Agomelatine
[CAS# 138112-76-2]

Identification

• Classification: API >> Nervous system medication >> Antidepressant, manic
• Name: Agomelatine
• Synonyms: N-(2-(7-Methoxynaphth-1-yl)ethyl)acetamide
• Molecular Formula: C₁₅H₁₇NO₂
• Molecular Weight: 243.30
• CAS Registry Number: 138112-76-2
• EC Number: 629-727-7
• SMILES: CC(=O)NCCC1=CC=CC2=C1C=C(C=C2)OC

Properties

• Density: 1.1±0.1 g/cm³ Calc.^*
• Boiling point: 478.8±28.0 °C 760 mmHg (Calc.)^*
• Flash point: 243.4±24.0 °C (Calc.)^*
• Solubility: DMSO 22mg/mL, Water $lessThan$1.2mg/mL, Ethanol $lessThan$1.2mg/mL (Expl.)
• Index of refraction: 1.582 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07;GHS09 Warning
• Risk Statements: H315-H319-H335-H400
• Safety Statements: P261-P264-P264+P265-P271-P273-P280-P302+P352-P304+P340-P305+P351+P338-P319-P321-P332+P317-P337+P317-P362+P364-P391-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute hazardous to the aquatic environment	Aquatic Acute	1	H400
Skin irritation	Skin Irrit.	2	H315
Eye irritation	Eye Irrit.	2	H319
Specific target organ toxicity - single exposure	STOT SE	3	H335
Specific target organ toxicity - single exposure	STOT SE	3	H336
Chronic hazardous to the aquatic environment	Aquatic Chronic	2	H411
Acute toxicity	Acute Tox.	4	H302

Discovery and Applications

Agomelatine is a synthetic compound developed as part of research into novel antidepressant therapies. It was discovered in the late 20th century during investigations into the pharmacological role of melatonin and its structural analogues. Researchers sought compounds that could mimic the action of melatonin at its receptors while also modulating other neurotransmitter systems relevant to mood regulation. Agomelatine emerged as a promising candidate because it showed strong affinity for melatonin MT₁ and MT₂ receptors while simultaneously acting as an antagonist at serotonin 5-HT_2C receptors. This dual mechanism distinguished it from conventional antidepressants, which primarily target monoamine reuptake systems.

The development of agomelatine followed the recognition that circadian rhythm disturbances play a role in depressive disorders. Melatonin itself regulates sleep–wake cycles but has limited therapeutic application because of its short half-life and broad effects. By modifying the molecular structure of melatonin, chemists were able to design agomelatine, which retained melatonergic activity but possessed improved pharmacokinetics and additional receptor interactions. Preclinical studies established that the compound could resynchronize circadian rhythms while enhancing dopaminergic and noradrenergic neurotransmission via 5-HT_2C receptor antagonism. These findings supported its further development as an antidepressant.

Agomelatine was introduced clinically in the early 2000s and received marketing authorization in Europe in 2009. Its therapeutic applications are primarily in the treatment of major depressive disorder, where it is administered orally. Clinical trials demonstrated that it was effective in reducing depressive symptoms and improving sleep quality without some of the side effects associated with other antidepressants, such as sexual dysfunction or significant weight gain. Because of its unique pharmacological profile, agomelatine has been particularly noted for restoring circadian rhythms in patients, making it useful in cases where sleep disturbances are a major component of the depressive illness.

Beyond depression, research has investigated the potential of agomelatine in the management of generalized anxiety disorder, bipolar depression, and other psychiatric conditions. Some studies have also examined its use in neurological disorders where circadian rhythm disruption is present, though its primary indication remains major depressive disorder. Its safety profile requires monitoring of liver function because of potential hepatotoxicity, which has limited its approval in certain regions.

The discovery and application of agomelatine illustrate the evolution of antidepressant research toward targeting multiple systems rather than focusing solely on monoamine reuptake. By acting simultaneously on melatonergic and serotonergic receptors, the compound represents a novel approach to managing depression, addressing both mood and circadian rhythm disturbances. Its development highlighted the value of integrating neurochemical and chronobiological perspectives in the design of therapeutic agents and expanded the pharmacological toolkit available for mood disorders.

References

2014. Changes in the prescribing pattern of antidepressant drugs in elderly patients: an Italian, nationwide, population-based study. European Journal of Clinical Pharmacology, 70(4).
DOI: 10.1007/s00228-013-1636-z

2020. Serotonin and its metabolites reduce oxidative stress in murine RAW264.7 macrophages and prevent inflammation. Journal of Physiology and Biochemistry, 76(1).
DOI: 10.1007/s13105-019-00714-3

2017. Melatonin, mitochondria, and the metabolic syndrome. Cellular and Molecular Life Sciences, 74(16).
DOI: 10.1007/s00018-017-2611-0