DEXTROMILNACIPRAN

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C15H22N2O
Molecular Weight	246.348
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

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

InChI

InChIKey=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

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/23499664
Curator's Comment: https://www.tga.gov.au/sites/default/files/auspar-milnacipran-hydrochloride-120124.pdf

Dextromilnacipran (1R, 2S/F2696) is an enantiomer of milnacipran, a serotonin/norepinephrine (5-HT/NE) reuptake inhibitor. Dextromilnacipran is pharmacologically less active as compared with racemic mixture and levomilnacipran (1S, 2R/F2695).

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serotonin transporter 183 Target ID: CHEMBL228 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23499664	Inhibitor 8504	290.0 nM [Ki]
Serotonin transporter 183 Target ID: CHEMBL228 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23499664	Inhibitor 8504	16.9 nM [Ki]
Norepinephrine transporter 197 Target ID: CHEMBL222 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23499664	Inhibitor 8504	139.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Fibromyalgia 90 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022256s013lbl.pdf	Primary		Approved 8583	SAVELLA Approved Use Savella is indicated for the management of fibromyalgia. Savella is not approved for use in pediatric patients [see Use in Specific Populations (8.4) Launch Date 2009
Unknown 2596

C_max

Value	Dose	Co-administered	Analyte	Population
132 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26663198/	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:		MILNACIPRAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
150 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8923123/	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:		MILNACIPRAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
1316.9 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26663198/	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:		MILNACIPRAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26663198/	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	MILNACIPRAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
8 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8923123/	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	MILNACIPRAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
6 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022256s023lbl.pdf	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	MILNACIPRAN plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
87% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8923123/	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:		MILNACIPRAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
87% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022256s023lbl.pdf	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:		MILNACIPRAN plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 2252 substrate 1946	inhibitor 2438 inducer 440	inhibitor 2507 substrate 1388	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 2153 CYP2A6 879 CYP2C19 2057 CYP2E1 1060	P-gp 2052 CYP2C19 1119 CYP1A2 1197	CYP1A2 832 CYP2B6 669 CYP2C8 198 CYP2C19 329 CYP3A4/5 133

Drug as perpetrator

Target	Modality	Activity
CYP1A2 2333	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=27 Page: 27.0	no
CYP1A2 2333	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP2A6 911	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP2B6 1160	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=27 Page: 27.0	no
CYP2C19 2141	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=27 Page: 27.0	no
CYP2C19 2141	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP2C8 1117	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=27 Page: 27.0	no
CYP2C9 2497	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=27 Page: 27.0	no
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP2E1 1146	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP3A4 2633	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP3A4/5 357	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=27 Page: 27.0	no

Drug as victim

Target	Modality	Activity	Clinical evidence
P-gp 2052	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=7 Page: 7.0	no
CYP2C19 1119	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=55 Page: 55.0	no	no (co-administration study) Comment: no changes in PK of warfarin or milnacipran were observed Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=55 Page: 55.0
CYP1A2 1197	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=55 Page: 55.0	no	unlikely (co-administration study) Comment: when coadministered with carbamazepine, exposure (Cmax and AUC) to milnacipran decreased by 18% and 19%, respectively; Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=55 Page: 55.0
CYP2D6 1388	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=55 Page: 55.0	no	unlikely (co-administration study) Comment: At steady state, Cmax and AUC for milnacipran increased by only 10% and 20% when coadministered with levomepromazine; no changes in PK of warfarin or milnacipran were observed Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=55 Page: 55.0
CYP3A4 1946	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=55 Page: 55.0	no	unlikely (co-administration study) Comment: when coadministered with carbamazepine, exposure (Cmax and AUC) to milnacipran decreased by 18% and 19%, respectively; Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=55 Page: 55.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_PharmR_P2.pdf#page=59 Page: 59.0

Sourcing

Vendor/Aggregator	ID	URL
3B Scientific (Wuhan) Corp	3B2-6287	http://www.3bsc.com/index/pro_info.php?id=116365
Acorn PharmaTech	ACN-035533	http://www.acornpharmatech.com/
AK Scientific, Inc. (AKSCI)	R211	http://www.aksci.com/item_detail.php?cat=R211
Ambinter	Amb22801750	http://www.ambinter.com/reference/22801750
BioCrick	BCC4194	http://www.biocrick.com/Milnacipran-BCC4194.html
BLD Pharm	BD00756442	http://www.bldpharm.com/products/96847-55-1.html
BLD Pharm	BD631023	http://www.bldpharm.com/products/92623-85-3.html
Chem Scene	CS-2009	http://www.chemscene.com/92623-85-3.html
ChemMol	99177637	http://www.chemmol.com/chemmol/99177637.html
ChemMol	99185159	http://www.chemmol.com/chemmol/99185159.html
Clearsynth	CS-P-00447	http://www.clearsynth.com/en/CSP00447.html
CSNpharm	CSN18592	https://www.csnpharm.com/products/milnacipran.html
Hairui	HR143593	http://www.hairuichem.com/en/product/92623-85-3.html
iChemical	EBD2321826	http://www.ichemical.com/products/92623-85-3.html?utm_source=PubChem&utm_medium=website&utm_campaign=product%20catalogs
Lab Network	LN01343162	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01343162
MedChem Express	HY-B0168	https://www.medchemexpress.com/milnacipran.html
MuseChem	I012513	https://www.musechem.com/product/I012513.html
OChem	10310	http://www.ocheminc.com/index.php?act=psearch&pid=623M853
Sigma-Aldrich	CDS022174_ALDRICH	https://www.sigmaaldrich.com/catalog/product/aldrich/cds022174?utm_source=pubchem&utm_campaign=pubchem_2017&utm_medium=referral
Smolecule	S006221	http://www.smolecule.com/products/s006221
Smolecule	S535456	http://www.smolecule.com/products/s535456
THE BioTek	bt-255210	https://www.thebiotek.com/product/inhibitors/bt-255210
THE BioTek	bt-276385	https://www.thebiotek.com/product/inhibitors/bt-276385

PubMed

Title	Date	PubMed
Anxiolytic-like effect of milnacipran in the four-plate test in mice: mechanism of action.	2005-07	15961146
The monoamine-mediated antiallodynic effects of intrathecally administered milnacipran, a serotonin noradrenaline reuptake inhibitor, in a rat model of neuropathic pain.	2005-05	15845695
Chronic treatment with milnacipran reverses the impairment of synaptic plasticity induced by conditioned fear stress.	2005-05	15619117
Remarkable effect of milnacipran, a serotonin-noradrenalin reuptake inhibitor (SNRI), on depressive symptoms in patients with Parkinson's disease who have insufficient response to selective serotonin reuptake inhibitors (SSRIs): two case reports.	2005-02	15694247
Lithium augmentation in milnacipran-refractory depression for the prevention of relapse following electroconvulsive therapy.	2005-01-22	15660714
[Effects of milnacipran on neuronal excitability and synaptic transmission in neurons of the rat locus coeruleus].	2005-01	15675357
Peripheral circulatory disturbance induced by milnacipran.	2005	15746495
Effectiveness of milnacipran for the treatment of chronic pain: a case series.	2004-12-17	15602099
The effect of milnacipran (serotonin noradrenaline reuptake inhibitor) on memory in Korsakoff's syndrome after encephalitis.	2004-12-13	15882773
[Review of antidepressants from the TCAs to the third generation drugs].	2004-12	15825674
Acute effect of milnacipran on the relationship between the locus coeruleus noradrenergic and dorsal raphe serotonergic neuronal transmitters.	2004-12	15589386
Post-treatment emergent adverse events in depressed patients following treatment with milnacipran and paroxetine.	2004-12	15570574
A comparative study of milnacipran and paroxetine in outpatients with major depression.	2004-12	15555719
Characterization of the anxiolytic-like effects of fluvoxamine, milnacipran and risperidone in mice using the conditioned fear stress paradigm.	2004-11-03	15507225
Differential effects of milnacipran, fluvoxamine and paroxetine for inhibited and agitated depression.	2004-11	15504656
Controlled comparison of two different doses of milnacipran in major depressive outpatients.	2004-11	15486520
Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats.	2004-11	15254142
Nociceptin/orphanin FQ, hedonic state and the response to abused drugs.	2004-10	15658507
The effectiveness of lithium augmentation of milnacipran: preliminary data using the modified Japanese Psychopharmacology Algorithm.	2004-10	15658504
Serotonin and noradrenaline reuptake inhibitors in animal models of pain.	2004-10	15378668
Clinical experience with dual action antidepressants in different chronic pain syndromes.	2004-10	15378667
A double-blind placebo-controlled trial of milnacipran in the treatment of fibromyalgia.	2004-10	15378666
Opioid and monoamine systems mediate the discriminative stimulus of tramadol in rats.	2004-09-13	15363988
Prediction of antidepressant response to milnacipran by norepinephrine transporter gene polymorphisms.	2004-09	15337646
In vitro inhibition of recombinant ligand-gated ion channels by high concentrations of milnacipran.	2004-09	14997275
Milnacipran treatment of a terminally ill cancer patient with major depressive disorder.	2004-08	15303248
Differential effects of fluvoxamine, paroxetine and milnacipran for depression, especially with regard to age.	2004-08	15303244
Prevalence of induced mania in patients treated with milnacipran: a comparison with paroxetine.	2004-08	15276667
Determination of milnacipran, a serotonin and noradrenaline reuptake inhibitor, in human plasma using liquid chromatography with spectrofluorimetric detection.	2004-07-05	15171932
A case of temporo-mandibular disorder with fibromyalgia treated with the antidepressant, milnacipran.	2004-07	15252831
Subjective and polysomnographic effects of milnacipran on sleep in depressed patients.	2004-07	15252822
A comparative study of milnacipran and imipramine in the treatment of major depressive disorder.	2004-06	15200743
The monoamine reuptake inhibitor milnacipran does not affect nociception to acute visceral distension in rats.	2004-05	15105216
Efficacy of milnacipran for depressive symptoms in schizophrenia spectrum disorders.	2004-04	15009832
Milnacipran, a serotonin and noradrenaline reuptake inhibitor, suppresses long-term potentiation in the rat hippocampal CA1 field via 5-HT1A receptors and alpha 1-adrenoceptors.	2004-03-04	15036582
Milnacipran: a dual norepinephrine and serotonin reuptake pump inhibitor.	2004-03	15330407
Peripheral nerve injury sensitizes the response to visceral distension but not its inhibition by the antidepressant milnacipran.	2004-03	15108984
Augmentation of milnacipran by risperidone in treatment for major depression.	2004-03	14731310
Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity.	2004-02-01	14744476
[Acute hepatitis associated with milnacipran treatment].	2004-02	15060467
Associations between baseline plasma MHPG (3-methoxy-4-hydroxyphenylglycol) levels and clinical responses with respect to milnacipran versus paroxetine treatment.	2004-02	14709941
Reboxetine: a norepinephrine selective reuptake pump inhibitor.	2004-01	15334987
Double-blind comparative study of the action of repeated administration of milnacipran versus placebo on cognitive functions in healthy volunteers.	2004-01	14716705
Effects of milnacipran on the inhibitory postsynaptic potential in neurons of the rat locus coeruleus.	2004	15682825
Ejaculation after defecation without orgasm induced by milnacipran.	2004	15616184
A method for designing conformationally restricted analogues based on allylic strain: synthesis of a novel class of noncompetitive NMDA receptor antagonists having the acrylamide structure.	2003-12-04	14640541
Milnacipran and pindolol: a randomized trial of reduction of antidepressant latency.	2003-12	14696018
Differential effects of milnacipran, fluvoxamine and paroxetine for depression, especially in gender.	2003-12	14680720
[Psychotropic drugs used in a psychiatric hospital (pharmaco-epidemiologic aspects)].	2003	14681962
[Experience with ixel (milnacipran hydrochloride) use in the treatment of patients with post-stroke depression].	2003	14669603

Patents

Sample Use Guides

In Vivo Use Guide

The recommended dose of Savella (Milnacipran) is 100 mg/day (50 mg twice daily). Based on efficacy and tolerability dosing may be titrated according to the following schedule: Day 1: 12.5 mg once Days 2-3: 25 mg/day (12.5 mg twice daily) Days 4-7: 50 mg/day (25 mg twice daily) After Day 7: 100 mg/day (50 mg twice daily) Based on individual patient response, the dose may be increased to 200 mg/day (100 mg twice daily). Doses above 200 mg/day have not been studied.

Route of Administration: Oral

In Vitro Use Guide

Milnacipran inhibits norepinephrine and serotonin reuptake in rat hypothalamic synaptosomes with IC50 values of 30 and 150 nM, respectively

Name

Type

Language

F-2696

Preferred Name

English

DEXTROMILNACIPRAN

Common Name

English

F2696

Code

English

(1R,2S)-MILNACIPRAN

Common Name

English

CYCLOPROPANECARBOXAMIDE, 2-(AMINOMETHYL)-N,N-DIETHYL-1-PHENYL-, (1R-CIS)-

Systematic Name

English

CYCLOPROPANECARBOXAMIDE, 2-(AMINOMETHYL)-N,N-DIETHYL-1-PHENYL-, (1R,2S)-

Systematic Name

English

Code System Code Type Description

FDA UNII

ES1O38J3C4