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]

Tasimelteon is a dual melatonin receptor agonist, a circadian regulator that resets the master clock in the suprachiasmatic nuclei of the hypothalamus by binding to both melatonin MT1 and MT2 receptors[3]. Tasimelteon's affinity for the MT2 receptor is four times greater than that of the MT1 receptor[2].

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Tasimelteon is a potent, selective agonist of human MT₁ and MT₂ melatonin receptors, with minimal affinity for other neurotransmitter receptors [1]
- High receptor binding selectivity: Exhibits nanomolar affinity for MT₁ (Ki=0.13 nM) and MT₂ (Ki=0.06 nM) receptors; >1000-fold lower affinity for 5-HT₁A, 5-HT₂A, dopamine D₂, and adrenergic α₁ receptors (Ki>100 nM), confirming specificity for melatonin receptors [1]
- Functional agonist activity: In MT₁/MT₂ receptor-expressing CHO cells, Tasimelteon dose-dependently inhibits forskolin-induced cAMP accumulation (MT₁ EC₅₀=0.4 nM, MT₂ EC₅₀=0.17 nM), demonstrating full agonist activity at both receptors [1]
- No significant cytotoxicity: Incubation of human hepatocytes or neuronal cells with Tasimelteon up to 10 μM for 72 hours shows >90% cell viability (MTT assay) [3]

Tasimelteon has a half-life of roughly two hours in rats and monkeys, which is longer than that of melatonin[1]. The mean absolute bioavailability of tasimelteon is about 38.3%. Tasimelteon's metabolites have higher oral-to-IV exposure ratios and lower metabolite-to-parent ratios following IV administration. These data suggest that while tasimelteon undergoes first-pass metabolism, a significant portion of its metabolism happens post- rather than presystemically. Tasimelteon administered intravenously orally was well tolerated[2].

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Synchronizes circadian rhythms in cynomolgus monkeys with non-24-hour sleep-wake disorder (N24SWD): Oral administration of Tasimelteon (0.5 mg/kg, 1 mg/kg, 2 mg/kg) once daily 1 hour before habitual bedtime for 4 weeks dose-dependently synchronizes the circadian rhythm (assessed by plasma melatonin and core body temperature rhythms); the 2 mg/kg dose achieves stable circadian alignment in 80% of monkeys (vs 10% in vehicle control) [1]
- Improves sleep parameters in rats with circadian disruption: Male Sprague-Dawley rats subjected to 12-hour light/dark cycle reversal were treated with oral Tasimelteon (1 mg/kg, 3 mg/kg) 30 minutes before bedtime. The 3 mg/kg dose reduces sleep latency by 40% (from 18 ± 3 minutes to 11 ± 2 minutes, p<0.01) and increases total sleep time by 15% (from 480 ± 25 minutes to 552 ± 30 minutes, p<0.05) compared to vehicle control [2]
- Enhances sleep consolidation in mice: C57BL/6 mice treated with oral Tasimelteon (0.3 mg/kg, 1 mg/kg) show dose-dependent increases in non-rapid eye movement (NREM) sleep duration (1 mg/kg: +22% vs vehicle) and decreases in wake after sleep onset (WASO) by 35% [2]
- No sedative effects at therapeutic doses: Open-field test in rats shows no significant reduction in locomotor activity after oral Tasimelteon (1–3 mg/kg), distinguishing it from hypnotic drugs with sedative properties [2]

MT₁/MT₂ receptor binding assay (radioligand competition): Human recombinant MT₁ or MT₂ receptor-expressing cell membranes are suspended in binding buffer (50 mM Tris-HCl pH 7.4, 10 mM MgCl₂, 1 mM EDTA, 0.1% BSA). Serial 3-fold dilutions of Tasimelteon (0.001–100 nM) are mixed with membrane suspension and [³H]-melatonin (final concentration 0.2 nM). The mixture is incubated at 25°C for 60 minutes, then filtered through glass fiber filters to separate bound and free ligand. Filters are washed with ice-cold binding buffer, and radioactivity is measured by liquid scintillation counting. Ki values are calculated using the Cheng-Prusoff equation [1]
- cAMP functional assay: MT₁ or MT₂ receptor-expressing CHO cells are seeded in 96-well plates and pre-incubated with Tasimelteon (0.001–100 nM) for 30 minutes. Forskolin (10 μM) is added to induce cAMP accumulation, and cells are incubated for an additional 30 minutes. cAMP levels are measured by ELISA, and EC₅₀ values are calculated from concentration-response curves [1]

Melatonin receptor-mediated calcium mobilization assay: MT₂ receptor-expressing HEK293 cells are loaded with a calcium-sensitive fluorescent dye and pre-incubated with Tasimelteon (0.01–100 nM) for 20 minutes. Calcium influx is measured by flow cytometry after receptor activation; EC₅₀=0.23 nM, confirming functional agonist activity [1]
- Hepatocyte metabolism assay: Human hepatocytes are incubated with Tasimelteon (1 μM) for 2 hours in the presence of NADPH. Metabolites are separated by HPLC-MS/MS, and metabolic clearance rate is calculated to assess in vitro metabolism [3]

Cynomolgus monkey N24SWD model: Adult cynomolgus monkeys with spontaneous non-24-hour sleep-wake cycles are randomized into vehicle control and treatment groups (n=6/group). Tasimelteon is formulated in 0.5% carboxymethylcellulose sodium (CMC-Na) + 0.1% Tween 80 and administered orally at 0.5 mg/kg, 1 mg/kg, or 2 mg/kg once daily 1 hour before habitual bedtime for 4 weeks. Circadian rhythms are monitored by continuous core body temperature recording and plasma melatonin sampling every 2 hours [1]
- Rat circadian disruption model: Male Sprague-Dawley rats (200–250 g) are subjected to 12-hour light/dark cycle reversal (light phase shifted by 12 hours) to induce circadian disruption. Rats are treated with oral Tasimelteon (1 mg/kg, 3 mg/kg) or vehicle 30 minutes before bedtime for 7 days. Sleep parameters (sleep latency, total sleep time, NREM/REM sleep duration) are recorded by electroencephalography (EEG) and electromyography (EMG) [2]
- Mouse sleep consolidation model: C57BL/6 mice (20–25 g) are housed in individual cages with sleep monitoring systems. Tasimelteon (0.3 mg/kg, 1 mg/kg) is administered orally 30 minutes before dark phase onset. Wake after sleep onset (WASO) and NREM sleep duration are analyzed over 12 hours [2]

Absorption, Distribution and Excretion
Following oral administration of radiolabeled tasimemone, 80% of the total radioactivity is excreted in the urine, and approximately 4% in the feces, with a mean recovery rate of 84%. Less than 1% of the dose is excreted in the urine as the parent compound. The apparent oral volume of distribution of tasimemone in young, healthy subjects at steady state is approximately 56–126 liters. Metabolism/Metabolites Tasimemone is extensively metabolized. Its metabolism primarily involves multisite oxidation and oxidative dealkylation, leading to ring opening of the dihydrofuran ring, followed by further oxidation to carboxylic acid. CYP1A2 and CYP3A4 are the major isoenzymes involved in tasimemone metabolism. Phenolic glucuronidation is the main phase II metabolic pathway. Biological Half-Life The observed mean elimination half-life of tasimemone is 1.3 ± 0.4 hours.

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Oral bioavailability: 30% in humans (20 mg dose), 28% in rats (1 mg/kg orally), 32% in dogs (0.5 mg/kg orally) [3]
-Plasma pharmacokinetics: In humans, after oral administration of 20 mg tasimedone, Cmax = 13.6 ng/mL, AUC₀–24h = 35.2 ng·h/mL, terminal half-life (t₁/₂) = 1.3 hours [3]
-In rats, after oral administration of 1 mg/kg, 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); the brain/plasma concentration ratio in rats was 0.8 1 hour after administration [3]
- Metabolism: It is mainly metabolized in human liver microsomes via cytochrome P450 1A2 (CYP1A2); the main metabolites (M1, M2) are inactive and formed by hydroxylation [3] - Excretion: 72-hour cumulative excretion: 85% is excreted in urine (60% as metabolites, 5% as the original drug), 10% is excreted in 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
Tasimemedone has been well tolerated in multiple clinical trials. The incidence of elevated serum enzymes was up to 10% in patients receiving tasimemedone, compared to 5% in the placebo control group, but no clinically significant liver injury cases were reported. In a meta-analysis of six trials with an average duration of 1 year, 6.5% of tasimemedone-treated subjects experienced ALT elevations exceeding 3 times the upper limit of normal, but no ALT elevations exceeding 10 times the upper limit of normal were observed, and none were accompanied by symptoms or jaundice. Most ALT elevations were single-incidence and resolved spontaneously without dose reduction or discontinuation. Tasimemedone has a limited market history, but no clinically significant liver injury cases have been identified. Tasimemedone is primarily metabolized via the cytochrome P450 system (mainly CYP1A2 and CYP3A4), which may lead to significant drug interactions. Potent enzyme inhibitors can increase serum concentrations of tasimemedone, while potent inducers can decrease them. Probability Score: E (Unlikely to cause clinically significant liver injury).
Drug Class: Sedative-Hypnotics
Subclass: Melatonin and its analogues: Melatonin, Rametamide
Use during Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no information regarding the use of tasimemedone during lactation. Infant drowsiness and feeding should be monitored, especially in breastfed newborns or preterm infants. Alternative medications may be preferred until more data are available.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.
Protein Binding
At therapeutic concentrations, tasimemedone binds to approximately 90% of proteins.

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Acute toxicity (mice): Oral LD₅₀ > 2000 mg/kg; no death or serious toxicity was observed at doses up to 2000 mg/kg [3]
- Subchronic toxicity (rats, 28 days): No significant changes were observed in body weight, food intake, hematological/biochemical parameters (ALT, AST, BUN, creatinine) at oral doses up to 100 mg/kg/day; no histopathological abnormalities were observed in major organs [3]
- Adverse reactions in humans: The most common treatment-related adverse events were mild to moderate, including headache (7-10%), somnolence (5-8%), fatigue (4-6%), and nausea (3-5%); no significant hepatotoxicity, nephrotoxicity, or cardiovascular toxicity was observed [2]
- Drug interactions: Inhibition of CYP1A2 (IC₅₀=1.2) tacimetidine (μM) and is metabolized by CYP1A2; co-administration with CYP1A2 inhibitors (e.g., fluvoxamine) increases the AUC of tacimetidine by 4.5 times; co-administration with CYP1A2 inducers (e.g., smoking) decreases the 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 belongs to the 1-benzofuran propionamide class, with its amide hydrogen atom substituted by [(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl. It is a melatonin receptor agonist used to treat non-24-hour sleep-wake rhythm disorders. It is a monocarboxylic acid amide belonging to the 1-benzofuran and cyclopropane classes, functionally related to propionamide compounds. Tasimelteon is a selective dual melatonin receptor agonist indicated for the treatment of non-24-hour sleep-wake rhythm disorders (N24HSWD). This condition is common in light-blind individuals and is typically characterized by nighttime insomnia and daytime sleepiness. In blind individuals, the lack of light stimulation leads to a prolonged 24-hour circadian rhythm cycle and may cause a gradual delay in sleep onset. Tasimelteon improves sleep by activating melatonin receptors MT1 and MT2 in the suprachiasmatic nucleus of the brain, using its "non-light" mechanism to resynchronize circadian rhythms. Tasimelteon is currently the only drug available for the treatment of non-24-hour sleep-wake disorders (N24HSWD) and received orphan drug designation from the U.S. Food and Drug Administration (FDA) in 2010. Tasimelteon is a melatonin receptor agonist. Its mechanism of action is as a melatonin receptor agonist. Tasimelteon is a melatonin receptor agonist used to treat non-24-hour sleep-wake disorders in blind patients. Tasimelteon treatment is associated with a low incidence of elevated serum enzymes, but no clinically significant cases of liver injury have been found.

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Drug Indications
Tasimelteon oral capsules are indicated for the treatment of non-24-hour sleep-wake rhythm disorders in adult patients and for the treatment of nocturnal sleep disorders in patients aged 16 years and older with Smith-Magenis syndrome.
Tasimelteon oral suspension is indicated for the treatment of nocturnal sleep disorders in patients aged 3 to 15 years with Smith-Magenis syndrome.
FDA Label
Hetlioz is indicated for the treatment of non-24-hour sleep-wake rhythm disorders in completely blind adult patients.
Treatment of non-24-hour sleep-wake disorders in totally blind patients

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

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Tacimetidine is a selective MT₁/MT₂ melatonin receptor agonist used to treat non-24-hour sleep-wake disorder (N24SWD), a circadian rhythm disorder characterized by a missynchronization of the body's biological clock with the 24-hour light-dark cycle[1][2]
- Its mechanism of action involves the activation of MT₁ and MT₂ receptors in the suprachiasmatic nucleus (SCN, the body's circadian rhythm pacemaker) of the hypothalamus, thereby modulating circadian rhythm synchronization and promoting the initiation and consolidation of sleep[1]
- Clinical efficacy: In a phase III clinical trial, tacimetidine (20 mg once daily before bedtime) enabled circadian rhythm synchronization in 41% of blind patients with non-24-hour sleep-wake disorder (N24SWD) (compared to 7% in the placebo group) and improved sleep efficiency (from 65% to 78%)[1][2]
- FDA-approved indication: Treatment of non-24-hour sleep-wake disorders in adults (approved in 2014) [2] - Recommended dose: 20 mg orally once daily, 1 hour before the patient's usual bedtime (regular daily dosing is crucial for circadian rhythm synchronization) [2] - Available in oral capsules; no dose adjustment is required for elderly patients or patients with mild to moderate hepatic or renal impairment [3] - Contraindicated in patients with known hypersensitivity to tacimetidine or any component of its formulations [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

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.19 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.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (10.19 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 (10.19 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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Solubility in Formulation 4: 5%DMSO + Corn oil: 2.0mg/ml (8.15mM)

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