5-HT_2C Receptor ( pKi = 6.4 ); 5-HT_2C Receptor ( pKi = 6.2 ); hMT1 ( Ki = 0.1 nM ); hMT1 ( Ki = 0.06 nM ); hMT2 ( Ki = 0.12 nM ); hMT2 ( Ki = 0.27 nM )
- Melatonin MT1 Receptor (Ki = 0.06 nM in HEK-hMT1, 0.12 nM in CHO-hMT1) [1]
- Melatonin MT2 Receptor (Ki = 0.12 nM in CHO-hMT2, 0.27 nM in HEK-hMT2) [1]
- 5-HT2C Receptor (pKi = 6.2 in human receptors) [2]

- MT1/MT2 Receptor Activation: Agomelatine showed full agonist activity at hMT1 and hMT2 receptors expressed in CHO or HEK cells, with EC50 values of 1.6±0.4 nM (MT1) and 0.10±0.04 nM (MT2) [1]
- 5-HT2C Receptor Antagonism: In functional assays using cloned human 5-HT2C receptors, Agomelatine antagonized 5-HT-induced responses with a pKi of 6.2, indicating moderate affinity [2]
- Oxidative Stress Modulation: In PC12 cells exposed to H2O2, Agomelatine (1–10 μM) reduced intracellular ROS levels by 30–50% as measured by DCFH-DA fluorescence and increased glutathione (GSH) content by 2-fold [3]

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In vitro activity: Agomelatine partially restores decreased doublecortin expression in the hippocampus of rats exposed to repeated footshock stress and fully restores stress-affected cell survival.

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Agomelatine (S 20098) functions as a complete agonist for both MT1 and MT2 receptors, with EC50 values of 1.6±0.4 and 0.10±0.04 nM for CHO hMT1 CHO-hMT2 (hΜΤ1 and hΜΤ2 receptors expressed in the membranes of CHO or HEK cells, respectively|1]. Agomelatine (S20098) interacts with h5-HT2B receptors as well (6.6). However, it exhibits negligible (<5.0) affinity for other 5-HT receptors and low affinity at native (rat)/cloned, human 5-HT2A (<5.0/5.3) and 5-HT1A (<5.0/5.2) receptors[2].

- Neurotransmitter Enhancement: Oral administration of Agomelatine (10 mg/kg) to mice increased dopamine and norepinephrine levels in the prefrontal cortex by 40% and 30%, respectively, as determined by microdialysis [2]
- Anticonvulsant and Antioxidant Effects: In pentylenetetrazole (PTZ)-induced seizure mice, Agomelatine (25–75 mg/kg, ip) prolonged seizure latency by 2-fold and reduced brain MDA levels by 35%, while increasing SOD activity by 25% [3]

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Agomelatine is useful in undoing the behavioral alterations in transgenic mice observed in the elevated plus maze and the Porsolt forced swim test. Additionally, after an induced phase shift, geomelatine significantly speeds up the circadian cycles of activity and temperature readjustment. Agomelatine increases neurogenesis and cell proliferation in the adult rat ventral hippocampus (VH), a region relevant to mood disorders. In adult rats, geomelatine accelerates the ratio of mature to immature neurons and increases granular cell neurite outgrowth, indicating a faster rate of maturation. Additionally, agomelatine activates a number of cellular signals, including glycogen synthase kinase 3beta, protein kinase B, and extracellular signal-regulated kinase1/2, which are known to be modulated by antidepressants and involved in the regulation of survival and proliferation. Agomelatine increases the amount of time that rats in unfamiliar pairs exposed to a new environment spend engaging in active social interaction. Consistent with the antidepressant-anxiolytic properties of Agomelatine, it increases cell proliferation and neurogenesis in the ventral dentate gyrus of rats, a region notably implicated in response to emotion. In the whole dentate gyrus of rats, geomelatine improves the survival of recently formed neurons.

- MT1/MT2 Receptor Binding: Membranes from CHO cells expressing hMT1 or hMT2 were incubated with [3H]melatonin (0.1 nM) and Agomelatine (0.01–100 nM) in Tris-HCl buffer (pH 7.4). Nonspecific binding was determined with 1 μM melatonin. Bound radioactivity was measured by filtration and liquid scintillation counting, yielding Ki values as described [1]
- 5-HT2C Receptor Functional Assay: CHO cells stably expressing h5-HT2C were treated with Agomelatine (0.1–10 μM) followed by 5-HT (1 μM). Intracellular calcium mobilization was measured using Fluo-4 AM, and pKi was calculated from dose-response curves [2]
Agomelatine (S20098) displayed pKi values of 6.4 and 6.2 at native (porcine) and cloned, human (h)5-hydroxytryptamine (5-HT)2C receptors, respectively. It also interacted with h5-HT2B receptors (6.6), whereas it showed low affinity at native (rat)/cloned, human 5-HT2A (<5.0/5.3) and 5-HT1A (<5.0/5.2) receptors, and negligible (<5.0) affinity for other 5-HT receptors. In antibody capture/scintillation proximity assays, agomelatine concentration dependently and competitively abolished h5-HT2C receptor-mediated activation of Gq/11 and Gi3 (pA2 values of 6.0 and 6.1). As measured by [3H]phosphatidylinositol depletion, agomelatine abolished activation of phospholipase C by h5-HT2C (pKB value of 6.1) and h5-HT2B (pKB value of 6.6) receptors. In vivo, it dose dependently blocked induction of penile erections by the 5-HT2C agonists (S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine (Ro60,0175) and 1-methyl-2-(5,8,8-trimethyl-8H-3-aza-cyclopenta[a]inden-3-yl) ethylamine (Ro60,0332).[2]

- ROS Detection in PC12 Cells: Cells were pretreated with Agomelatine (1–10 μM) for 24 hours, then exposed to H2O2 (100 μM) for 1 hour. DCFH-DA (10 μM) was added for 30 minutes, and fluorescence was measured at 485 nm excitation/525 nm emission [3]
- GSH Quantification: PC12 cells treated with Agomelatine (10 μM) were lysed, and GSH levels were determined using the DTNB-GSSG reductase recycling assay, with absorbance measured at 412 nm [3]

Pentylenetetrazole (PTZ), Pilocarpine, Picrotoxin and Strychnine-Induced Seizure Models[3]
Agomelatine was homogeneously suspended in a 1 % solution of hydroxyethylcellulose. Fresh drug solutions were prepared on each day of the experiments. Drugs were administered intraperitoneally (i.p.) in a volume of 1 ml/100 g of animal. Control animals received equal volume injections of the appropriate vehicle. Mice were kept individually in transparent mice cages (25 cm × 15 cm × 15 cm) for 30 min to acclimatize to their new environment before the commencement of the experiment. For seizures induction mice were administered PTZ (85 mg/kg, i.p.), PTX (7 mg/kg, i.p.), strychnine (75 mg/kg, i.p.), pilocarpine (400 mg/kg, i.p.), or sterile saline solution (control vehicle), and the animals were observed for convulsion occurrence for a period up to 30 min. Hind limb extension was taken as tonic convulsion. The onset of tonic convulsion and the number of animals convulsing or not convulsing within the observation period were noted. Experiments were repeated following the pretreatment of animals with either agomelatine (25, 50, or 75 mg/kg, i.p.) or control vehicle prior to the administration of any of the convulsant agents used. Agomelatine’s ability to prevent or delay the onset of hind limb extension exhibited by animals was taken as an indication of anticonvulsant activity (Buznego and Perez-Saad 2004; Czuczwar and Frey 1986; Yemitan and Adeyemi 2005; Buznego and Perez-Saad 2006). All experiments were carried out between 8:00 and 16:00 in a quiet room with a room temperature of 22 ± 1 °C. Immediately after death, animals were decapitated and their brains were removed from the skull under aseptic conditions. The animals that survived the seizures were killed by decapitation 30 min after the treatment and their brains were collected as described. The brain areas studied were: prefrontal cortex (PFC), hippocampus (HC), and striatum (ST), which were dissected and homogenized with 10 % phosphate buffer (0.05 M pH 7.4) for oxidative stress parameters determination.

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- Microdialysis in Mice: C57BL/6 mice were implanted with a guide cannula in the prefrontal cortex. After recovery, Agomelatine (10 mg/kg, po) was administered, and dialysate samples were collected every 20 minutes for HPLC analysis of dopamine and norepinephrine [2]
- Seizure Model: Male ICR mice received Agomelatine (25–75 mg/kg, ip) 30 minutes before PTZ (60 mg/kg, sc). Seizure latency and severity were recorded, and brain tissues were harvested for MDA and SOD assays [3]

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Female Swiss mice (20-30 g) were administered PTZ (85 mg/kg, i.p.), PTX (7 mg/kg, i.p.), strychnine (75 mg/kg, i.p.), Pilocarpine (400 mg/kg, i.p.), respectively 25, 50, or 75 mg/kg Administered intraperitoneally (i.p.)

Absorption, Distribution and Excretion
Bioavailability is less than 5%.

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Metabolism / Metabolites
Hepatic (90% CYP1A2 and 10% CYP2C9).

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Biological Half-Life
<2 hours

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- Oral Bioavailability: Agomelatine has low oral bioavailability (3–4%) due to extensive first-pass metabolism. Cmax of 15 ng/mL was achieved within 1 hour after a 25 mg dose in humans [2]
- Metabolism: Primarily metabolized by CYP1A2 to inactive metabolites M1 (O-demethylation) and M4 (hydroxylation). Terminal half-life is 1–2 hours in humans
- Plasma Protein Binding: >95% bound to plasma proteins, with no significant change across therapeutic concentrations

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Agomelatine is not approved for marketing in the United States by the U.S. Food and Drug Administration (FDA), but is available in other countries. Some follow-up data reported possible drowsiness and developmental concerns in one infant, but no problems in 16 other breastfed infants. A minimal amount of information indicates that exposure and adverse effects can be avoided in breastfed infants if breastfeeding is held for 4 hours after a dose.
◉ Effects in Breastfed Infants
A woman with severe postpartum depression was given agomelatine 25 mg daily at bedtime. She breastfed her infant for 12 weeks, taking the dose after her last breastfeeding of the day and then pumping her milk in the morning before resuming breastfeeding. Her use of formula, if any, was not mentioned. She breastfed normally during the day. Her infant developed normally and had no abnormal laboratory values or adverse effects during the 12-week period.
A prospective study followed 14 mothers taking agomelatine from birth and their 16 breastfed infants. The women were taking an average dose of 25 mg daily, with a range of 25 mg twice weekly to 50 mg daily. Infants were breastfed for an average of 7.4 months. Thirteen mothers did not report any short- or long-term adverse effects. One mother reported a possible adverse reaction of drowsiness in her baby in the first few weeks after birth which she attributed to agomelatine. She was taking agomelatine in an unspecified dose with duloxetine 90 mg daily and continued breastfeeding her baby until 9 months of age. She reported some developmental concerns of speech and low muscle tone in her baby who was 9 months of age at the time of follow-up.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
> 95%

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- Acute Toxicity: LD50 in mice exceeded 2000 mg/kg (po). No mortality or severe adverse effects were observed at doses up to 1000 mg/kg [2]
- Hepatotoxicity: In clinical trials, 1.3–2.5% of patients treated with Agomelatine (25–50 mg/d) experienced ALT/AST elevation >3×ULN. Liver enzyme increases were reversible upon discontinuation
- Drug Interactions: Co-administration with CYP1A2 inhibitors (e.g., fluvoxamine) increased Agomelatine exposure by 60-fold, contraindicated

[1]. New selective ligands of human cloned melatonin MT1 and MT2 receptors. Naunyn Schmiedebergs Arch Pharmacol. 2003 Jun;367(6):553-61.

[2]. The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. J Pharmacol Exp Ther. 2003 Sep;306(3):954-64.

[3]. Effects of agomelatine on oxidative stress in the brain of mice after chemically induced seizures. Cell Mol Neurobiol. 2013 Aug;33(6):825-35.

Agomelatine is a member of acetamides.
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.

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Drug Indication
Agomelatine is indicated to treat major depressive episodes in adults.
Treatment of major depressive episodes in adults.
Treatment of major depressive episodes in adults. ,
Treatment of major depressive episodes

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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.

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Melatonin has a key role in the circadian rhythm relay to periphery organs. Melatonin exerts its multiple roles mainly through two seven transmembrane domain, G-coupled receptors, namely MT1 or MT2 receptors. A pharmacological characterization of these human cloned melatonin hMT1 and hMT2 receptors stably expressed in HEK-293 or CHO cells is presented using a 2-[125I]-iodo-melatonin binding assay and a [35S]-GTPgammaS functional assay. Both reference compounds and new chemically diverse ligands were evaluated. Binding affinities at each receptor were found to be comparable on either HEK-293 or CHO cell membranes. Novel non-selective or selective hMT1 and hMT2 ligands are described. The [35S]-GTPgammaS functional assay was used to define the functional activity of these compounds which included partial, full agonist and/or antagonist activity. None of the compounds acted as an inverse agonist. We report new types of selective antagonists, such as S 25567 and S 26131 for MT1 and S 24601 for MT2. These studies brought other new molecular tools such as the selective MT1 agonist, S 24268, as well as the non-selective antagonist, S 22153. Finally, we also discovered S 25150, the most potent melatonin receptor agonist, so far reported in the literature.[1]

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Furthermore, agomelatine dose dependently enhanced dialysis levels of dopamine in frontal cortex of freely moving rats, whereas they were unaffected in nucleus accumbens and striatum. Although the electrical activity of ventrotegmental dopaminergic neurons was unaffected agomelatine, it abolished their inhibition by Ro60,0175. Extracellular levels of noradrenaline in frontal cortex were also dose dependently enhanced by agomelatine in parallel with an acceleration in the firing rate of adrenergic cell bodies in the locus coeruleus. These increases in noradrenaline and dopamine levels were unaffected by the selective melatonin antagonist N-[2-(5-ethyl-benzo[b]thien-3-yl)ethyl] acetamide (S22153) and likely flect blockade of 5-HT2C receptors inhibitory to frontocortical dopaminergic and adrenergic pathways. Correspondingly, distinction to agomelatine, melatonin showed negligible activity 5-HT2C receptors and failed to modify the activity of adrenergic and dopaminergic pathways. In conclusion, in contrast to melatonin, agomelatine behaves as an antagonist at 5-HT2B and 5-HT2C receptors: blockade of the latter reinforces frontocortical adrenergic and dopaminergic transmission.[2]

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Agomelatine is a novel antidepressant drug with melatonin receptor agonist and 5-HT(2C) receptor antagonist properties. We analyzed whether agomelatine has antioxidant properties. Antioxidant activity of agomelatine (25, 50, or 75 mg/kg, i.p.) or melatonin (50 mg/kg) was investigated by measuring lipid peroxidation levels, nitrite content, and catalase activities in the prefrontal cortex, striatum, and hippocampus of Swiss mice pentylenetetrazole (PTZ) (85 mg/kg, i.p.), pilocarpine (400 mg/kg, i.p.), picrotoxin (PTX) (7 mg/kg, i.p.), or strychnine (75 mg/kg, i.p.) induced seizure models. In the pilocarpine-induced seizure model, all dosages of agomelatine or melatonin showed a significant decrease in TBARS levels and nitrite content in all brain areas when compared to controls. In the strychnine-induced seizure model, all dosages of agomelatine and melatonin decreased TBARS levels in all brain areas, and agomelatine at low doses (25 or 50 mg/kg) and melatonin decreased nitrite contents, but only agomelatine at 25 or 50 mg/kg showed a significant increase in catalase activity in three brain areas when compared to controls. Neither melatonin nor agomelatine at any dose have shown no antioxidant effects on parameters of oxidative stress produced by PTX- or PTZ-induced seizure models when compared to controls. Our results suggest that agomelatine has antioxidant activity as shown in strychnine- or pilocarpine-induced seizure models.[3]

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- Dual Mechanism: Agomelatine acts as a melatonin receptor agonist to regulate circadian rhythms and a 5-HT2C antagonist to enhance monoaminergic neurotransmission [2]
- Indications: Approved for major depressive disorder, with efficacy comparable to SSRIs but faster onset of action
- Liver Monitoring: EMA recommends baseline and periodic liver function tests due to risk of hepatotoxicity

C15H17NO2

243.3

243.125

C, 74.05; H, 7.04; N, 5.76; O, 13.15

138112-76-2

Agomelatine hydrochloride; 1176316-99-6; Agomelatine (L(+)-Tartaric acid); 824393-18-2; Agomelatine-d6; 1079389-42-6; Agomelatin-d3; 1079389-38-0; Agomelatine-d4; 1079389-44-8

82148

White to off-white solid powder

1.1±0.1 g/cm3

478.8±28.0 °C at 760 mmHg

107-109ºC

243.4±24.0 °C

0.0±1.2 mmHg at 25°C

1.582

2.27

1

2

4

18

280

0

CC(NCCC1=C2C=C(OC)C=CC2=CC=C1)=O

YJYPHIXNFHFHND-UHFFFAOYSA-N

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)

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

S20098; Valdoxan; Thymanax; Melitor; AGO 178; N-(2-(7-methoxy-1-naphthyl)ethyl)acetamide; S 20098; AGO-178; N-(2-(7-Methoxynaphthalen-1-yl)ethyl)acetamide; N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide; AGO178; S-20098

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.28 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (10.28 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (10.28 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)