Reboxetine is an antidepressant drug used in the treatment of clinical depression, panic disorder and ADD/ADHD. Its mesylate (i.e. methanesulfonate) salt is sold under tradenames including Edronax, Norebox, Prolift, Solvex, Davedax or Vestra. Reboxetine has two chiral centers, but it only exists as two enantiomers, (R,R)-(-)- and (S,S)-(+)-reboxetine.

Structure

Similar Structures

Synonyms

Reboxetina

Product Ingredients

Ingredient	UNII	CAS	InChI Key
Reboxetine mesilate	L94J81YNNY	98769-84-7	CGTZMJIMMUNLQD-STYNFMPRSA-N

International/Other Brands

Davedax / Edronax / Norebox / Prolift / Solvex / Vestra

Categories

UNII

947S0YZ36I

CAS number

71620-89-8

Weight

Average: 313.397
Monoisotopic: 313.167793605

Chemical Formula

C₁₉H₂₃NO₃

InChI Key

CBQGYUDMJHNJBX-RTBURBONSA-N

InChI

InChI=1S/C19H23NO3/c1-2-21-16-10-6-7-11-17(16)23-19(15-8-4-3-5-9-15)18-14-20-12-13-22-18/h3-11,18-20H,2,12-14H2,1H3/t18-,19-/m1/s1

IUPAC Name

(2R)-2-[(R)-(2-ethoxyphenoxy)(phenyl)methyl]morpholine

SMILES

[H][C@@](OC1=CC=CC=C1OCC)(C1=CC=CC=C1)[C@@]1([H])CNCCO1

Pharmacology

Indication

For the treatment of clinical depression.

Pharmacodynamics

Reboxetine is a selective noradrenaline reuptake inhibitor (NaRI), the first drug of new antidepressant class. Reboxetine is an a-ariloxybenzyl derivative of morpholine. Reboxetine is primarily used to treat depression but has also been found useful in the treatment of narcolepsy and panic disorders.

Mechanism of action

Reboxetine is a selective inhibitor of noradrenaline reuptake. It inhibits noradrenaline reuptake in vitro to a similar extent to the tricyclic antidepressant desmethylimipramine. Reboxetine does not affect dopamine or serotonin reuptake and it has low in vivo and in vitro affinity for adrenergic, cholinergic, histaminergic, dopaminergic and serotonergic receptors.

Target	Actions	Organism
ASodium-dependent noradrenaline transporter	inhibitor	Humans

Absorption

Reboxetine is rapidly and extensively absorbed following oral administration.

Volume of distribution

Not Available

Protein binding

98%

Metabolism

Reboxetine is metabolized by dealkylation, hydroxylation and oxidation followed by glucuronide or sulphate conjugation. It is metabolized by the cytochrome P450 CYP isoenzyme 3A4.

Route of elimination

Not Available

Half life

12.5 hours

Clearance

Not Available

Toxicity

Reports of seizures (rare) have been reported

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
Unlock Additional Data
(R)-warfarin	The metabolism of (R)-warfarin can be decreased when combined with Reboxetine.
(S)-Warfarin	The metabolism of (S)-Warfarin can be decreased when combined with Reboxetine.
2,5-Dimethoxy-4-ethylthioamphetamine	The risk or severity of adverse effects can be increased when Reboxetine is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,5-diiodothyropropionic acid	The metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Reboxetine.
4-Bromo-2,5-dimethoxyamphetamine	The risk or severity of adverse effects can be increased when Reboxetine is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-hydroxycoumarin	The metabolism of 4-hydroxycoumarin can be decreased when combined with Reboxetine.
4-Methoxyamphetamine	The risk or severity of adverse effects can be increased when Reboxetine is combined with 4-Methoxyamphetamine.
5-androstenedione	The metabolism of 5-androstenedione can be decreased when combined with Reboxetine.
5-methoxy-N,N-dimethyltryptamine	The risk or severity of adverse effects can be increased when Reboxetine is combined with 5-methoxy-N,N-dimethyltryptamine.
6-Deoxyerythronolide B	The metabolism of Reboxetine can be decreased when combined with 6-Deoxyerythronolide B.

Additional Data Available

Extended Description

Extended description of the mechanism of action and particular properties of each drug interaction.

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Severity

A severity rating for each drug interaction, from minor to major.

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Evidence Level

A rating for the strength of the evidence supporting each drug interaction.

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Action

An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions

Not Available

References

General References

Fleishaker JC: Clinical pharmacokinetics of reboxetine, a selective norepinephrine reuptake inhibitor for the treatment of patients with depression. Clin Pharmacokinet. 2000 Dec;39(6):413-27. [PubMed:11192474]
Edwards DM, Pellizzoni C, Breuel HP, Berardi A, Castelli MG, Frigerio E, Poggesi I, Rocchetti M, Dubini A, Strolin Benedetti M: Pharmacokinetics of reboxetine in healthy volunteers. Single oral doses, linearity and plasma protein binding. Biopharm Drug Dispos. 1995 Aug;16(6):443-60. [PubMed:7579027]
Wienkers LC, Allievi C, Hauer MJ, Wynalda MA: Cytochrome P-450-mediated metabolism of the individual enantiomers of the antidepressant agent reboxetine in human liver microsomes. Drug Metab Dispos. 1999 Nov;27(11):1334-40. [PubMed:10534319]
Kasper S, el Giamal N, Hilger E: Reboxetine: the first selective noradrenaline re-uptake inhibitor. Expert Opin Pharmacother. 2000 May;1(4):771-82. [PubMed:11249515]

External Links

PubChem Compound: 127151
PubChem Substance: 46504845
ChemSpider: 112870
ChEBI: 135342
ChEMBL: CHEMBL383921
Therapeutic Targets Database: DAP000720
PharmGKB: PA144614921
HET: 41X
Wikipedia: Reboxetine

ATC Codes

N06AX18 — Reboxetine

PDB Entries

4xnx

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
1	Completed	Basic Science	Amphetamine-Related Disorders / Moods Disorders / Substance-Related Disorders	1
1	Recruiting	Treatment	Incontinence, Fecal / Stress Urinary Incontinence (SUI)	1
1	Unknown Status	Treatment	Schizophrenic Disorders	1
2	Completed	Treatment	Major Depressive Disorder (MDD)	1
2	Completed	Treatment	Pain NOS	3
2	Recruiting	Treatment	Cataplexy Narcolepsy / Excessive Sleepiness / Narcolepsy	1
2	Terminated	Treatment	Diabetic Neuropathies	1
2	Terminated	Treatment	Pain NOS	4
2	Withdrawn	Treatment	Attention Deficit Disorder With Hyperactivity (ADHD)	1
3	Completed	Supportive Care	Bone Mineral Density Quantitative Trait Locus 7	1
3	Completed	Treatment	Fibromyalgia	1
3	Terminated	Treatment	Anxiety Disorders / Dementias / Depression / Psychosomatic Disorders / Schizophrenic Disorders	1
3	Terminated	Treatment	Fibromyalgia	2
4	Completed	Treatment	Cerebral Stroke	1
4	Unknown Status	Treatment	Abdominal Pain (AP) / Major Depressive Disorder (MDD) / Pain NOS	1
4	Unknown Status	Treatment	Depression	1
4	Unknown Status	Treatment	Schizophrenic Disorders	1
Not Available	Completed	Basic Science	Cognitive Performance in Major Depression	1
Not Available	Completed	Treatment	Healthy Volunteers	1
Not Available	Completed	Treatment	Major Depressive Disorder (MDD)	1
Not Available	Not Yet Recruiting	Basic Science	Healthy Volunteers	1

Pharmacoeconomics

Manufacturers: Not Available
Packagers: Not Available
Dosage forms: Not Available
Prices: Not Available
Patents: Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	170-171 °C (Mesylate salt)	Not Available
water solubility	8 mg/mL (Mesylate salt)	Not Available
logP	3.1	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0223 mg/mL	ALOGPS
logP	3.06	ALOGPS
logP	3.28	ChemAxon
logS	-4.2	ALOGPS
pKa (Strongest Basic)	7.91	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	4	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	39.72 Å²	ChemAxon
Rotatable Bond Count	6	ChemAxon
Refractivity	89.48 m³·mol^-1	ChemAxon
Polarizability	34.51 Å³	ChemAxon
Number of Rings	3	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET features

Property	Value	Probability
Human Intestinal Absorption	+	0.9968
Blood Brain Barrier	+	0.9381
Caco-2 permeable	+	0.575
P-glycoprotein substrate	Substrate	0.7914
P-glycoprotein inhibitor I	Inhibitor	0.8825
P-glycoprotein inhibitor II	Non-inhibitor	0.5968
Renal organic cation transporter	Non-inhibitor	0.5581
CYP450 2C9 substrate	Non-substrate	0.8237
CYP450 2D6 substrate	Non-substrate	0.9116
CYP450 3A4 substrate	Non-substrate	0.5402
CYP450 1A2 substrate	Non-inhibitor	0.9045
CYP450 2C9 inhibitor	Non-inhibitor	0.8063
CYP450 2D6 inhibitor	Non-inhibitor	0.5687
CYP450 2C19 inhibitor	Non-inhibitor	0.9026
CYP450 3A4 inhibitor	Inhibitor	0.6318
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.5218
Ames test	Non AMES toxic	0.9141
Carcinogenicity	Non-carcinogens	0.9083
Biodegradation	Not ready biodegradable	0.9372
Rat acute toxicity	2.0972 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Strong inhibitor	0.7754
hERG inhibition (predictor II)	Inhibitor	0.717

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Taxonomy

Description: This compound belongs to the class of organic compounds known as phenol ethers. These are aromatic compounds containing an ether group substituted with a benzene ring.
Kingdom: Organic compounds
Super Class: Benzenoids
Class: Phenol ethers
Sub Class: Not Available
Direct Parent: Phenol ethers
Alternative Parents: Phenoxy compounds / Aralkylamines / Alkyl aryl ethers / Morpholines / Oxacyclic compounds / Dialkylamines / Dialkyl ethers / Azacyclic compounds / Organopnictogen compounds / Hydrocarbon derivatives
Substituents: Phenoxy compound / Phenol ether / Alkyl aryl ether / Aralkylamine / Monocyclic benzene moiety / Morpholine / Oxazinane / Dialkyl ether / Secondary aliphatic amine / Ether
Molecular Framework: Aromatic heteromonocyclic compounds
External Descriptors: Not Available

Targets

Property	Measurement	pH	Temperature (°C)	References
Ki (nM)	0.3	7.4	37	19836247
Ki (nM)	11	N/A	N/A	12431845
Ki (nM)	15.8	N/A	N/A	11454918

Details1. Sodium-dependent noradrenaline transporter

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Norepinephrine:sodium symporter activity
Specific Function: Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name: SLC6A2
Uniprot ID: P23975
Uniprot Name: Sodium-dependent noradrenaline transporter
Molecular Weight: 69331.42 Da

References

Rauhut AS, Mullins SN, Dwoskin LP, Bardo MT: Reboxetine: attenuation of intravenous nicotine self-administration in rats. J Pharmacol Exp Ther. 2002 Nov;303(2):664-72. [PubMed:12388649]
Wilson AA, Johnson DP, Mozley D, Hussey D, Ginovart N, Nobrega J, Garcia A, Meyer J, Houle S: Synthesis and in vivo evaluation of novel radiotracers for the in vivo imaging of the norepinephrine transporter. Nucl Med Biol. 2003 Feb;30(2):85-92. [PubMed:12623106]
Lin KS, Ding YS, Kim SW, Kil KE: Synthesis, enantiomeric resolution, F-18 labeling and biodistribution of reboxetine analogs: promising radioligands for imaging the norepinephrine transporter with positron emission tomography. Nucl Med Biol. 2005 May;32(4):415-22. [PubMed:15878511]
Spivak B, Strous RD, Shaked G, Shabash E, Kotler M, Weizman A: Reboxetine versus fluvoxamine in the treatment of motor vehicle accident-related posttraumatic stress disorder: a double-blind, fixed-dosage, controlled trial. J Clin Psychopharmacol. 2006 Apr;26(2):152-6. [PubMed:16633143]
Mitchell HA, Ahern TH, Liles LC, Javors MA, Weinshenker D: The effects of norepinephrine transporter inactivation on locomotor activity in mice. Biol Psychiatry. 2006 Nov 15;60(10):1046-52. Epub 2006 Aug 7. [PubMed:16893531]
Kasper S, el Giamal N, Hilger E: Reboxetine: the first selective noradrenaline re-uptake inhibitor. Expert Opin Pharmacother. 2000 May;1(4):771-82. [PubMed:11249515]

Enzymes

Details1. Cytochrome P450 3A4

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate
Inhibitor

General Function: Vitamin d3 25-hydroxylase activity
Specific Function: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name: CYP3A4
Uniprot ID: P08684
Uniprot Name: Cytochrome P450 3A4
Molecular Weight: 57342.67 Da

References

Kuhn UD, Kirsch M, Merkel U, Eberhardt AM, Wenda B, Maurer I, Hartter S, Hiemke C, Volz HP, Balogh A: Reboxetine and cytochrome P450--comparison with paroxetine treatment in humans. Int J Clin Pharmacol Ther. 2007 Jan;45(1):36-46. doi: 10.5414/cpp45036. [PubMed:17256449]
Fleishaker JC: Clinical pharmacokinetics of reboxetine, a selective norepinephrine reuptake inhibitor for the treatment of patients with depression. Clin Pharmacokinet. 2000 Dec;39(6):413-27. [PubMed:11192474]

Details2. Cytochrome P450 2D6

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Steroid hydroxylase activity
Specific Function: Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name: CYP2D6
Uniprot ID: P10635
Uniprot Name: Cytochrome P450 2D6
Molecular Weight: 55768.94 Da

References

Wienkers LC, Allievi C, Hauer MJ, Wynalda MA: Cytochrome P-450-mediated metabolism of the individual enantiomers of the antidepressant agent reboxetine in human liver microsomes. Drug Metab Dispos. 1999 Nov;27(11):1334-40. [PubMed:10534319]
Kuhn UD, Kirsch M, Merkel U, Eberhardt AM, Wenda B, Maurer I, Hartter S, Hiemke C, Volz HP, Balogh A: Reboxetine and cytochrome P450--comparison with paroxetine treatment in humans. Int J Clin Pharmacol Ther. 2007 Jan;45(1):36-46. doi: 10.5414/cpp45036. [PubMed:17256449]

Transporters

Details1. P-glycoprotein 1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Xenobiotic-transporting atpase activity
Specific Function: Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name: ABCB1
Uniprot ID: P08183
Uniprot Name: Multidrug resistance protein 1
Molecular Weight: 141477.255 Da

References

Weiss J, Dormann SM, Martin-Facklam M, Kerpen CJ, Ketabi-Kiyanvash N, Haefeli WE: Inhibition of P-glycoprotein by newer antidepressants. J Pharmacol Exp Ther. 2003 Apr;305(1):197-204. [PubMed:12649369]

Drug created on June 13, 2005 07:24 / Updated on September 08, 2019 05:35

Reboxetine

Identification

Structure for Reboxetine (DB00234)

Pharmacology

Interactions

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Taxonomy

Targets

References

Enzymes

References

References

Transporters

References