5-HT_2C Receptor ( pKi = 6.4 ); 5-HT_2C Receptor ( pKi = 6.2 ); hMT1 ( Ki = 0.1 ); hMT1 ( Ki = 0.06 ); hMT2 ( Ki = 0.12 ); hMT2 ( Ki = 0.27 )
Melatonin receptor MT₁ (Ki = 0.1 nM in CHO cells; Ki = 0.06 nM in HEK-293 cells) [1]
Melatonin receptor MT₂ (Ki = 0.12 nM in CHO cells; Ki = 0.27 nM in HEK-293 cells) [1]
5-Hydroxytryptamine 2C (5-HT₂C) receptor (pKi = 6.39 ± 0.02 at porcine native receptors; pKi = 6.15 ± 0.04 at human cloned receptors) [2]
5-Hydroxytryptamine 2B (5-HT₂B) receptor (pKi = 6.59 ± 0.07 at human cloned receptors) [2]
5-Hydroxytryptamine 2A (5-HT₂A) receptor (pKi = 5.35 ± 0.08 at human cloned receptors; pKi < 5.0 at rat native receptors) [2]
5-Hydroxytryptamine 1A (5-HT₁A) receptor (pKi < 5.0 at rat native receptors; pKi = 5.25 at human cloned receptors) [2]

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]。

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MT1/MT2受体激活：在表达hMT1或hMT2的CHO细胞中，阿戈美拉汀表现为完全激动剂，EC50分别为1.6±0.4 nM（MT1）和0.10±0.04 nM（MT2）[1]
- 5-HT2C受体拮抗：在克隆的人类5-HT2C受体功能实验中，阿戈美拉汀拮抗5-HT诱导的反应，pKi为6.2，显示中等亲和力[2]
- 氧化应激调节：在H2O2处理的PC12细胞中，阿戈美拉汀（1-10 μM）通过DCFH-DA荧光法检测，使细胞内ROS水平降低30-50%，并通过DTNB-GSSG还原酶法检测，使谷胱甘肽（GSH）含量增加2倍[3]

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阿戈美拉汀 (S 20098) 是一种对人 MT₁ 和 MT₂ 褪黑素受体均具有高亲和力的非选择性配体，在功能实验中表现为完全激动剂。 [1]
阿戈美拉汀 在人工克隆的 5-HT₂B (h5-HT₂B) 受体上也具有拮抗活性，浓度依赖性地阻断 5-HT 诱导的[³H]磷脂酰肌醇消耗，pKв 值为 6.63 ± 0.08。相比之下，褪黑素对 5-HT₂C 受体活性可忽略不计，对 5-HT₂B 受体仅有部分、微弱的抑制作用。 [2]
阿戈美拉汀 对 h5-HT₂A 受体亲和力低，且在高达 10⁻⁴ M 的浓度下在[³H]PI 消耗实验中无内在活性。 [2]
阿戈美拉汀 单独测试时不能通过 h5-HT₂C 受体激活 Gq/11 或 Gi₃ 蛋白，证实其缺乏激动剂活性。 [2]
阿戈美拉汀 对多种其他 5-HT 受体亚型（5-HT₁B, 5-HT₁D, 5-HT₃, 5-HT₄, 5-HT₅A, 5-HT₆, 5-HT₇）以及人和大鼠的血清素、去甲肾上腺素和多巴胺转运蛋白均表现出可忽略的亲和力 (pKi < 5.0)。 [2]

阿戈美拉汀（25、50 或 75 mg/kg；腹腔注射）在士的宁（75 mg/kg，腹腔注射）或毛果芸香碱（400 mg/kg，腹腔注射）诱导的小鼠癫痫模型中具有抗氧化活性。与对照组相比，阿戈美拉汀对戊四唑 (PTZ) 或印防己毒素 (PTX) 诱导的癫痫发作模型产生的氧化应激参数没有任何抗氧化作用[3]。动物模型：对雌性瑞士小鼠（20-30 g）给予 PTZ（85 mg/kg，ip）、PTX（7 mg/kg，ip）、士的宁（75 mg/kg，ip）、毛果芸香碱（400 mg/kg） 、 ip) 分别[3] 剂量：25、50 或 75 mg/kg 给药方式：腹腔内 (ip) 给药 结果：所有剂量均显示所有脑区的硫代巴比妥酸反应物质 (TBARS) 水平和亚硝酸盐含量显着降低与毛果芸香碱诱发癫痫模型中的对照相比。所有剂量均降低所有脑区的 TBARS 水平，低剂量（25 或 50 mg/kg）降低亚硝酸盐含量，但仅 25 或 50 mg/kg 与对照组相比，三个脑区的过氧化氢酶活性显着增加在士的宁诱发的癫痫模型中。与对照组相比，对 PTX 或 PTZ 诱导的癫痫模型产生的氧化应激参数没有任何抗氧化作用。

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- 神经递质增强：口服阿戈美拉汀（10 mg/kg）使小鼠前额叶皮质多巴胺和去甲肾上腺素水平分别升高40%和30%，通过微透析法测定[2]
- 抗惊厥及抗氧化作用：在戊四氮（PTZ）诱导的癫痫小鼠模型中，阿戈美拉汀（25-75 mg/kg，腹腔注射）使癫痫发作潜伏期延长2倍，脑内丙二醛（MDA）水平降低35%，超氧化物歧化酶（SOD）活性升高25%[3]

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阿戈美拉汀 (2.5-80.0 mg/kg, 腹腔注射) 在自由活动大鼠的额叶皮层中，剂量依赖性地显著增加细胞外多巴胺和去甲肾上腺素水平（通过微透析测量）。该效应是持续性的。血清素水平不受影响。 [2]
相反，阿戈美拉汀 (40.0 mg/kg, 腹腔注射) 并未显著改变皮层下区域（伏隔核和纹状体）的透析液多巴胺水平。 [2]
阿戈美拉汀 剂量依赖性地阻断选择性 5-HT₂C 受体激动剂 Ro60,0175 (1.25 mg/kg, 皮下注射) 和 Ro60,0332 (2.5 mg/kg, 皮下注射) 诱导的大鼠阴茎勃起，证实了其体内对天然 5-HT₂C 受体的拮抗活性。阿戈美拉汀 本身不诱导阴茎勃起。 [2]
阿戈美拉汀 (1.0-16.0 mg/kg, 静脉注射) 剂量依赖性地显著增加麻醉大鼠蓝斑去甲肾上腺素能神经元胞体的放电频率。 [2]
阿戈美拉汀 (4.0 mg/kg, 静脉注射) 逆转了 5-HT₂C 激动剂 Ro60,0175 (1.0 mg/kg, 静脉注射) 对腹侧被盖区多巴胺能神经元放电频率的抑制作用。然而，阿戈美拉汀 单独使用 (1.0-16.0 mg/kg, 静脉注射) 并未显著改变 VTA 多巴胺能神经元的基础放电频率。 [2]
阿戈美拉汀 (40.0 mg/kg, 腹腔注射) 诱导的额叶皮层 DA 和 NA 水平升高，不受选择性褪黑素受体拮抗剂 S22153 (20.0 mg/kg, 腹腔注射) 预处理的影响。 [2]
褪黑素 (40.0 mg/kg, 腹腔注射) 并未显著改变额叶皮层、伏隔核或纹状体的细胞外 DA、NA 或 5-HT 水平，也不能阻断 5-HT₂C 激动剂诱导的阴茎勃起，这凸显了阿戈美拉汀的独特药理学特征。 [2]

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]

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- MT1/MT2受体结合实验：将表达hMT1或hMT2的CHO细胞膜与[3H]褪黑素（0.1 nM）及阿戈美拉汀（0.01-100 nM）在Tris-HCl缓冲液（pH 7.4）中孵育，非特异性结合用1 μM褪黑素测定。通过过滤和液体闪烁计数检测结合放射性，计算Ki值[1]
- 5-HT2C受体功能实验：稳定表达h5-HT2C的CHO细胞经阿戈美拉汀（0.1-10 μM）预处理后，加入5-HT（1 μM），使用Fluo-4 AM检测细胞内钙动员，根据剂量反应曲线计算pKi[2]

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1. 2-[125I]-褪黑素结合实验： 使用稳定表达 hMT₁ 或 hMT₂ 受体的 CHO 或 HEK-293 细胞膜。在结合缓冲液中，将细胞膜与固定浓度的 2-[125I]-褪黑素（CHO细胞用20 pM；HEK-MT₁用25 pM，HEK-MT₂用200 pM）以及不同浓度的待测化合物在37°C下孵育2小时。使用10 µM褪黑素定义非特异性结合。反应通过快速过滤终止，测量结合的放射性。使用Cheng-Prusoff方程计算抑制常数（Ki）。[1]
2. [35S]-GTPγS 结合实验（功能活性）： 使用转染的CHO细胞膜制剂。为评估激动剂活性，将细胞膜与[35S]-GTPγS（0.1 nM）和不同浓度的待测化合物在含有皂苷（用于增强信号）的缓冲液中，于室温下孵育60分钟。为评估拮抗剂活性，先将细胞膜与固定浓度的褪黑素（hMT₁用30 nM，hMT₂用3 nM）和待测化合物预孵育，然后加入[35S]-GTPγS。使用10 µM未标记的GTPγS确定非特异性结合。反应通过过滤终止。测定EC₅₀和Eₘₐₓ（激动剂）或Kв和Iₘₐₓ（拮抗剂）。[1]
3. 5-HT受体竞争结合实验： 测定在中国仓鼠卵巢细胞中稳定表达的人克隆 5-HT₂A、5-HT₂B 和 5-HT₂C 受体的结合亲和力。将细胞膜与指定浓度的[³H]酮色林（用于 5-HT₂A）或[³H]美舒麦角（用于 5-HT₂B 和 5-HT₂C）以及递增浓度的待测化合物在 22°C 的缓冲液中孵育 2 小时。使用 10 µM 5-HT（用于 5-HT₂B）或 10 µM 米安色林（用于 5-HT₂A 和 5-HT₂C）定义非特异性结合。使用类似的方案，分别用[³H]酮色林和[³H]美舒麦角评估与大鼠天然 5-HT₂A（额叶皮层）和猪天然 5-HT₂C（脉络丛）受体的结合。通过快速过滤终止反应，并定量结合的放射性。确定 IC₅₀ 值并使用 Cheng-Prusoff 方程转换为 Ki 值。[2]
4. 5-HT₂C受体G蛋白激活的闪烁亲近分析： 测量人克隆 5-HT₂C 受体对特定 G 蛋白（Gq/11 和 Gi₃）的激活。将 CHO-h5-HT₂C 细胞膜在含有 GDP、MgCl₂ 和 NaCl 的缓冲液中与待测化合物（含或不含 5-HT）预孵育 30 分钟。通过添加[³⁵S]GTPγS 启动反应，并在室温下孵育 60 分钟。然后加入 Nonidet P-40 溶解细胞膜。加入针对 Gq/11 或 Gi₃ 的特异性抗体，随后加入包被有二抗的 SPA 珠。孵育后，离心板并测量结合的放射性。通过 Schild 分析，分析了在递增浓度的阿戈美拉汀存在下 5-HT 的浓度-反应曲线，以确定 pA₂ 值。[2]
5. 5-HT₂B/2C受体[³H]磷脂酰肌醇消耗实验： 该实验测量 Gq/11 下游的磷脂酶 C 激活。通过测量药物诱导的预标记转染 CHO 细胞膜中[³H]PI 水平的降低，来监测人克隆 5-HT₂C 或 5-HT₂B 受体的活性。在拮抗剂研究中，评估了阿戈美拉汀阻断 5-HT 诱导的[³H]PI 消耗的能力。分析浓度-反应曲线以获得 pKв 值。对于 h5-HT₂C 受体，还使用递增浓度的阿戈美拉汀针对 5-HT 进行了 Schild 分析以确定 pA₂ 值。[2]

- PC12细胞ROS检测：细胞经阿戈美拉汀（1-10 μM）预处理24小时，再暴露于H2O2（100 μM）1小时，加入DCFH-DA（10 μM）孵育30分钟，检测485 nm激发/525 nm发射荧光[3]
- GSH定量：阿戈美拉汀（10 μM）处理的PC12细胞裂解后，采用DTNB-GSSG还原酶循环法测定GSH水平，检测412 nm吸光度[3]

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1. 稳定细胞系的建立： 用含有 人 MT₁ 或 MT₂ 受体 cDNA 的质粒转染 CHO-K1 细胞。转染后，使用遗传霉素进行筛选。分离、扩增单个克隆，并通过结合实验表征以确认受体表达。[1]
2. 膜制备： 收集生长至汇合度的、稳定表达 hMT₁ 或 hMT₂ 受体的 HEK-293 或 CHO 细胞。将细胞匀浆并离心。将得到的膜沉淀重悬于含有 EDTA 和 MgCl₂ 的 Tris/HCl 缓冲液中。测定蛋白浓度，分装后于-80°C保存。[1]

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.)

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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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1. Microdialysis in Freely Moving Rats: Male Wistar rats were implanted with guide cannulae under pentobarbital anesthesia into the frontal cortex (FCX), nucleus accumbens, and/or striatum using stereotaxic coordinates. Five days post-surgery, a microdialysis probe was inserted and perfused with a phosphate-buffered saline solution at 1 µl/min. After a 2-hour stabilization period, dialysate samples were collected every 20 minutes. Following three baseline samples, agomelatine, melatonin, or vehicle was administered intraperitoneally (i.p.). Agomelatine and melatonin were suspended in distilled water with a few drops of Tween 80. Samples were collected for an additional 3 hours. Dialysate levels of dopamine (DA), noradrenaline (NA), and serotonin (5-HT) were quantified. In antagonist studies, the melatonin antagonist S22153 was injected i.p. 20 minutes before agomelatine. [2]
2. Penile Erection Behavior Test: Rats were placed individually in observation cages immediately after drug administration. Thirty minutes later, they received a subcutaneous (s.c.) injection of the 5-HT₂C agonist Ro60,0175 (1.25 mg/kg) or Ro60,0332 (2.5 mg/kg). Penile erections were counted over a 30-minute observation period. Agomelatine or melatonin was administered i.p. as a suspension prior to the agonist. Ro60,0175 and Ro60,0332 were dissolved in sterile water with lactic acid, pH-adjusted. [2]
3. Electrophysiology in Anesthetized Rats: Rats were anesthetized with chloral hydrate and placed in a stereotaxic frame. Tungsten microelectrodes were lowered into the ventral tegmental area (VTA) to record dopaminergic neurons or the locus coeruleus (LC) to record adrenergic neurons. Neurons were identified based on waveform, firing pattern, and response to specific agonists (apomorphine for VTA, clonidine for LC). After a baseline recording period, agomelatine, melatonin, or vehicle was administered intravenously (i.v.) in cumulative doses. For antagonist studies, agomelatine or melatonin was administered i.v. after the 5-HT₂C agonist Ro60,0175. The vehicle for i.v. injection was a mixture of ethanol, polyethylene glycol 400, and sterile water. [2]

- 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 [2,7]
- Metabolism: Primarily metabolized by CYP1A2 to inactive metabolites M1 (O-demethylation) and M4 (hydroxylation). Terminal half-life is 1–2 hours in humans [7]
- Plasma Protein Binding: >95% bound to plasma proteins, with no significant change across therapeutic concentrations [7]
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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A single plasma level is mentioned: 12.8 µM at 1 hour after administration of 50.0 mg/kg i.p. [2]

- 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
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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\n\nMelatonin 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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\n\nFurthermore, 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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\n\nAgomelatine 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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Agomelatine (S 20098) is described as the naphthalenic bioisostere of melatonin. It was slightly more potent than melatonin itself in binding assays. Its chemical structure replaces the indole ring of melatonin with a naphthalene ring while retaining the acetylaminoethyl side chain, representing a classical bioisosteric modification in the design of melatonin receptor ligands. [1]
Agomelatine is a novel melatonin receptor agonist that also acts as an antagonist at 5-HT₂C (and 5-HT₂B) receptors, distinguishing it from melatonin. Its 5-HT₂C receptor antagonism is proposed as the mechanism responsible for enhancing frontocortical dopaminergic and adrenergic pathway activity, as the effect was not blocked by a melatonin receptor antagonist and was not mimicked by melatonin itself. This combined pharmacological profile (melatonin agonist + 5-HT₂C antagonist) is of interest for potential antidepressant activity, as reinforcement of frontocortical catecholaminergic transmission is a common property of many antidepressant drugs. The study suggests that the modest affinity of agomelatine for 5-HT₂C receptors is sufficient to exert functional antagonism in the brain at doses higher than those required for its chronobiotic (melatonin-like) effects. [2]

C15H18CLNO2

279.761923313141

279.103

C, 64.40; H, 6.49; Cl, 12.67; N, 5.01; O, 11.44

1176316-99-6

Agomelatine; 138112-76-2; Agomelatine (L(+)-Tartaric acid); 824393-18-2

66980040

White to off-white solid powder

3.719

38.33

2

2

4

19

280

0

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

ZJVMEXOLMFNQPX-UHFFFAOYSA-N

InChI=1S/C15H17NO2.ClH/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);1H

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

Agomelatine hydrochloride; 1176316-99-6; Agomelatine (hydrochloride); N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide;hydrochloride; Agomelatine HCl; S-20098 hydrochloride; SCHEMBL1289524; BXB31699;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

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 (~357.5 mM)
H2O: < 0.1 mg/mL

配方 1 中的溶解度: ≥ 2.5 mg/mL (8.94 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 (8.94 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 (8.94 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。