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Agomelatine

July 24, 2017
Common Name

Agomelatine Description

Agomelatine is structurally closely related to melatonin. Agomelatine is a potent agonist at melatonin receptors and an antagonist at serotonin-2C (5-HT2C) receptors, tested in an animal model of depression. Agomelatine was discovered and developed by the European pharmaceutical company Servier Laboratories Lspan. Servier continue to develop the drug and conduct phase III trials in the European Union. In 2005 Servier submitted Agomelatine to the European Medicines Agency (EMEA). On 27 Jliy 2006 the Committee for Medical Products for Human Use (CHMP) of the EMEA recommended a refusal of the marketing authorisation of Valdoxan/Thymanax. The major concern was that efficacy had not been sufficiently shown. In 2006 Servier sold the rights to develop Agomelatine in the US to Novartis. The development for the US market was discontinued in October 2011. It is currently sold in Australia under the Valdoxan trade name. Structure

MOLSDF3D-SDFPDBSMILESInChI View 3D Structure

Synonyms

Value Source ValdoxanKegg S-20098HMDB S20098HMDB N-(2-(7-Methoxy-1-naphthyl)ethyl)acetamideMeSH ThymanaxMeSH ago 178MeSH ago-178MeSH

Chemical Formlia

C15H17NO2 Average Molecliar Weight

243.301 Monoisotopic Molecliar Weight

243.125928793 IUPAC Name

N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide Traditional Name

agomelatine CAS Registry Number

138112-76-2 SMILES

COC1=CC2=C(C=CC=C2CCNC(C)=O)C=C1

InChI Identifier

InChI=1S/C15H17NO2/c1-11(17)16-9-8-13-5-3-4-12-6-7-14(18-2)10-15(12)13/h3-7,10H,8-9H2,1-2H3,(H,16,17)

InChI Key

YJYPHIXNFHFHND-UHFFFAOYSA-N Chemical Taxonomy Description

This compound belongs to the class of chemical entities known as n-acetyl-2-arylethylamines. These are compounds containing an acetamide group that is N-linked to an arylethylamine. Kingdom

Chemical entities Super Class

Organic compounds Class

Organic acids and derivatives Sub Class

Carboxylic acids and derivatives Direct Parent

N-acetyl-2-arylethylamines Alternative Parents

  • Naphthalenes
  • Anisoles
  • Alkyl aryl ethers
  • Secondary carboxylic acid amides
  • Organopnictogen compounds
  • Organonitrogen compounds
  • Organic oxides
  • Hydrocarbon derivatives
  • Carbonyl compounds

    • Substituents

  • N-acetyl-2-arylethylamine
  • Naphthalene
  • Anisole
  • Alkyl aryl ether
  • Benzenoid
  • Secondary carboxylic acid amide
  • Ether
  • Organic oxide
  • Organooxygen compound
  • Organonitrogen compound
  • Organopnictogen compound
  • Organic nitrogen compound
  • Carbonyl group
  • Organic oxygen compound
  • Hydrocarbon derivative
  • Aromatic homopolycyclic compound

    • Molecliar Framework

    Aromatic homopolycyclic compounds External Descriptors

    Not Available Ontology Status

    Expected but not Quantified Origin

  • Drug

    • Biofunction

  • Antidepressants

    • Application

  • Pharmaceutical

    • Cellliar locations

  • Membrane

    • Physical Properties State

    Solid Experimental Properties

    Property Value Reference Melting PointNot AvailableNot Available Boiling PointNot AvailableNot Available Water Solubility7.76e-03 g/LNot Available LogPNot AvailableNot Available

    Predicted Properties

    Property Value Source Water Solubility0.0078 mg/mLALOGPS logP2.83ALOGPS logP2.04ChemAxon logS-4.5ALOGPS pKa (Strongest Acidic)15.96ChemAxon pKa (Strongest Basic)-0.94ChemAxon Physiological Charge0ChemAxon Hydrogen Acceptor Count2ChemAxon Hydrogen Donor Count1ChemAxon Polar Surface Area38.33 Å2ChemAxon Rotatable Bond Count4ChemAxon Refractivity71.64 m3·mol-1ChemAxon Polarizability27.18 Å3ChemAxon Number of Rings2ChemAxon Bioavailability1ChemAxon Rlie of FiveYesChemAxon Ghose FilterYesChemAxon Vebers RlieYesChemAxon MDDR-like RlieYesChemAxon

    Spectra Spectra

    Spectrum Type Description Splash Key LC-MS/MS

    LC-MS/MS Spectrum – , positivesplash10-000i-1910000000-17cebfbe6b9845617b5dView in MoNA Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 10V, PositiveNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 20V, PositiveNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 40V, PositiveNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 10V, NegativeNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 20V, NegativeNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 40V, NegativeNot Available

    Biological Properties Cellliar Locations

  • Membrane

    • Biofluid Locations

  • Blood
  • Urine

    • Tissue Location

    Not Available Pathways

    Not Available Normal Concentrations

    Biofluid Status Value Age Sex Condition Reference Details BloodExpected but not Quantified Not AvailableNot AvailableTaking drug identified by DrugBank entry DB06594

  • 21059682

    • details UrineExpected but not Quantified Not AvailableNot AvailableTaking drug identified by DrugBank entry DB06594

  • 21059682

    • details

    Abnormal Concentrations

    Not Available Associated Disorders and Diseases Disease References

    None Associated OMIM IDs

    None External Links DrugBank ID

    DB06594 DrugBank Metabolite ID

    Not Available Phenol Explorer Compound ID

    Not Available Phenol Explorer Metabolite ID

    Not Available FoodDB ID

    Not Available KNApSAcK ID

    Not Available Chemspider ID

    74141 KEGG Compound ID

    Not Available BioCyc ID

    Not Available BiGG ID

    Not Available Wikipedia Link

    Agomelatine NuGOwiki Link

    HMDB15636 Metagene Link

    HMDB15636 METLIN ID

    Not Available PubChem Compound

    82148 PDB ID

    Not Available ChEBI ID

    108209

    Product: Flavoxate (hydrochloride)

    References Synthesis Reference Not Available Material Safety Data Sheet (MSDS) Not Available General References
    1. Millan MJ, Brocco M, Gobert A, Dekeyne A: Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade. Psychopharmacology (Berl). 2005 Feb;177(4):448-58. Epub 2004 Jul 31. [PubMed:15289999 ]
    2. Racagni G, Riva MA, Popoli M: The interaction between the internal clock and antidepressant efficacy. Int Clin Psychopharmacol. 2007 Oct;22 Suppl 2:S9-S14. [PubMed:17917564 ]
    3. Hardeland R, Poeggeler B, Srinivasan V, Trakht I, Pandi-Perumal SR, Cardinali DP: Melatonergic drugs in clinical practice. Arzneimittelforschung. 2008;58(1):1-10. doi: 10.1055/s-0031-1296459. [PubMed:18368944 ]

    Enzymes

    General function:
    Involved in monooxygenase 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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan.
    Gene Name:
    CYP2C9
    Uniprot ID:
    P11712
    Molecular weight:
    55627.365
    References
    1. Dolder CR, Nelson M, Snider M: Agomelatine treatment of major depressive disorder. Ann Pharmacother. 2008 Dec;42(12):1822-31. doi: 10.1345/aph.1L296. Epub 2008 Nov 25. [PubMed:19033480 ]
    General function:
    Involved in monooxygenase 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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen. Participates in the bioactivation of carcinogenic aromatic and heterocyclic amines. Catalizes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin.
    Gene Name:
    CYP1A2
    Uniprot ID:
    P05177
    Molecular weight:
    58406.915
    References
    1. Carney RM, Shelton RC: Agomelatine for the treatment of major depressive disorder. Expert Opin Pharmacother. 2011 Oct;12(15):2411-9. doi: 10.1517/14656566.2011.607812. [PubMed:21916789 ]
    General function:
    Involved in G-protein coupled receptor protein signaling pathway
    Specific function:
    This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system
    Gene Name:
    HTR2C
    Uniprot ID:
    P28335
    Molecular weight:
    51820.7
    References
    1. Millan MJ, Brocco M, Gobert A, Dekeyne A: Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade. Psychopharmacology (Berl). 2005 Feb;177(4):448-58. Epub 2004 Jul 31. [PubMed:15289999 ]
    General function:
    Involved in G-protein coupled receptor protein signaling pathway
    Specific function:
    High affinity receptor for melatonin. Likely to mediates the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that inhibit adenylate cyclase activity
    Gene Name:
    MTNR1A
    Uniprot ID:
    P48039
    Molecular weight:
    39374.3
    References
    1. Millan MJ, Brocco M, Gobert A, Dekeyne A: Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade. Psychopharmacology (Berl). 2005 Feb;177(4):448-58. Epub 2004 Jul 31. [PubMed:15289999 ]
    General function:
    Involved in G-protein coupled receptor protein signaling pathway
    Specific function:
    High affinity receptor for melatonin. Likely to mediates the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that inhibit adenylate cyclase activity
    Gene Name:
    MTNR1B
    Uniprot ID:
    P49286
    Molecular weight:
    40187.9
    References
    1. Millan MJ, Brocco M, Gobert A, Dekeyne A: Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade. Psychopharmacology (Berl). 2005 Feb;177(4):448-58. Epub 2004 Jul 31. [PubMed:15289999 ]

    PMID: 12922928

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