Identification

Name
Viloxazine
Accession Number
DB09185
Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Description

Viloxazine is a selective norepinephrine reuptake inhibitor (NRI) that was used in some European countries as an antidepressant drug. It structurally differs from conventional tri- or tetra-cyclic antidepressants and it does not produce sedative anticholinergic or adrenergic effects in man [1]. While displaying amphetamine-like CNS stimulant effects, there is little evidence of drug dependence from viloxazine therapy. Viloxazine hydrochloride is a common active ingredient in drug formulation. It was discovered and brought to market in 1976 by Imperial Chemical Industries and in early 2000's, it was withdrawn from the market.

Structure
Thumb
Synonyms
  • 2-((2-Ethoxyphenoxy)methyl)morpholine
  • Viloxazina
  • Viloxazinum
Product Ingredients
IngredientUNIICASInChI Key
Viloxazine hydrochlorideOQW30I133235604-67-2HJOCKFVCMLCPTP-UHFFFAOYSA-N
International/Other Brands
Emovit / Vicilan / Vivalan / Vivarint
Categories
UNII
5I5Y2789ZF
CAS number
46817-91-8
Weight
Average: 237.299
Monoisotopic: 237.136493476
Chemical Formula
C13H19NO3
InChI Key
YWPHCCPCQOJSGZ-UHFFFAOYSA-N
InChI
InChI=1S/C13H19NO3/c1-2-15-12-5-3-4-6-13(12)17-10-11-9-14-7-8-16-11/h3-6,11,14H,2,7-10H2,1H3
IUPAC Name
2-[(2-ethoxyphenoxy)methyl]morpholine
SMILES
CCOC1=CC=CC=C1OCC1CNCCO1

Pharmacology

Indication

Indicated for the treatment of clinical depression.

Structured Indications
Not Available
Pharmacodynamics

Viloxazine is a selective noradrenaline reuptake inhibitor (NRI) with minimal inhibitory effect on the reuptake of 5-HT. It is also shown to upregulate the levels of GABA-B receptors in the rat frontal cortex. It is shown to form a complex with the human norepinephrine transporter (hNET) [8]. The S(-)-stereoisomer of viloxazine exhibits more potent pharmacological actions [9].

Mechanism of action

Viloxazine inhibits noradrenaline uptake in rat and mouse heart tissue and has a weak effect on the uptake of 5-HT [1]. In a docking study, the amino group of viloxazine points towards Asp75 in the drug binding pocket of the transporter and forms hydrogen bonds with Phe72, Asp75 and Phe317. The rest of the drug molecule forms hydrophobic interactions with other key residues in the binding pocket [8].

TargetActionsOrganism
ASodium-dependent noradrenaline transporter
inhibitor
Human
Absorption

Viloxazine is rapidly and almost completely absorbed following oral administration. The peak plasma concentration (Cmax) ranges between 540 and 1,600 ng/mL and the mean time to reach Cmax is approximately 86 minutes [6]. Increase in plasma drug concentration is dose-proportional [1].

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Viloxazine is thought to be extensively metabolized into 5-hydroxy derivative and glucuronidated phenol. Other detected metabolites include 4-hydroxy isomer and its glucuronide, together with the sulphate conjugates of the phenolic metabolites [1].

Route of elimination

Viloxazine is rapidly eliminated via urine and about 2% of the administered dose is recovered in the feces. About 12-15% of the total drug is eliminated as unchanged parent drug [1].

Half life

Elimination half life is approximately 3-4 hours [6].

Clearance
Not Available
Toxicity

Common adverse effects are nausea and vomiting. Other side effects are dry mouth, dizziness, headache, drowsiness, sleep disturbances, bad taste, anorexia, heartburn and indigestion, constipation, diarrhoea, ataxia, tremor, dyskinesia, paraesthesia, confusion, restlessness, irritability, hypomania and mania, sweating, palpitation, tachycardia, increased and decreased blood pressure, pruritus and skin rashes [6].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
VemurafenibThe risk or severity of QTc prolongation can be increased when Vemurafenib is combined with Viloxazine.Approved
Food Interactions
Not Available

References

General References
  1. Pinder RM, Brogden RN, Speight TM, Avery GS: Viloxazine: a review of its pharmacological properties and therapeutic efficacy in depressive illness. Drugs. 1977 Jun;13(6):401-21. [PubMed:324751]
  2. Lippman W, Pugsley TA: Effects of viloxazine, an antidepressant agent, on biogenic amine uptake mechanisms and related activities. Can J Physiol Pharmacol. 1976 Aug;54(4):494-509. [PubMed:974878]
  3. Sebjanic V, Grombein S: Viloxazine (Vivalan ICI) in depression: results of a field trial of 276 patients in neuropsychiatric practice. Adv Biochem Psychopharmacol. 1982;32:113-20. [PubMed:7046360]
  4. Case DE, Reeves PR: The disposition and metabolism of I.C.I. 58,834 (viloxazine) in humans. Xenobiotica. 1975 Feb;5(2):113-29. [PubMed:1154799]
  5. Thomare P, Bourin M, Kergueris MF, Ortega A, Larousse C: Effects of administration route on pharmacokinetics of viloxazine in the rabbit. Methods Find Exp Clin Pharmacol. 1992 Mar;14(2):125-9. [PubMed:1598024]
  6. Kergueris MF, Bourin M, Ribeyrol M, Beneroso N, Normand YL, Larousse C: Comparative pharmacokinetic study of conventional and sustained-release viloxazine in normal volunteers. Neuropsychobiology. 1989;20(3):136-40. [PubMed:2761683]
  7. Vandel B, Vandel S, Jounet JM, Blum D: Pharmacokinetics of viloxazine hydrochloride in man. Eur J Drug Metab Pharmacokinet. 1982 Jan-Mar;7(1):65-8. [PubMed:7067726]
  8. Zheng G, Xue W, Wang P, Yang F, Li B, Li X, Li Y, Yao X, Zhu F: Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study. Sci Rep. 2016 May 27;6:26883. doi: 10.1038/srep26883. [PubMed:27230580]
  9. Danchev ND, Rozhanets VV, Zhmurenko LA, Glozman OM, Zagorevskii VA: [Behavioral and radioreceptor analysis of viloxazine stereoisomers]. Biull Eksp Biol Med. 1984 May;97(5):576-8. [PubMed:6326891]
External Links
KEGG Drug
D08673
PubChem Compound
5666
PubChem Substance
310265093
ChemSpider
5464
BindingDB
50025691
ChEBI
94405
ChEMBL
CHEMBL306700
Wikipedia
Viloxazine
ATC Codes
N06AX09 — Viloxazine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2CompletedOtherAdhd1

Pharmacoeconomics

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

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility1.24 mg/mLALOGPS
logP1.71ALOGPS
logP1.49ChemAxon
logS-2.3ALOGPS
pKa (Strongest Basic)8.19ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area39.72 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity65.2 m3·mol-1ChemAxon
Polarizability26.32 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot 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 / Alkyl aryl ethers / Morpholines / Oxacyclic compounds / Dialkylamines / Dialkyl ethers / Azacyclic compounds / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Phenoxy compound / Phenol ether / Alkyl aryl ether / Monocyclic benzene moiety / Morpholine / Oxazinane / Dialkyl ether / Secondary aliphatic amine / Ether / Oxacycle
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
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
  1. Zheng G, Xue W, Wang P, Yang F, Li B, Li X, Li Y, Yao X, Zhu F: Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study. Sci Rep. 2016 May 27;6:26883. doi: 10.1038/srep26883. [PubMed:27230580]

Drug created on October 16, 2015 13:16 / Updated on December 01, 2017 17:21