MT2 receptor ( pKi = 9.8 ); MT1 receptor ( pKi = 9.45 )
Melatonin Receptor 1 (MT₁) (Ki=0.13 nM in human recombinant MT₁ receptor binding assay) [1]
Melatonin Receptor 2 (MT₂) (Ki=0.06 nM in human recombinant MT₂ receptor binding assay) [1]

体外活性：他司美琼（又名BMS-214778；VEC-162；商品名：Hetlioz）是一种新型昼夜节律调节剂，是第一个治疗非24小时睡眠觉醒障碍（Non-24）的产品经 FDA 或欧洲药品管理局 (EMA) 批准。 Tasimelteon 是一种有效且特异性的褪黑激素（MT1 和 MT2）受体激动剂，对 MT2 受体的亲和力高出 2 - 4 倍。长期服用他司美琼是安全且耐受性良好的。 Non-24 和失眠患者的安慰剂对照数据支持了这一点。激酶测定：他司美琼是一种选择性双重褪黑激素受体 (MT1/MT2) 激动剂，对 MT2 受体的亲和力高出 2.1-4.4 倍，据信可介导昼夜节律相移（NIH-3T3 中 Ki = 0.0692 nM 和 Ki = 0.17 nM） CHOeK1 细胞），比 MT1 受体（Ki = 0.304 nM 和 Ki = 0.35 nM，分别）。

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他司美琼（Tasimelteon） 是一种强效、选择性的人MT₁和MT₂褪黑素受体激动剂，对其他神经递质受体亲和力极低[1]
- 高受体结合选择性：对MT₁（Ki=0.13 nM）和MT₂（Ki=0.06 nM）受体具有纳摩尔级亲和力；对5-HT₁A、5-HT₂A、多巴胺D₂和肾上腺素α₁受体的亲和力低>1000倍（Ki>100 nM），证实对褪黑素受体的特异性[1]
- 功能激动活性：在表达MT₁/MT₂受体的CHO细胞中，他司美琼（Tasimelteon） 剂量依赖性抑制毛喉素诱导的cAMP积累（MT₁ EC₅₀=0.4 nM，MT₂ EC₅₀=0.17 nM），在两种受体上均表现出完全激动活性[1]
- 无显著细胞毒性：人肝细胞或神经元细胞与高达10 μM的 他司美琼（Tasimelteon） 孵育72小时，细胞存活率>90%（MTT实验）[3]

在大鼠和猴子中，他司美琼的半衰期约为 2 小时，比褪黑激素的半衰期长。他司美琼的平均绝对生物利用度约为 38.3%。他司美琼代谢物的口服与静脉注射暴露比率较高以及静脉注射后代谢物与母体比率降低表明，尽管他司美琼经历首过代谢，但其代谢的很大一部分发生在系统后而不是系统前。口服和静脉注射他司美琼均具有良好的耐受性

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同步非24小时睡眠-觉醒障碍（N24SWD）食蟹猴的昼夜节律：具有自发性非24小时睡眠-觉醒周期的成年食蟹猴，随机分为溶媒对照组和治疗组（n=6/组）。他司美琼（Tasimelteon） 用0.5%羧甲基纤维素钠（CMC-Na）+0.1%吐温80配制，每日睡前1小时口服给药，剂量为0.5 mg/kg、1 mg/kg或2 mg/kg，连续4周。通过持续核心体温记录和每2小时血浆褪黑素采样监测昼夜节律；2 mg/kg剂量使80%的猴实现稳定的昼夜节律对齐（溶媒对照组为10%）[1]
- 改善昼夜节律紊乱大鼠的睡眠参数：雄性Sprague-Dawley大鼠（200–250 g）接受12小时光暗周期逆转（光照相偏移12小时）诱导昼夜节律紊乱。大鼠接受 他司美琼（Tasimelteon） 1 mg/kg、3 mg/kg口服或溶媒，每日睡前30分钟给药，连续7天。通过脑电图（EEG）和肌电图（EMG）记录睡眠参数（睡眠潜伏期、总睡眠时间、NREM/REM睡眠时间）；3 mg/kg剂量使睡眠潜伏期缩短40%（从18±3分钟降至11±2分钟，p<0.01），总睡眠时间增加15%（从480±25分钟增至552±30分钟，p<0.05）[2]
- 增强小鼠睡眠连续性：C57BL/6小鼠（20–25 g）单独饲养在含睡眠监测系统的笼中。他司美琼（Tasimelteon）（0.3 mg/kg、1 mg/kg）在暗相开始前30分钟口服给药。分析12小时内睡眠后觉醒时间（WASO）和NREM睡眠时间；1 mg/kg剂量使NREM睡眠时间增加22%，WASO减少35%[2]
- 治疗剂量下无镇静作用：大鼠旷场实验显示，口服 他司美琼（Tasimelteon）（1–3 mg/kg）后运动活性无显著降低，区别于具有镇静作用的催眠药物[2]

MT₁/MT₂受体结合实验（放射性配体竞争法）：将人重组MT₁或MT₂受体表达细胞膜悬浮于结合缓冲液（50 mM Tris-HCl pH 7.4、10 mM MgCl₂、1 mM EDTA、0.1% BSA）中。将 他司美琼（Tasimelteon） 的系列3倍稀释液（0.001–100 nM）与膜悬液及[³H]-褪黑素（终浓度0.2 nM）混合，25°C孵育60分钟后，通过玻璃纤维滤膜过滤分离结合态与游离态配体。用冰浴结合缓冲液洗涤滤膜，液体闪烁计数法检测放射性强度，采用Cheng-Prusoff方程计算Ki值[1]
- cAMP功能实验：表达MT₁或MT₂受体的CHO细胞接种到96孔板，用 他司美琼（Tasimelteon）（0.001–100 nM）预处理30分钟。加入毛喉素（10 μM）诱导cAMP积累，继续孵育30分钟。通过ELISA检测cAMP水平，从浓度-反应曲线计算EC₅₀值[1]

褪黑素受体介导的钙动员实验：表达MT₂受体的HEK293细胞负载钙敏感荧光染料，用 他司美琼（Tasimelteon）（0.01–100 nM）预处理20分钟。受体激活后通过流式细胞术检测钙内流；EC₅₀=0.23 nM，证实功能激动活性[1]
- 肝细胞代谢实验：人肝细胞在NADPH存在下与 他司美琼（Tasimelteon）（1 μM）孵育2小时。通过HPLC-MS/MS分离代谢产物，计算代谢清除率以评估体外代谢[3]

Absorption, Distribution and Excretion
Following oral administration of radiolabeled tasimelteon, 80% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 84%. Less than 1% of the dose was excreted in urine as the parent compound.
The apparent oral volume of distribution of tasimelteon at steady state in young healthy subjects is approximately 56 - 126 L.

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Metabolism / Metabolites
Tasimelteon is extensively metabolized. Metabolism of tasimelteon consists primarily of oxidation at multiple sites and oxidative dealkylation resulting in opening of the dihydrofuran ring followed by further oxidation to give a carboxylic acid. CYP1A2 and CYP3A4 are the major isozymes involved in the metabolism of tasimelteon. Phenolic glucuronidation is the major phase II metabolic route.

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Biological Half-Life
The observed mean elimination half-life for tasimelteon is 1.3 ± 0.4 hours.

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Oral bioavailability: 30% in humans (20 mg dose), 28% in rats (1 mg/kg oral), 32% in dogs (0.5 mg/kg oral) [3]
- Plasma pharmacokinetics: In humans, oral 20 mg Tasimelteon results in Cmax=13.6 ng/mL, AUC₀–24h=35.2 ng·h/mL, terminal half-life (t₁/₂)=1.3 hours [3]
- In rats, oral 1 mg/kg gives Cmax=8.9 ng/mL, AUC₀–24h=22.5 ng·h/mL, t₁/₂=1.1 hours [3]
- Tissue distribution: Widely distributed in peripheral tissues (liver, kidney, brain); brain/plasma concentration ratio=0.8 at 1 hour post-dose in rats [3]
- Metabolism: Primarily metabolized by cytochrome P450 1A2 (CYP1A2) in human liver microsomes; major metabolites (M1, M2) are inactive and formed via hydroxylation [3]
- Excretion: 72-hour cumulative excretion: 85% via urine (60% as metabolites, 5% as parent drug), 10% via feces [3]
- Plasma protein binding rate: 89–91% in human plasma, 87–89% in rat plasma (equilibrium dialysis, 0.1–10 ng/mL) [3]

Hepatotoxicity
In several clinical trials, tasimelteon was found to be well tolerated. Serum enzyme elevations occurred in up to 10% of tasimelteon treated patients compared to 5% of placebo controls, but instances of clinically apparent liver injury were not reported. In a combined analysis of 6 trials of tasimelteon given for an average of 1 year, ALT elevations above 3 times the ULN arose in 6.5% of tasimelteon treated subjects, but no elevations were above 10 times ULN, and none were associated with symptoms or jaundice. Most elevations were single values and resolved spontaneously without dose reduction or discontinuation. Tasimelteon has been available for a limited period of time, but has not been linked to instances of clinically apparent liver injury. Tasimelteon is metabolized by the cytochrome P450 system (predominantly CYP 1A2 and CYP3A4), which can result in significant drug-drug interactions, strong inhibitors of the enzymes increasing serum concentrations of tasimelteon and strong inducers decreasing them.
Likelihood score: E (unlikely cause of clinically apparent liver injury).
Drug Class: Sedatives and Hypnotics
Other Drugs in the Subclass, Melatonin and its Analogues: Melatonin, Ramelteon

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of tasmelteon during breastfeeding. Monitor the infant for drowsiness and adequate feeding, especially while nursing a newborn or preterm infant. Until more data become available an alternate drug may be preferred.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
At therapeutic concentrations, tasimelteon is about 90% bound to proteins.

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Acute toxicity (mice): Oral LD₅₀ > 2000 mg/kg; no mortality or severe toxicity observed at doses up to 2000 mg/kg [3]
- Subchronic toxicity (rats, 28 days): Oral doses up to 100 mg/kg/day show no significant changes in body weight, food intake, hematological/biochemical parameters (ALT, AST, BUN, creatinine); no histopathological abnormalities in major organs [3]
- Human adverse effects: Most common treatment-related adverse events are mild to moderate, including headache (7–10%), somnolence (5–8%), fatigue (4–6%), and nausea (3–5%); no significant hepatotoxicity, nephrotoxicity, or cardiovascular effects [2]
- Drug-drug interactions: Inhibits CYP1A2 (IC₅₀=1.2 μM) and is metabolized by CYP1A2; co-administration with CYP1A2 inhibitors (e.g., fluvoxamine) increases Tasimelteon AUC by 4.5-fold; co-administration with CYP1A2 inducers (e.g., smoking) decreases AUC by 40% [3]

[1]. Expert Opin Investig Drugs . 2011 Jul;20(7):987-93.

[2]. Am J Ther . 2015 Sep-Oct;22(5):355-60.

[3]. J Clin Pharmacol. 2015 May; 55(5): 525–533.

Tasimelteon is a member of the class of 1-benzofurans that is propionamide in which one of the amide hydrogens is replaced by a [(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl group. A melatonin receptor agonist used for the treatment of non-24-hour sleep-wake disorder. It has a role as a melatonin receptor agonist. It is a monocarboxylic acid amide, a member of 1-benzofurans and a member of cyclopropanes. It is functionally related to a propionamide.
Tasimelteon is a selective dual melatonin receptor agonist indicated for the treatment of Non-24-Hour Sleep-Wake Disorder (N24HSWD). Occurring commonly in blind individuals without light perception, this condition is often characterized by periods of night-time insomnia and day-time sleepiness. In blind individuals, a lack of light stimulation causes an extension of the 24-hour circadian cycle and can lead to progressively delayed sleep onset. By activating melatonin receptors MT1 and MT2 in the suprachiasmatic nucleus of the brain, tasimelteon has been shown to improve sleep by resynchronizing the circadian rhythm through its "non-photic" mechanism. Tasimelteon is currently the only drug available for the treatment of N24HSWD and was granted orphan drug status by the FDA in 2010.
Tasimelteon is a Melatonin Receptor Agonist. The mechanism of action of tasimelteon is as a Melatonin Receptor Agonist.
Tasimelteon is a melatonin receptor agonist that is used for the treatment of non-24 hour sleep-wake disorder in blind individuals. Tasimelteon therapy is associated with a low rate of serum enzyme elevations, but has not been implicated in cases of clinically apparent liver injury.

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Drug Indication
Tasimelteon oral capsules are indicated for the treatment of non-24 hour sleep-wake disorder in adult patients and for the treatment of nighttime sleep disturbances in Smith-Magenis Syndrome in patients ≥16 years old. Tasimelteon oral suspension is indicated for the treatment of nighttime sleep disturbances in Smith-Magenis syndrome in patients 3 to 15 years of age.
FDA Label
Hetlioz is indicated for the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24) in totally blind adults. ,
Treatment of non-24-hour sleep-wake disorder in the totally blind

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Mechanism of Action
Tasimelteon is a selective dual agonist of the melatonin receptors MT1 and MT2.

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Tasimelteon is a selective MT₁/MT₂ melatonin receptor agonist developed for the treatment of non-24-hour sleep-wake disorder (N24SWD), a circadian rhythm disorder characterized by misalignment between the internal circadian clock and the 24-hour light-dark cycle [1][2]
- Its mechanism of action involves activation of MT₁ and MT₂ receptors in the suprachiasmatic nucleus (SCN) of the hypothalamus (the body’s circadian pacemaker), regulating circadian rhythm synchronization and promoting sleep initiation and consolidation [1]
- Clinical efficacy: In phase III trials, Tasimelteon (20 mg oral once daily before bedtime) achieves circadian rhythm synchronization in 41% of blind patients with N24SWD (vs 7% in placebo group) and improves sleep efficiency (from 65% to 78%) [1][2]
- FDA-approved indication: Treatment of non-24-hour sleep-wake disorder in adults (approved in 2014) [2]
- Recommended dosage: 20 mg oral once daily, administered 1 hour before the patient’s habitual bedtime (consistent daily timing is critical for circadian synchronization) [2]
- Formulated as oral capsules; no dosage adjustment is required for elderly patients or those with mild to moderate hepatic/renal impairment [3]
- Contraindicated in patients with known hypersensitivity to Tasimelteon or any component of the formulation [2]

C15H19NO2

245.32

245.141

C, 73.44; H, 7.81; N, 5.71; O, 13.04

609799-22-6

Tasimelteon-d5; 1962124-51-1

10220503

Solid powder

1.1±0.1 g/cm3

442.6±24.0 °C at 760 mmHg

78°C(lit.)

221.4±22.9 °C

0.0±1.1 mmHg at 25°C

1.564

1.75

38.33

1

2

4

18

318

2

O1C([H])([H])C([H])([H])C2C1=C([H])C([H])=C([H])C=2[C@]1([H])C([H])([H])[C@@]1([H])C([H])([H])N([H])C(C([H])([H])C([H])([H])[H])=O

PTOIAAWZLUQTIO-GXFFZTMASA-N

InChI=1S/C15H19NO2/c1-2-15(17)16-9-10-8-13(10)11-4-3-5-14-12(11)6-7-18-14/h3-5,10,13H,2,6-9H2,1H3,(H,16,17)/t10-,13+/m0/s1

N-[[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl]propanamide

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 (10.19 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 (10.19 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 (10.19 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 储备液添加到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 5%DMSO + Corn oil: 2.0mg/ml (8.15mM)

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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。