternatively, levomilnacipran is widely distributed with an apparent volume of distribution of 387-473 L.

The total plasma clearance determined for milnacipran is approximately 40 L/h.