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]

Agomelatine (S-20098; BAN, rINN; Valdoxan, Melitor, Thymanax) is a dual-action compound with high affinity for two classes of targets:
- Melatonin MT1 receptor (human recombinant): Ki = 0.1 nM (using [³H]-melatonin as the radioligand); EC50 = 0.2 nM (functional agonism in cAMP inhibition assay) [1]
- Melatonin MT2 receptor (human recombinant): Ki = 0.3 nM (using [³H]-melatonin as the radioligand); EC50 = 0.5 nM (functional agonism in cAMP inhibition assay) [1]
- 5-HT2C receptor (human recombinant): Ki = 63 nM (using [³H]-mesulergine as the radioligand); IC50 = 116 nM (antagonism of 5-HT-induced calcium mobilization) [2]
- No significant binding to 5-HT1A/2A/3/7 receptors (Ki > 1000 nM) or melatonin-related enzymes (e.g., AANAT, Ki > 1000 nM) [1,2]

- 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]

---

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.

---

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].

---

MT1/MT2 receptor-mediated cAMP inhibition: HEK293 cells transfected with human MT1 or MT2 receptors were treated with Agomelatine (0.01–10 nM) for 30 minutes, then stimulated with 10 μM forskolin. For MT1: 0.5 nM Agomelatine inhibited forskolin-induced cAMP accumulation by 50% (EC50 = 0.2 nM); for MT2: 1 nM Agomelatine achieved 50% inhibition (EC50 = 0.5 nM) (ELISA detection) [1]
- 5-HT2C receptor antagonism: HEK293 cells expressing human 5-HT2C receptors were pre-treated with Agomelatine (10–1000 nM) for 30 minutes, then stimulated with 1 μM 5-HT. At 100 nM, 5-HT-induced intracellular calcium elevation was inhibited by 70%; IC50 = 116 nM (Fura-2 AM fluorescence ratiometry, 340/380 nm) [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]

---

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.

---

Enhancement of frontocortical dopaminergic and adrenergic activity in rats: Male Sprague-Dawley rats (250–300 g) were orally administered Agomelatine (5, 10, 20 mg/kg). At 10 mg/kg, frontal cortex dopamine levels increased by 45% and norepinephrine levels increased by 38% vs. vehicle (HPLC-ECD detection) 2 hours post-dose [2]
- Attenuation of oxidative stress in chemically induced seizure mice: Male Swiss albino mice (20–25 g) were intraperitoneally (i.p.) injected with pentylenetetrazole (PTZ, 80 mg/kg) to induce seizures, then orally treated with Agomelatine (5, 10, 20 mg/kg) once daily for 7 days before PTZ injection. At 10 mg/kg:
- Brain malondialdehyde (MDA, oxidative stress marker) levels decreased by 30% vs. PTZ-only group [3]
- Brain superoxide dismutase (SOD, antioxidant enzyme) activity increased by 25% vs. PTZ-only group [3]

- 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]

---

Human MT1/MT2 Receptor Binding Assay: The 200 μL reaction system contained 50 μg of membrane protein from HEK293 cells expressing human MT1 or MT2 receptors, 0.5 nM [³H]-melatonin (radioligand), and Agomelatine (0.001–10 nM). Incubated at 25°C for 60 minutes in 50 mM Tris-HCl (pH 7.4, 10 mM MgCl₂, 0.1% BSA). Terminated by filtration through glass fiber filters pre-soaked in 0.3% polyethyleneimine. Filters washed 3× with cold assay buffer, radioactivity measured via liquid scintillation counter. Non-specific binding determined with 10 μM unlabeled melatonin; Ki calculated via Cheng-Prusoff equation [1]
- Human 5-HT2C Receptor Binding Assay: The 200 μL reaction system contained 50 μg of membrane protein from HEK293 cells expressing human 5-HT2C receptors, 0.5 nM [³H]-mesulergine (radioligand), and Agomelatine (1–1000 nM). Incubated at 37°C for 45 minutes in 50 mM Tris-HCl (pH 7.4, 120 mM NaCl, 5 mM KCl). Terminated by filtration through glass fiber filters. Filters washed 3× with cold buffer, radioactivity quantified. Non-specific binding determined with 10 μM unlabeled mesulergine; Ki calculated via Cheng-Prusoff equation [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]

---

HEK293-MT1/MT2 cAMP Inhibition Assay: HEK293 cells stably expressing human MT1 or MT2 receptors were seeded in 24-well plates (2×10⁵ cells/well) and cultured in DMEM + 10% FBS for 24 hours. Medium replaced with serum-free DMEM containing 0.5 mM IBMX (phosphodiesterase inhibitor). Agomelatine (0.01–10 nM) added, incubated at 37°C for 30 minutes, then 10 μM forskolin added for 15 minutes. Cells lysed with 0.1 M HCl, cAMP levels measured via competitive ELISA. Inhibition % calculated vs. forskolin-only group [1]
- HEK293-5-HT2C Calcium Mobilization Assay: HEK293 cells expressing human 5-HT2C receptors were seeded in 96-well black-walled plates (5×10⁴ cells/well) and cultured for 24 hours. Medium replaced with Krebs-Ringer buffer containing 2 μM Fura-2 AM, loaded at 37°C for 45 minutes. Agomelatine (10–1000 nM) added, incubated 30 minutes, then 1 μM 5-HT added. Fluorescence intensity (excitation 340/380 nm, emission 510 nm) measured; 340/380 nm ratio used to quantify calcium levels [2]

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.) 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.

---

- 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]

---

---

Rat Frontocortical Neurotransmitter Assay: Male Sprague-Dawley rats (8 weeks old, 250–300 g) housed at 22±2°C (12 h light/dark cycle) were fasted for 12 hours before dosing. Randomized into 4 groups (n=6/group):
1. Vehicle: Oral gavage of 0.5% carboxymethylcellulose sodium (CMC-Na, 10 mL/kg);
2. Agomelatine 5 mg/kg: Oral gavage of Agomelatine (5 mg/kg, dissolved in 0.5% CMC-Na);
3. Agomelatine 10 mg/kg: Oral gavage of Agomelatine (10 mg/kg);
4. Agomelatine 20 mg/kg: Oral gavage of Agomelatine (20 mg/kg).
Two hours post-dose, rats were euthanized; frontal cortex dissected, homogenized in ice-cold perchloric acid. Dopamine and norepinephrine levels measured via HPLC-ECD [2]
- PTZ-Induced Seizure Mouse Model: Male Swiss albino mice (6–8 weeks old, 20–25 g) housed at 22±2°C (12 h light/dark cycle) were randomized into 4 groups (n=8/group):
1. Vehicle + Saline: Oral gavage of 0.5% CMC-Na (10 mL/kg/day) for 7 days + i.p. saline on day 7;
2. Vehicle + PTZ: Oral gavage of 0.5% CMC-Na for 7 days + i.p. PTZ (80 mg/kg) on day 7;
3. Agomelatine 10 mg/kg + PTZ: Oral gavage of Agomelatine (10 mg/kg/day) for 7 days + i.p. PTZ on day 7;
4. Agomelatine 20 mg/kg + PTZ: Oral gavage of Agomelatine (20 mg/kg/day) for 7 days + i.p. PTZ on day 7.
Twenty-four hours after PTZ injection, mice were euthanized; brains dissected to measure MDA levels (thiobarbituric acid method) and SOD activity (xanthine oxidase method) [3]

Absorption, Distribution and Excretion
Bioavailability is less than 5%. Metabolism/Metabolites Hepatic metabolism (90% via CYP1A2, 10% via CYP2C9). Biological Half-Life <2 hours> - Oral bioavailability: Due to extensive first-pass metabolism, agomelatine has low oral bioavailability (3-4%). In humans, peak plasma concentration (Cmax) reaches 15 ng/mL within 1 hour after administration of 25 mg [2]. - Metabolism: Primarily metabolized via CYP1A2 to inactive metabolites M1 (O-demethylation) and M4 (hydroxylation). The terminal half-life in humans is 1-2 hours. - Plasma protein binding: >95% bound to plasma proteins, with no significant variation across the therapeutic concentration range.

---

Plasma protein binding: Agomelatine has a protein binding rate of 90% in human plasma (ultrafiltration, plasma concentration range: 0.1-10 μg/mL)[1]
-Oral bioavailability: In male Sprague-Dawley rats, the oral bioavailability of agomelatine (10 mg/kg) was 35%, while the oral bioavailability of intravenous injection (5 mg/kg) was 35%[2]
-Plasma pharmacokinetics: In rats intravenously injected with 5 mg/kg agomelatine: Cmax = 1.8 μg/mL, Tmax = 5 min, elimination half-life (t1/2) = 2.3 h. Oral administration of 10 mg/kg: Cmax = 0.5 μg/mL, Tmax = 1.2 h, t1/2 = 2.8 h (HPLC-UV detection) [2]

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Agomelatine has not yet received marketing approval from the U.S. Food and Drug Administration (FDA), but it is available in other countries. Some follow-up data show that one infant may have experienced drowsiness and developmental problems, but 16 other breastfed infants did not experience any problems. Limited information suggests that breastfed infants may avoid exposure to the drug and adverse reactions if breastfeeding is stopped within 4 hours of taking the medication.
◉ Effects on Breastfed Infants
A woman with severe postpartum depression took 25 mg of agomelatine daily at bedtime. She breastfed her infant for 12 weeks, taking the medication after the last breastfeeding session each day, and then pumping breast milk in the morning before continuing breastfeeding. It was not mentioned whether she used formula. She breastfed normally during the day. Her infant developed normally and did not experience any abnormal laboratory findings or adverse reactions during the 12 weeks. A prospective study followed 14 mothers who took agomelatine from birth and their 16 breastfed infants. The mothers took an average of 25 mg of agomelatine daily, ranging from 25 mg twice weekly to 50 mg daily. The infants were breastfed for an average of 7.4 months. Thirteen mothers reported no short- or long-term adverse reactions. One mother reported that her infant experienced drowsiness in the first few weeks after birth, which she believed was related to agomelatine. This mother was taking both agomelatine (dosage not specified) and duloxetine (90 mg daily) and continued breastfeeding until her infant was 9 months old. She reported that her 9-month-old infant had some language development problems and hypotonia at follow-up. ◉ Effects on breastfeeding and lactation
As of the revision date, no relevant published information was found.

---

Protein binding
> 95%

---

- Acute toxicity: The LD50 in mice exceeds 2000 mg/kg (orally). No deaths or serious adverse reactions were observed at doses up to 1000 mg/kg [2]
- Hepatotoxicity: In clinical trials, 1.3% to 2.5% of patients treated with agomelatine (25-50 mg/d) experienced ALT/AST elevations exceeding 3 times the upper limit of normal. The elevation of liver enzymes was reversible after discontinuation of the drug.
- Drug interactions: Concomitant use with CYP1A2 inhibitors (e.g., fluvoxamine) can increase agomelatine exposure by 60-fold and is contraindicated.

---

Acute in vivo toxicity: The LD50 of agomelatine administered intraperitoneally in male ICR mice was 420 mg/kg. Mice receiving doses >300 mg/kg experienced transient sedation and ataxia, while no deaths were observed at doses ≤200 mg/kg [1]
- Subacute toxicity: Rats were orally administered agomelatine (10, 30, 100 mg/kg/day) for 28 days, with no significant changes in body weight (change <5%), serum ALT/AST/BUN/creatinine levels, or pathological damage to liver, kidney, or brain tissue [2]

[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 belongs to the acetamide class of compounds. Its structure is closely related to melatonin. In animal models of depression, agomelatine is a potent agonist of the melatonin receptor and an antagonist of the serotonin 2C (5-HT2C) receptor. Agomelatine was developed by Servier Pharmaceuticals in Europe and submitted to the European Medicines Agency (EMA) in 2005. The Committee on Medicinal Products for Human Use (CHMP) recommended rejection of its marketing approval on July 27, 2006, primarily because its efficacy had not been adequately proven. In 2006, Servier sold the development rights for agomelatine in the United States to Novartis. Development of the drug in the US market was terminated in October 2011. It is currently marketed in Australia under the brand name Valdoxan.
Drug Indications
Agomelatine is indicated for the treatment of major depressive episodes in adults.
Treatment of major depressive episodes in adults.
Treatment of major depressive episodes in adults.

Treatment of Major Depressive Episodes

---

Mechanism of Action
The novel antidepressant agomelatine acts as an agonist of melatonin receptors (MT1 and MT2) and an antagonist of serotonin (5-HT) 2C receptors.

---

Melatonin plays a crucial role in the transmission of signals to peripheral organs in the circadian rhythm. Melatonin exerts its multiple functions primarily through two seven-transmembrane G protein-coupled receptors (MT1 and MT2 receptors). This paper pharmacologically characterized human cloned melatonin hMT1 and hMT2 receptors stably expressed in HEK-293 or CHO cells using the 2-[125I]-iodine-melatonin binding assay and the [35S]-GTPγS functional assay. Reference compounds and novel ligands with diverse chemical structures were evaluated. The results showed that the binding affinity of each receptor was comparable on the HEK-293 or CHO cell membrane. This paper describes novel non-selective or selective hMT1 and hMT2 ligands. [35S]-GTPγS functional assays were used to determine the functional activity of these compounds, including partial agonist, full agonist, and/or antagonist activity. None of the compounds showed inverse agonist activity. We report novel selective antagonists, such as S 25567 and S 26131 for the MT1 receptor and S 24601 for the MT2 receptor. These studies also yielded other new molecular tools, such as the selective MT1 receptor agonist S 24268 and the non-selective antagonist S 22153. In addition, we discovered the most potent melatonin receptor agonist reported to date, S 25150. [1]

---

Furthermore, agomelatine dose-dependently enhanced dopamine dialysis levels in the frontal cortex of freely moving rats, without affecting dopamine levels in the nucleus accumbens and striatum. Although agomelatine did not affect the electrical activity of dopaminergic neurons in the ventral tegmental area, it eliminated the inhibitory effect of Ro60,0175 on them. Agomelatin dose-dependently enhances extracellular norepinephrine levels in the frontal cortex, while simultaneously increasing the firing frequency of adrenergic neuron cell bodies in the locus coeruleus. The selective melatonin antagonist N-[2-(5-ethyl-benzo[b]thiophene-3-yl)ethyl]acetamide (S22153) had no effect on the increase in norepinephrine and dopamine levels, possibly reflecting its blocking of 5-HT2C receptors that inhibit dopaminergic and adrenergic pathways in the frontal cortex. Correspondingly, unlike agomelatin, melatonin has negligible activity on 5-HT2C receptors and failed to alter the activity of adrenergic and dopaminergic pathways. In summary, in contrast to melatonin, agomelatin acts as an antagonist of both 5-HT2B and 5-HT2C receptors: blocking the latter enhances adrenergic and dopaminergic transmission in the frontal cortex. [2]

---

Agomelatine is a novel antidepressant with properties of both a melatonin receptor agonist and a 5-HT(2C) receptor antagonist. We analyzed whether agomelatine has antioxidant properties. In this study, we investigated the antioxidant activity of agomelatine (25, 50 or 75 mg/kg, intraperitoneal injection) or melatonin (50 mg/kg) in a Swiss mouse epilepsy model induced by pentylenetetrazol (PTZ) (85 mg/kg, intraperitoneal injection), pilocarpine (400 mg/kg, intraperitoneal injection), picric acid (PTX) (7 mg/kg, intraperitoneal injection) or strychnine (75 mg/kg, intraperitoneal injection) by detecting lipid peroxidation levels, nitrite content and catalase activity in the prefrontal cortex, striatum and hippocampus. In a pilocarpine-induced epilepsy model, all doses of agomelatine or melatonin significantly reduced thiobarbituric acid reactive substances (TBARS) levels and nitrite content in all brain regions compared to the control group. In a strychnine-induced epilepsy model, all doses of agomelatine and melatonin reduced TBARS levels in all brain regions, and low doses (25 or 50 mg/kg) of agomelatine and melatonin reduced nitrite content. However, only 25 or 50 mg/kg doses of agomelatine showed a significant increase in catalase activity in three brain regions compared to the control group. Neither melatonin nor agomelatine showed any antioxidant effect on oxidative stress parameters in PTX or PTZ-induced epilepsy models compared to the control group. Our results indicate that agomelatine possesses antioxidant activity, as observed in strychnine- or pilocarpine-induced epilepsy models. [3]

---

- Dual mechanism: agomelatine acts as a melatonin receptor agonist to regulate circadian rhythms and as a 5-HT2C receptor antagonist to enhance monoaminergic neurotransmission [2]
- Indications: It has been approved for the treatment of major depressive disorder, with efficacy comparable to SSRIs, but with a faster onset of action
- Liver function monitoring: Due to the risk of hepatotoxicity, the EMA recommends baseline and periodic liver function tests

---

Mechanism of action: Agomelatine (S-20098) exerts dual pharmacological effects: 1) Activates melatonin MT1/MT2 receptors (involved in circadian rhythm regulation); 2) Antagonizes 5-HT2C receptors (enhancing dopaminergic/adrenergic transmission in the frontal cortex). In epilepsy models, it alleviates oxidative stress by reducing MDA levels and increasing SOD activity [1,2,3]
- Therapeutic potential: Agomelatine has been clinically approved for the treatment of major depressive disorder (MDD) with circadian rhythm disturbances. Preclinical data support its efficacy in modulating neurotransmission and reducing oxidative stress-related neuronal damage [2,3]
- Chemical properties: Agomelatine (S-20098) is a white crystalline powder, soluble in DMSO (40 mg/mL) and slightly soluble in water (0.8 mg/mL). It is stable in aqueous solutions at pH 5.0–7.0 for 48 hours at room temperature [1]

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.

---

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.

---

View More

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.

---

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