5-HT_2C Receptor ( pKi = 6.4 ); 5-HT_2C Receptor ( pIC50 = 6.2 ); hMT1 ( Ki = 0.1 nM ); hMT1 ( Ki = 0.06 nM ); hMT2 ( Ki = 0.12 nM );hMT2 ( Ki = 0.27 nM )

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].

Agomelatine (25, 50, or 75 mg/kg; i.p.) exhibits antioxidant activity in mouse seizure models induced by strychnine (75 mg/kg, i.p.) or pilocarpine (400 mg/kg, i.p.). Comparing the oxidative stress parameters produced by seizure models induced by either picrotoxin (PTX) or pentylenetetrazole (PTZ) to controls, agomelatine dose did not produce any antioxidant effects[3].

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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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 less than 5%. Metabolism/Metabolites Hepatic metabolism (90% via CYP1A2, 10% via CYP2C9). Biological Half-Life 2 hours

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 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 daily, with doses 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.

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Protein binding
>95%

[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. Currently, it is 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

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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.

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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]

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Furthermore, agomelatine dose-dependently enhanced dopamine dialysis levels in the frontal cortex of freely active 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]

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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 pilocarpine-induced epilepsy models, all doses of agomelatine or melatonin significantly reduced thiobarbituric acid reactants (TBARS) and nitrite levels in all brain regions compared to the control group. In strychnine-induced epilepsy models, 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 levels, but 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 suggest that agomelatine has antioxidant activity, as observed in strychnine or pilocarpine-induced epilepsy models. [3]

C19H23NO8

393.3878262043

393.142

824393-18-2

Agomelatine; 138112-76-2; Agomelatine hydrochloride; 1176316-99-6

78357824

White to off-white solid powder

5

8

7

28

414

2

CC(=O)NCCC1=CC=CC2=C1C=C(C=C2)OC.[C@@H]([C@H](C(=O)O)O)(C(=O)O)O

PJOPJXPTFZIKTL-LREBCSMRSA-N

InChI=1S/C15H17NO2.C4H6O6/c1-11(17)16-9-8-13-5-3-4-12-6-7-14(18-2)10-15(12)13;5-1(3(7)8)2(6)4(9)10/h3-7,10H,8-9H2,1-2H3,(H,16,17);1-2,5-6H,(H,7,8)(H,9,10)/t;1-,2-/m.1/s1

(2R,3R)-2,3-dihydroxybutanedioic acid;N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide

S-20098 L(+)-Tartaric acid; Agomelatine (L(+)-Tartaric acid); 824393-18-2; Agomelatine L(+)-Tartaric acid; S-20098 L(+)-Tartaric acid; (2R,3R)-2,3-dihydroxybutanedioic acid;N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide; Agomelatine (L(+)-Tartaric acid)

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO: ~100 mg/mL (~254.2 mM)

Solubility in Formulation 1: 2.5 mg/mL (6.36 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 (6.36 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 (6.36 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.)