Agomelatine

Identification

Name

Agomelatine

Accession Number

DB06594

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 developed in Europe by Servier Laboratories Ltd. and submitted to the European Medicines Agency (EMA) in 2005. The Committee for Medical Products for Human Use (CHMP) recommended refusal of marketing authorization on 27 July 2006. 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.

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Agomelatine (DB06594)

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Weight

Average: 243.301
Monoisotopic: 243.125928793

Chemical Formula

C₁₅H₁₇NO₂

Synonyms

• Agomelatina
• Agomelatine

External IDs

• AGO 178
• AGO-178
• AGO178C
• S-20098
• S20098

Pharmacology

Indication

Agomelatine is indicated to treat major depressive episodes in adults.

Contraindications & Blackbox Warnings

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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 depression models, (learned helplessness test, despair test, and chronic mild stress) circadian rhythm desynchronisation, and in stress and anxiety models. 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.

Target	Actions	Organism
A5-hydroxytryptamine receptor 2C	antagonist	Humans
AMelatonin receptor type 1A	agonist	Humans
AMelatonin receptor type 1B	agonist	Humans

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

Adverse Effects

Learn about our commercial Adverse Effects data.

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Toxicity

Not Available

Affected organisms

Not Available

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
Unlock Additional Data
Abametapir	The serum concentration of Agomelatine can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Agomelatine can be increased when combined with Abatacept.
Abiraterone	The serum concentration of Agomelatine can be increased when it is combined with Abiraterone.
Acenocoumarol	The metabolism of Acenocoumarol can be decreased when combined with Agomelatine.
Acetaminophen	The metabolism of Agomelatine can be decreased when combined with Acetaminophen.
Acetazolamide	The risk or severity of adverse effects can be increased when Acetazolamide is combined with Agomelatine.
Acetohexamide	The metabolism of Acetohexamide can be decreased when combined with Agomelatine.
Acetophenazine	The risk or severity of adverse effects can be increased when Acetophenazine is combined with Agomelatine.
Acetylsalicylic acid	The metabolism of Acetylsalicylic acid can be decreased when combined with Agomelatine.
Aclidinium	Agomelatine may increase the central nervous system depressant (CNS depressant) activities of Aclidinium.

Additional Data Available

Extended Description
Extended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
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Severity
Severity
A severity rating for each drug interaction, from minor to major.
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Evidence Level
Evidence Level
A rating for the strength of the evidence supporting each drug interaction.
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Action
Action
An effect category for each drug interaction. Know how this interaction affects the subject drug.
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Food Interactions

Not Available

Products

International/Other Brands

Melitor (Servier Laboratories Ltd.) / Valdoxan (Servier Laboratories Ltd.)

Categories

ATC Codes

N06AX22 — Agomelatine

• N06AX — Other antidepressants
• N06A — ANTIDEPRESSANTS
• N06 — PSYCHOANALEPTICS
• N — NERVOUS SYSTEM

Drug Categories

• Acetates
• Acids, Acyclic
• Amides
• Antidepressive Agents
• Central Nervous System Agents
• Central Nervous System Depressants
• Cytochrome P-450 CYP1A2 Substrates
• Cytochrome P-450 CYP2C9 Inhibitors
• Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• Fatty Acids
• Fatty Acids, Volatile
• Lipids
• Melatonin, agonists
• Nervous System
• Psychoanaleptics
• Serotonin 5-HT2 Receptor Antagonists
• Serotonin 5-HT2C Receptor Antagonists
• Serotonin Agents
• Serotonin Receptor Antagonists

Chemical TaxonomyProvided by Classyfire

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

Alkyl aryl ether / Anisole / Aromatic homopolycyclic compound / Benzenoid / Carbonyl group / Ether / Hydrocarbon derivative / N-acetyl-2-arylethylamine / Naphthalene / Organic nitrogen compound

Molecular Framework

Aromatic homopolycyclic compounds

External Descriptors

Not Available

Chemical Identifiers

UNII

137R1N49AD

CAS number

138112-76-2

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

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

ZINC

ZINC000000005608

PharmGKB

PA165958363

PDBe Ligand

AWY

Wikipedia

Agomelatine

PDB Entries

5q1s / 6me5

MSDS

Download (15.5 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Delusional Disorder / Schizoaffective Disorders / Schizophrenia	1
4	Completed	Treatment	Major Depressive Disorder (MDD)	1
4	Not Yet Recruiting	Treatment	Circadian Rhythm Disorders / Depression / Parkinson's Disease (PD) / Sleep disorders and disturbances	1
4	Unknown Status	Treatment	Major Depressive Disorder (MDD)	1
3	Completed	Prevention	Major Depressive Disorder (MDD)	1
3	Completed	Treatment	Major Depressive Disorder (MDD)	6
3	Terminated	Treatment	Anxiety Disorders / Dementias / Depression / Psychosomatic Disorders / Schizophrenia	1
3	Terminated	Treatment	Major Depressive Disorder (MDD)	1
3	Withdrawn	Treatment	Depressive Disorder, Treatment-Resistant	1
2	Completed	Treatment	Obsessive Compulsive Disorder (OCD)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, coated	Oral	25 mg
Tablet, film coated	Oral
Tablet, coated		25 mg
Tablet
Tablet	Oral	25 mg

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	~0.5 mg/ml in 1:1 EtOH:PBS (pH 7.2); ~30 mg/ml in EtOH, DMF & DMSO	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.00776 mg/mL	ALOGPS
logP	2.83	ALOGPS
logP	2.04	ChemAxon
logS	-4.5	ALOGPS
pKa (Strongest Acidic)	15.96	ChemAxon
pKa (Strongest Basic)	-0.94	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	2	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	38.33 Å2	ChemAxon
Rotatable Bond Count	4	ChemAxon
Refractivity	71.64 m3·mol-1	ChemAxon
Polarizability	27.18 Å3	ChemAxon
Number of Rings	2	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	1.0
Blood Brain Barrier	+	0.9923
Caco-2 permeable	+	0.7464
P-glycoprotein substrate	Substrate	0.5356
P-glycoprotein inhibitor I	Non-inhibitor	0.6423
P-glycoprotein inhibitor II	Non-inhibitor	0.6412
Renal organic cation transporter	Non-inhibitor	0.5291
CYP450 2C9 substrate	Non-substrate	0.7647
CYP450 2D6 substrate	Substrate	0.7219
CYP450 3A4 substrate	Substrate	0.7276
CYP450 1A2 substrate	Inhibitor	0.8543
CYP450 2C9 inhibitor	Non-inhibitor	0.7758
CYP450 2D6 inhibitor	Non-inhibitor	0.5445
CYP450 2C19 inhibitor	Non-inhibitor	0.7478
CYP450 3A4 inhibitor	Non-inhibitor	0.7746
CYP450 inhibitory promiscuity	High CYP Inhibitory Promiscuity	0.5467
Ames test	AMES toxic	0.6796
Carcinogenicity	Non-carcinogens	0.8958
Biodegradation	Not ready biodegradable	0.8296
Rat acute toxicity	2.2095 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9236
hERG inhibition (predictor II)	Inhibitor	0.6648

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 GC-MS Spectrum - GC-MS	Predicted GC-MS	Not Available
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
MS/MS Spectrum - , positive	LC-MS/MS	splash10-000i-1910000000-17cebfbe6b9845617b5d

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Drug created on March 19, 2008 10:39 / Updated on June 12, 2020 10:52