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 )

体外活性：阿戈美拉汀完全使受应激影响的细胞存活正常化，并部分逆转遭受慢性足部电击应激的大鼠海马中双皮质素表达的减少。

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Agomelatine (S 20098) 是 MT1 和 MT2 受体的完全激动剂，对于 CHO hMT1 CHO-hMT2（在 CHO 或 HEK 细胞膜中表达的 hMT1 和 hMT2 受体）的 EC50 值为 1.6±0.4、0.10±0.04 nM[1]。阿戈美拉汀 (S20098) 还与 h5-HT2B 受体 (6.6) 相互作用，但它对天然（大鼠）/克隆人 5-HT2A (<5.0/5.3) 和 5-HT1A (<5.0/5.2) 受体表现出低亲和力，对其他 5-HT 受体的亲和力可忽略不计（<5.0）[2]。

阿戈美拉汀可有效逆转 Porsolt 强迫游泳测试以及高架十字迷宫中注意到的转基因小鼠行为变化。阿戈美拉汀还显着加速诱导相移后温度和活动的昼夜节律周期的重新调整。阿戈美拉汀可增强成年大鼠腹侧海马（VH）的细胞增殖和神经发生，该区域与情绪障碍有关。阿戈美拉汀增加成年大鼠成熟与未成熟神经元的比例，并增强颗粒细胞的神经突生长，表明成熟加速。阿戈美拉汀还激活多种细胞信号（细胞外信号调节激酶1/2、蛋白激酶 B 和糖原合酶激酶 3β），已知这些信号受抗抑郁药调节并参与增殖/存活的控制。阿戈美拉汀可以增加暴露在新环境中的陌生老鼠进行积极社交互动的时间。阿戈美拉汀可增加大鼠腹侧齿状回的细胞增殖和神经发生，该区域特别与情绪反应有关，这与阿戈美拉汀的抗抑郁抗焦虑特性一致。阿戈美拉汀可增加大鼠整个齿状回中新形成的神经元的存活率。

Agomelatine （S20098）在本地（猪）和克隆（人）5-羟色胺（5-HT）2C受体上的pKi值分别为6.4和6.2。它也与h5-HT2B受体相互作用（6.6），而对天然（大鼠）/克隆、人类5-HT2A（<5.0/5.3）和5-HT1A（<5.0/5.2）受体的亲和力较低，对其他5-HT受体的亲和力可忽略（<5.0）。在抗体捕获/闪烁接近实验中，阿戈美拉汀浓度依赖性和竞争性地消除了h5-HT2C受体介导的Gq/11和Gi3的激活（pA2值为6.0和6.1）。通过[3H]磷脂酰肌醇耗损测定，阿戈美拉汀可消除h5-HT2C （pKB值为6.1）和h5-HT2B （pKB值为6.6）受体对磷脂酶C的激活。在体内，它可以剂量依赖性地阻断5- ht2c激动剂(S)-2-（6-氯-5-氟吲哚-1-基）-1-甲基乙胺（Ro60,0175）和1-甲基-2-（5,8,8-三甲基- 8h -3-氮杂-环五[a]吲哚-3-基）乙胺对阴茎勃起的诱导作用（Ro60,0332）。[2]

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 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

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%

[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]

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

38.33

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (10.28 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (10.28 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (10.28 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。