DT-Web

DB04896 - Milnacipran


Identification
Name Milnacipran
Accession Number DB04896
Type small molecule
Description Milnacipran is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. It more potently inhibits norepinephrine uptake than serotonin. It is provided as a racemic mixture. FDA approved in January 2009.
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 246.348
Groups approved
Monoisotopic Weight 246.173213336
Pharmacology
Indication Milnacipran is used to treat moderate to severe clinical depression but this indication is not yet FDA-approved in the USA. Milnacipran is labelled for the treatment of fibromyalgia pain.
Mechanism of action Milnacipran inhibits norepinephrine and serotonin reuptake in a 3:1 ratio, in practical use this means a balanced (equal) action upon both transmitters. The serotonin reuptake inhibition is likely to improve depression, while the norepinephrine reuptake inihibition probably improves chronic pain. Milnacipran exerts no significant actions on postynaptic H1, alpha-1, D1, D2, and muscarinic receptors, as well as on benzodiazepine/opiate binding sites. [Wikipedia]
Absorption Milnacipran is well absorbed following oral administration with an absolute bioavailability of 85-90%. Meals have no effect on absorption. Peak concentrations occur 2 -4 hours post-administration and is delayed in elderly patients. Time to steady state = 36 - 48 hours;
Protein binding Plasma protein binding is 13%.
Biotransformation Hepatic metabolism of milnacipran occurs via glucuronidation. No involvement of CYP450 isozymes or active metabolites found.
Route of elimination It is excreted predominantly unchanged in urine (50%- 60%, 24% as l-milnacipran and 31% as d-milnacipran). The l-milnacipran carbamoyl-O-glucuronide was the major metabolite excreted in urine and accounted for approximately 17% of the dose; approximately 2% of the dose was excreted in urine as d-milnacipran carbamoyl-O-glucuronide. Approximately 8% of the dose was excreted in urine as the N-desethyl milnacipran metabolite.
Toxicity LD50, oral, rat: 213 mg/kg. The most frequently occurring adverse reactions (>= 5% and greater than placebo) were nausea, headache, constipation, dizziness, insomnia, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increased, dry mouth, and hypertension.
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions
Drug Mechanism of interaction
Clonidine Because Savella inhibits norepinephrine reuptake, co-administration with clonidine may inhibit clonidine's anti-hypertensive effect.
Desvenlafaxine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
Digoxin Use of Savella concomitantly with digoxin may be associated with potentiation of adverse hemodynamic effects. Co-administration of Savella and intravenous digoxin should be avoided.
Furazolidone Increase serotonin levels. Combination therapy is contraindicated.
Iobenguane Milnacipran decreases the effects of Iobenguane thus increases the risk of producing a false-negative result. May discontinue milnacipran for at least 5 half-live.
Isocarboxazid Increase serotonin levels. Combination therapy is contraindicated.
Moclobemide Increase serotonin levels. Combination therapy is contraindicated.
Pargyline Increase serotonin levels. Combination therapy is contraindicated.
Phenelzine Increase serotonin levels. Combination therapy is contraindicated.
Procarbazine Increase serotonin levels. Combination therapy is contraindicated.
Rasagiline Increase serotonin levels. Combination therapy is contraindicated.
Tranylcypromine Increased risk of serotonin syndrome. Concomitant therapy should be avoided. A significant washout period, dependent on the half-lives of the agents, should be employed between therapies.
Venlafaxine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
Zolmitriptan Use of two serotonin modulators, such as zolmitriptan and milnacipran, increases the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.
Food Interactions Not Available

Targets


Sodium-dependent serotonin transporter
Name Sodium-dependent serotonin transporter
Gene Name SLC6A4
Pharmacological action yes
Actions inhibitor
References
  • Leo RJ, Brooks VL: Clinical potential of milnacipran, a serotonin and norepinephrine reuptake inhibitor, in pain. Curr Opin Investig Drugs. 2006 Jul;7(7):637-42. - Pubmed
  • Moret C, Charveron M, Finberg JP, Couzinier JP, Briley M: Biochemical profile of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug. Neuropharmacology. 1985 Dec;24(12):1211-9. - Pubmed
DTHybrid score 0.3601
Sodium-dependent noradrenaline transporter
Name Sodium-dependent noradrenaline transporter
Gene Name SLC6A2
Pharmacological action yes
Actions inhibitor
References
  • Leo RJ, Brooks VL: Clinical potential of milnacipran, a serotonin and norepinephrine reuptake inhibitor, in pain. Curr Opin Investig Drugs. 2006 Jul;7(7):637-42. - Pubmed
  • Moret C, Charveron M, Finberg JP, Couzinier JP, Briley M: Biochemical profile of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug. Neuropharmacology. 1985 Dec;24(12):1211-9. - Pubmed
DTHybrid score 0.4868
Glutamate [NMDA] receptor subunit zeta-1
Name Glutamate [NMDA] receptor subunit zeta-1
Gene Name GRIN1
Pharmacological action unknown
Actions inhibitor
References
  • Kohno T, Kimura M, Sasaki M, Obata H, Amaya F, Saito S: Milnacipran inhibits glutamatergic N-methyl-D-aspartate receptor activity in spinal dorsal horn neurons. Mol Pain. 2012 Jun 19;8:45. doi: 10.1186/1744-8069-8-45. - Pubmed
DTHybrid score 0.6209

Predictions


Id Partner name Gene Name Score
713 Sodium-dependent dopamine transporter SLC6A3 0.1795
4119 Cytochrome P450 2D6 CYP2D6 0.1315
4512 Cytochrome P450 3A4 CYP3A4 0.0885
556 Alpha-1A adrenergic receptor ADRA1A 0.0645
5469 Head decoration protein shp 0.0562
1588 Multidrug resistance protein 1 ABCB1 0.052
6016 Cytochrome P450 2C19 CYP2C19 0.0493
3941 Amine oxidase [flavin-containing] A MAOA 0.0463
6030 Cytochrome P450 2B6 CYP2B6 0.0459
502 5-hydroxytryptamine 2A receptor HTR2A 0.0446
131 Synaptic vesicular amine transporter SLC18A2 0.0438
590 5-hydroxytryptamine 2C receptor HTR2C 0.0415
492 Histamine H1 receptor HRH1 0.0413
4200 Cytochrome P450 1A2 CYP1A2 0.039
3939 Amine oxidase [flavin-containing] B MAOB 0.0381
318 Alpha-2A adrenergic receptor ADRA2A 0.0367
439 Glutamate [NMDA] receptor subunit epsilon-4 GRIN2D 0.0363
471 Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) SLC6A14 0.034
1181 Alpha-1-acid glycoprotein 1 ORM1 0.034
4757 Cytochrome P450 2C9 CYP2C9 0.0335
482 Glycine receptor subunit alpha-1 GLRA1 0.0305
103 Muscarinic acetylcholine receptor M1 CHRM1 0.0299
378 Alpha-2C adrenergic receptor ADRA2C 0.0273
6013 Cytochrome P450 2E1 CYP2E1 0.0272
436 5-hydroxytryptamine 2B receptor HTR2B 0.0272
6151 Monocarboxylate transporter 10 SLC16A10 0.0266
6070 Nischarin NISCH 0.0261
632 Alpha-1B adrenergic receptor ADRA1B 0.0235
6144 Solute carrier family 22 member 2 SLC22A2 0.023
706 Glutamate [NMDA] receptor subunit 3A GRIN3A 0.0227
6147 Solute carrier family 22 member 3 SLC22A3 0.0221
591 Glutamate [NMDA] receptor subunit 3B GRIN3B 0.0207
3970 Voltage-dependent N-type calcium channel subunit alpha-1B CACNA1B 0.0207
6145 Solute carrier family 22 member 1 SLC22A1 0.0201
696 Kappa-type opioid receptor OPRK1 0.0193
198 Sodium channel protein type 10 subunit alpha SCN10A 0.0187
629 Alpha-2B adrenergic receptor ADRA2B 0.0182
320 5-hydroxytryptamine 1A receptor HTR1A 0.0179
51 Muscarinic acetylcholine receptor M3 CHRM3 0.0172
4118 Cytochrome P450 3A5 CYP3A5 0.0171
709 ATP-sensitive inward rectifier potassium channel 1 KCNJ1 0.017
505 Glutamate [NMDA] receptor subunit epsilon-3 GRIN2C 0.0161
617 Muscarinic acetylcholine receptor M2 CHRM2 0.016
274 Muscarinic acetylcholine receptor M5 CHRM5 0.0154
4924 Cytochrome P450 2C8 CYP2C8 0.0154
450 Muscarinic acetylcholine receptor M4 CHRM4 0.015
6107 Cytochrome P450 3A7 CYP3A7 0.0149
464 Glutamate [NMDA] receptor subunit epsilon-2 GRIN2B 0.0145
587 Serum albumin ALB 0.0143
193 Beta-1 adrenergic receptor ADRB1 0.0143
766 Beta-2 adrenergic receptor ADRB2 0.014
837 Glutamate [NMDA] receptor subunit epsilon-1 GRIN2A 0.0139
789 Alpha-1D adrenergic receptor ADRA1D 0.0132
831 D(2) dopamine receptor DRD2 0.0123
1636 Trace amine-associated receptor 1 TAAR1 0.0121
1656 CYP2B protein CYP2B 0.0113
6432 Transporter snf 0.0111
467 Delta-type opioid receptor OPRD1 0.0104
1517 Beta-3 adrenergic receptor ADRB3 0.0101
23 D(1A) dopamine receptor DRD1 0.0098
6106 Cytochrome P450 2C18 CYP2C18 0.0096
6182 Cytochrome P450 2J2 CYP2J2 0.0086
847 Mu-type opioid receptor OPRM1 0.0084
872 Gamma-aminobutyric-acid receptor subunit alpha-1 GABRA1 0.007
474 Acetylcholinesterase ACHE 0.0069
118 Organic cation/carnitine transporter 2 SLC22A5 0.0068
6024 Cytochrome P450 1A1 CYP1A1 0.0065
5878 Alpha-7 nicotinic cholinergic receptor subunit CHRFAM7A 0.0061
5718 Cytochrome P450 2A6 CYP2A6 0.0059
215 Sodium channel protein type 11 subunit alpha SCN11A 0.0058
6099 Potassium voltage-gated channel subfamily D member 3 KCND3 0.0052
6098 Potassium voltage-gated channel subfamily D member 2 KCND2 0.0052
341 5-hydroxytryptamine 3 receptor HTR3A 0.005
6018 UDP-glucuronosyltransferase 1-9 UGT1A9 0.0047
1732 ATP-binding cassette sub-family G member 2 ABCG2 0.0046
6178 UDP-glucuronosyltransferase 2B7 UGT2B7 0.0046
2981 Phospholipase A2, membrane associated PLA2G2A 0.0044
1757 Myeloperoxidase MPO 0.0044
828 Phenylalanine-4-hydroxylase PAH 0.0043
3109 Phenylalanine-4-hydroxylase phhA 0.0043
904 Glutathione S-transferase P GSTP1 0.0042
833 Organic cation/carnitine transporter 1 SLC22A4 0.0042
3923 Cholinesterase BCHE 0.0042
220 Sodium channel protein type 5 subunit alpha SCN5A 0.0041
94 5-hydroxytryptamine 4 receptor HTR4 0.0037
6086 Gamma-aminobutyric acid receptor subunit gamma-2 GABRG2 0.0036
4100 Gamma-aminobutyric-acid receptor subunit beta-2 GABRB2 0.0036
1360 Sphingomyelin phosphodiesterase SMPD1 0.0036
922 Glutamate receptor 4 GRIA4 0.0032
924 Glutamate receptor, ionotropic kainate 3 GRIK3 0.0032
919 Glutamate receptor, ionotropic kainate 4 GRIK4 0.0032
920 Glutamate receptor, ionotropic kainate 5 GRIK5 0.0032
4018 Glutamate receptor delta-2 subunit GRID2 0.0032
4027 Glutamate receptor delta-1 subunit GRID1 0.0032
4024 Mitochondrial glutamate carrier 2 SLC25A18 0.0032
4025 Mitochondrial glutamate carrier 1 SLC25A22 0.0032
1912 Excitatory amino acid transporter 1 SLC1A3 0.0032
4019 Excitatory amino acid transporter 4 SLC1A6 0.0032
4026 Aspartyl aminopeptidase DNPEP 0.0032
915 Delta 1-pyrroline-5-carboxylate synthetase ALDH18A1 0.0032
4022 Glutamate--ammonia ligase domain-containing protein 1 LGSN 0.0032
4021 Probable glutamyl-tRNA synthetase, mitochondrial EARS2 0.0032
4023 N-acetylglutamate synthase, mitochondrial NAGS 0.0032
4016 Excitatory amino acid transporter 5 SLC1A7 0.0032
4017 5-oxoprolinase OPLAH 0.0032
1047 Excitatory amino acid transporter 2 SLC1A2 0.0032
927 Metabotropic glutamate receptor 8 GRM8 0.0032
925 Metabotropic glutamate receptor 4 GRM4 0.0032
664 Glutamate decarboxylase 2 GAD2 0.0032
3890 Glutamate decarboxylase 2 GAD2 0.0032
926 Metabotropic glutamate receptor 7 GRM7 0.0032
4020 Glutamyl aminopeptidase ENPEP 0.0032
6100 BDNF/NT-3 growth factors receptor NTRK2 0.0031
319 Opioid receptor, sigma 1 OPRS1 0.0031
625 Glutamate carboxypeptidase 2 FOLH1 0.003
830 Glutamate dehydrogenase 2, mitochondrial GLUD2 0.0028
5 Glutaminase liver isoform, mitochondrial GLS2 0.0027
917 Glutaminase kidney isoform, mitochondrial GLS 0.0027
355 GMP synthase [glutamine-hydrolyzing] GMPS 0.0027
4353 GMP synthase [glutamine-hydrolyzing] guaA 0.0027
3984 Probable glutamyl-tRNA(Gln) amidotransferase subunit B, mitochondrial PET112L 0.0027
3991 Glutamine-dependent NAD(+) synthetase NADSYN1 0.0027
3982 Phosphoribosylformylglycinamidine synthase PFAS 0.0027
5261 Phosphoribosylformylglycinamidine synthase purL 0.0027
668 Glutamate--cysteine ligase regulatory subunit GCLM 0.0027
6079 Neuronal acetylcholine receptor subunit alpha-3 CHRNA3 0.0027
916 Metabotropic glutamate receptor 1 GRM1 0.0027
6164 POU domain, class 5, transcription factor 1 POU5F1 0.0027
923 Glutamate receptor 3 GRIA3 0.0026
665 Phosphoserine aminotransferase PSAT1 0.0026
4652 Phosphoserine aminotransferase serC 0.0026
801 Kynurenine/alpha-aminoadipate aminotransferase mitochondrial AADAT 0.0026
3895 Kynurenine--oxoglutarate transaminase 3 CCBL2 0.0026
420 Glutamate decarboxylase 1 GAD1 0.0026
3900 Glutamate decarboxylase 1 GAD1 0.0026
174 Sigma 1-type opioid receptor SIGMAR1 0.0026
83 Alpha-aminoadipic semialdehyde synthase, mitochondrial AASS 0.0026
210 Bifunctional aminoacyl-tRNA synthetase [Includes: Glutamyl-tRNA synthetase EPRS 0.0026
382 Glutamate receptor, ionotropic kainate 1 GRIK1 0.0026
201 Glutamate dehydrogenase 1, mitochondrial GLUD1 0.0025
1618 High affinity nerve growth factor receptor NTRK1 0.0025
773 Folylpolyglutamate synthase, mitochondrial FPGS 0.0025
1671 Excitatory amino acid transporter 3 SLC1A1 0.0025
448 Vitamin K-dependent gamma-carboxylase GGCX 0.0025
426 Aspartate aminotransferase, mitochondrial GOT2 0.0025
914 Formimidoyltransferase-cyclodeaminase FTCD 0.0024
186 Glutamate--cysteine ligase catalytic subunit GCLC 0.0024
3876 Aromatic-L-amino-acid decarboxylase DDC 0.0024
3877 Growth-inhibiting protein 18 GIG18 0.0024
1086 Potassium voltage-gated channel subfamily KQT member 2 KCNQ2 0.0024
763 Tyrosine aminotransferase TAT 0.0023
5493 Tyrosine aminotransferase Not Available 0.0023
795 Branched-chain-amino-acid aminotransferase, mitochondrial BCAT2 0.0023
586 Aspartate aminotransferase, cytoplasmic GOT1 0.0023
735 Alanine aminotransferase 1 GPT 0.0023
3904 Alanine aminotransferase 2 GPT2 0.0023
124 Histamine H2 receptor HRH2 0.0022
242 Asparagine synthetase [glutamine-hydrolyzing] ASNS 0.0022
33 Cystine/glutamate transporter SLC7A11 0.0022
574 Branched-chain-amino-acid aminotransferase, cytosolic BCAT1 0.0021
3426 Glutamine synthetase glnA 0.0021
3987 Glutamine synthetase GLUL 0.0021
280 4-aminobutyrate aminotransferase, mitochondrial ABAT 0.0021
705 Glutamate receptor 1 GRIA1 0.0021
725 5-hydroxytryptamine 1D receptor HTR1D 0.0019
858 Potassium voltage-gated channel subfamily A member 1 KCNA1 0.0019
885 5-hydroxytryptamine 1B receptor HTR1B 0.0019
20 Prostaglandin G/H synthase 1 PTGS1 0.0018
813 Neuronal acetylcholine receptor subunit alpha-2 CHRNA2 0.0018
738 Monocarboxylate transporter 1 SLC16A1 0.0018
921 Glutamate receptor 2 GRIA2 0.0016
918 Glutamate receptor, ionotropic kainate 2 GRIK2 0.0016
4114 Voltage-dependent L-type calcium channel subunit beta-3 CACNB3 0.001
4112 Voltage-dependent L-type calcium channel subunit beta-4 CACNB4 0.001
392 Voltage-dependent P/Q-type calcium channel subunit alpha-1A CACNA1A 0.001
4113 Voltage-dependent L-type calcium channel subunit alpha-1F CACNA1F 0.0009
15 Voltage-dependent T-type calcium channel subunit alpha-1I CACNA1I 0.0009
333 Voltage-dependent L-type calcium channel subunit beta-1 CACNB1 0.0009
781 ATP-sensitive inward rectifier potassium channel 11 KCNJ11 0.0009
535 Voltage-dependent T-type calcium channel subunit alpha-1G CACNA1G 0.0009
4110 Voltage-dependent L-type calcium channel subunit beta-2 CACNB2 0.0008
4115 Voltage-dependent L-type calcium channel subunit alpha-1D CACNA1D 0.0008
4111 Voltage-dependent L-type calcium channel subunit alpha-1S CACNA1S 0.0008
478 Voltage-dependent L-type calcium channel subunit alpha-1C CACNA1C 0.0008
6148 Multidrug resistance-associated protein 7 ABCC10 0.0007
101 Potassium voltage-gated channel subfamily H member 2 KCNH2 0.0007
1709 Canalicular multispecific organic anion transporter 2 ABCC3 0.0007
776 Bile salt export pump ABCB11 0.0006
2164 Multidrug resistance-associated protein 4 ABCC4 0.0006
862 Multidrug resistance-associated protein 1 ABCC1 0.0006
1490 Solute carrier organic anion transporter family member 1B1 SLCO1B1 0.0006
6139 Solute carrier organic anion transporter family member 1A2 SLCO1A2 0.0006
1735 Canalicular multispecific organic anion transporter 1 ABCC2 0.0005
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