Identification

Name
Agomelatine
Accession Number
DB06594
Type
Small Molecule
Groups
Approved, Investigational
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 Ltd. 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 July 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
Thumb
Synonyms
  • Agomelatina
  • Valdoxan
External IDs
S-20098 / S20098
International/Other Brands
Melitor (Servier Laboratories Ltd.) / Valdoxan (Servier Laboratories Ltd.)
Categories
UNII
137R1N49AD
CAS number
138112-76-2
Weight
Average: 243.301
Monoisotopic: 243.125928793
Chemical Formula
C15H17NO2
InChI Key
YJYPHIXNFHFHND-UHFFFAOYSA-N
InChI
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)
IUPAC Name
N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide
SMILES
COC1=CC2=C(C=CC=C2CCNC(C)=O)C=C1

Pharmacology

Indication

Agomelatine is indicated for the treatment of major depressive episodes in adults.

Pharmacodynamics

Agomelatine resynchronises circadian rhythms in animal models of delayed sleep phase syndrome and other circadian rhythm disruptions. It increases noradrenaline and dopamine release specifically in the frontal cortex and has no influence on the extracellular levels of serotonin. Agomelatine has shown an antidepressant-like effect in animal models of depression (learned helplessness test, despair test, chronic mild stress) as well as in models with circadian rhythm desynchronisation and in models related to stress and anxiety. In humans, agomelatine has positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset. Controlled studies in humans have shown that agomelatine is as effective as the SSRI antidepressants paroxetine and sertraline in the treatment of major depression

Mechanism of action

The novel antidepressant agent, agomelatine, behaves as an agonist at melatonin receptors (MT1 and MT2) and as an antagonist at serotonin (5-HT)(2C) receptors.

TargetActionsOrganism
A5-hydroxytryptamine receptor 2C
antagonist
Human
AMelatonin receptor type 1A
agonist
Human
AMelatonin receptor type 1B
agonist
Human
Absorption

Bioavailability is less than 5%.

Volume of distribution
Not Available
Protein binding

> 95%

Metabolism

Hepatic (90% CYP1A2 and 10% CYP2C9).

Route of elimination
Not Available
Half life

<2 hours

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

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Agomelatine.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Agomelatine.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Agomelatine is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3-isobutyl-1-methyl-7H-xanthineThe serum concentration of 3-isobutyl-1-methyl-7H-xanthine can be increased when it is combined with Agomelatine.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when 3,4-Methylenedioxyamphetamine is combined with Agomelatine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Agomelatine.
4-hydroxycoumarinThe risk or severity of adverse effects can be increased when Agomelatine is combined with 4-hydroxycoumarin.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Methoxyamphetamine is combined with Agomelatine.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Agomelatine is combined with 5-methoxy-N,N-dimethyltryptamine.
6-O-benzylguanineThe serum concentration of 6-O-benzylguanine can be increased when it is combined with Agomelatine.
Food Interactions
Not Available

References

Synthesis Reference

Jean-Claude Souvie, Isaac Gonzalez Blanco, Gilles Thominot, Genevieve Chapuis, Stephane Horvath, Gerard Damien, "Process for the synthesis and crystalline form of agomelatine." U.S. Patent US20050182276, issued August 18, 2005.

US20050182276
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. 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]
  3. 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]
External Links
Human Metabolome Database
HMDB0015636
KEGG Drug
D02578
PubChem Compound
82148
PubChem Substance
175427076
ChemSpider
74141
BindingDB
50035179
ChEBI
134990
ChEMBL
CHEMBL10878
PharmGKB
PA165958363
HET
AWY
Wikipedia
Agomelatine
ATC Codes
N06AX22 — Agomelatine
PDB Entries
5q1s
MSDS
Download (15.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedPreventionMajor Depressive Disorder (MDD)1
3CompletedTreatmentMajor Depressive Disorder (MDD)6
3TerminatedTreatmentAnxiety Disorders / Dementias / Depression / Psychosomatic Disorders / Schizophrenic Disorders1
3TerminatedTreatmentMajor Depressive Disorder (MDD)1
4CompletedTreatmentDelusional Disorder / Schizoaffective Disorders / Schizophrenia-spectrum-disorders / Schizophrenic Disorders1
4Unknown StatusTreatmentMajor Depressive Disorder (MDD)1
Not AvailableCompletedNot AvailableDepressive Disorders1
Not AvailableCompletedNot AvailableFibromyalgia / Major Depressive Disorder (MDD)1
Not AvailableWithdrawnHealth Services ResearchMajor Depressive Disorder (MDD)1

Pharmacoeconomics

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

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility~0.5 mg/ml in 1:1 EtOH:PBS (pH 7.2); ~30 mg/ml in EtOH, DMF & DMSONot Available
Predicted Properties
PropertyValueSource
Water Solubility0.00776 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
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9923
Caco-2 permeable+0.7464
P-glycoprotein substrateSubstrate0.5356
P-glycoprotein inhibitor INon-inhibitor0.6423
P-glycoprotein inhibitor IINon-inhibitor0.6412
Renal organic cation transporterNon-inhibitor0.5291
CYP450 2C9 substrateNon-substrate0.7647
CYP450 2D6 substrateSubstrate0.7219
CYP450 3A4 substrateSubstrate0.7276
CYP450 1A2 substrateInhibitor0.8543
CYP450 2C9 inhibitorNon-inhibitor0.7758
CYP450 2D6 inhibitorNon-inhibitor0.5445
CYP450 2C19 inhibitorNon-inhibitor0.7478
CYP450 3A4 inhibitorNon-inhibitor0.7746
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5467
Ames testAMES toxic0.6796
CarcinogenicityNon-carcinogens0.8958
BiodegradationNot ready biodegradable0.8296
Rat acute toxicity2.2095 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9236
hERG inhibition (predictor II)Inhibitor0.6648
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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
MS/MS Spectrum - , positiveLC-MS/MSsplash10-000i-1910000000-17cebfbe6b9845617b5d

Taxonomy

Description
This compound belongs to the class of organic compounds known as n-acetyl-2-arylethylamines. These are compounds containing an acetamide group that is N-linked to an arylethylamine.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Carboxylic acid 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
Molecular Framework
Aromatic homopolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including ergot alkaloid derivatives, 1-2,5,-dimethoxy-4-...
Gene Name
HTR2C
Uniprot ID
P28335
Uniprot Name
5-hydroxytryptamine receptor 2C
Molecular Weight
51820.705 Da
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]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Organic cyclic compound binding
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 ...
Gene Name
MTNR1A
Uniprot ID
P48039
Uniprot Name
Melatonin receptor type 1A
Molecular Weight
39374.315 Da
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]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Melatonin receptor activity
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 ...
Gene Name
MTNR1B
Uniprot ID
P49286
Uniprot Name
Melatonin receptor type 1B
Molecular Weight
40187.895 Da
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]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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 un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Yasar U: Does celecoxib inhibit agomelatine metabolism via CYP2C9 or CYP1A2? Drug Des Devel Ther. 2018 Jul 11;12:2169-2172. doi: 10.2147/DDDT.S169358. eCollection 2018. [PubMed:30034221]
  2. Manikandan S: Agomelatine: A novel melatonergic antidepressant. J Pharmacol Pharmacother. 2010 Jul;1(2):122-3. doi: 10.4103/0976-500X.72369. [PubMed:21350627]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
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]

Drug created on March 19, 2008 10:39 / Updated on November 05, 2018 17:49