MT1 receptor ( Ki = 14 pM ); MT receptor (chicken) ( Ki = 23.1 pM ); MT2 receptor ( Ki = 112 pM )

Ramelteon (p.o. ; 0.1 and 1 mg/kg) quickens the running wheel activity rhythm's reentrainment to the updated light-dark cycle[3]. Ramelteon (p.o. ; 3, 10, and 30 mg/kg) does not appear to have any negative effects on learning or memory in rats when tested using the water maze task and the delayed match to position task, suggesting that MT1/MT2 receptor agonists are not addictive[3]. Ramelteon (0.0001, 0.001, 0.01, and 0.1 mg/kg; p.o.; 8 hours) increases slow-wave sleep at doses of 0.001, 0.01, and 0.1 mg/kg, increases rapid eye movement sleep at a dose of 0.1 mg/kg, and significantly reduces wakefulness at doses of 0.001, 0.01, and 0.1 mg/kg[4].

The human MT1 gene is inserted into CHO cells via cDNA. At confluence, cells are removed and collected by centrifugation in Hanks' balanced salt solution, which is free of calcium and magnesium and contains 5 mM EDTA. Before the binding tests are carried out, the cells are homogenized in an ice-cold 50 mM Tris-HCl buffer, twice cleaned, pelleted, and kept at -30°C. The thawed homogenate is combined with the test compound and 40 pM 2-[125I]melatonin in a volume of 1 mL, and it is then incubated for 150 minutes at 25°C. After adding 3 mL of ice-cold buffer and vacuum-filtering the mixture through a Whatman GF/B, the reaction is stopped. A g-counter is used to count the radioactivity after the filter has been cleaned twice.

Ramelteon exhibits a very high affinity with Ki values of 14.0, 112, and 23.1 pM for chick forebrain melatonin receptors (comprising of melatonin1 and melatonin2 receptors) and human melatonin1 and melatonin2 receptors (expressed in CHO cells). Ramelteon's hamster brain melatonin3 binding site affinity is incredibly weak (Ki: 2.65 μM) in comparison to melatonin's (24.1 nM) affinity for the same binding site. Furthermore, there is no discernible affinity for any of the many ligand binding sites (benzodiazepine receptors, dopamine receptors, opiate receptors, ion channels, and transporters) or impact on the activity of different enzymes that ramelteon is supposed to inhibit. In CHO cells expressing human melatonin1 and melatonin2 receptors, ramelteon inhibits the production of cAMP stimulated by forskolin.

Absorption, Distribution and Excretion
Rapid, total absorption is at least 84%.
Following oral administration of radiolabeled ramelteon, 84% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 88%. Less than 0.1% of the dose was excreted in urine and feces as the parent compound.
73.6 L
In vitro protein binding of ramelteon is approximately 82% in human serum, independent of concentration. Binding to albumin accounts for most of that binding, since 70% of the drug is bound in human serum albumin. Ramelteon is not distributed selectively to red blood cells. Ramelteon has a mean volume of distribution after intravenous administration of 73.6 L, suggesting substantial tissue distribution.
Ramelteon is absorbed rapidly, with median peak concentrations occurring at approximately 0.75 hour (range, 0.5 to 1.5 hours) after fasted oral administration. Although the total absorption of ramelteon is at least 84%, the absolute oral bioavailability is only 1.8% due to extensive first-pass metabolism
Distributed into milk in rats; not known whether ramelteon is distributed into human milk.
Following oral administration of radiolabeled ramelteon, 84% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 88%. Less than 0.1% of the dose was excreted in urine and feces as the parent compound. Elimination was essentially complete by 96 hours post-dose. Repeated once daily dosing with Rozerem does not result in significant accumulation owing to the short elimination half-life of ramelteon (on average, approximately 1- 2.6 hours). The half-life of M-II is 2 to 5 hours and independent of dose. Serum concentrations of the parent drug and its metabolites in humans are at or below the lower limits of quantitation within 24 hours

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Metabolism / Metabolites
Hepatic
Metabolism of ramelteon consists primarily of oxidation to hydroxyl and carbonyl derivatives, with secondary metabolism producing glucuronide conjugates. CYP1A2 is the major isozyme involved in the hepatic metabolism of ramelteon; the CYP2C subfamily and CYP3A4 isozymes are also involved to a minor degree. The rank order of the principal metabolites by prevalence in human serum is M-II, M-IV, M-I, and M-III. These metabolites are formed rapidly and exhibit a monophasic decline and rapid elimination. The overall mean systemic exposure of M-II is approximately 20- to 100-fold higher than parent drug.

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Biological Half-Life
~1-2.6 hours

Hepatotoxicity
In several clinical trials, ramelteon was found to be well tolerated and not associated with serum enzyme elevations or evidence of liver injury. Despite, wide scale use, it has not been convincingly linked to instances of clinically apparent liver injury. A single report of worsening liver disease with jaundice, ascites, bacterial peritonitis and death in a patient with alcoholic liver disease who had started ramelteon therapy a month before has been reported. Ramelteon is not recommended in patients with impaired hepatic function.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Data from one patient indicates that ramelteon and its principle active metabolite have low levels in milk. 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
Prolactin levels increased by 4.9 mcg/L (34%) in non-breastfeeding women with chronic insomnia who were taking ramelteon 16 mg nightly for 6 months. No clinical symptoms of hyperprolactinemia were reported. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Protein Binding
~82% (in human serum)

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Interactions
Substrates of CYP isoenzymes 1A2 (e.g., theophylline), 2C9 (e.g., warfarin), 2C19 (e.g., omeprazole), 2D6 (e.g., dextromethorphan), or 3A4 (e.g., midazolam): Pharmacokinetic interaction unlikely.
Inducers of CYP isoenzymes: Pharmacokinetic interaction observed during concomitant use with rifampin (decreased concentrations of ramelteon and active metabolite). Possibly reduced ramelteon efficacy when used concomitantly with potent CYP inducers such as rifampin.
Inhibitors of CYP2D6 isoenzyme: Pharmacokinetic interaction with fluoxetine unlikely.
Inhibitors of CYP2C9 isoenzyme: Pharmacokinetic interaction observed during concomitant use with fluconazole (increased concentrations of ramelteon and active metabolite). Caution if used concomitantly with fluconazole or other potent inhibitors of CYP2C9.
For more Interactions (Complete) data for Ramelteon (7 total), please visit the HSDB record page.

[1]. Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology. 2005;48(2):301-310.

[2]. Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia. Sleep. 2009;32(3):351-360.

[3]. Ramelteon (TAK-375) accelerates reentrainment of circadian rhythm after a phase advance of the light-dark cycle in rats. J Biol Rhythms. 2005;20(1):27-37.

[4]. The sleep-promoting action of ramelteon (TAK-375) in freely moving cats. Sleep. 2004;27(7):1319-1325.

N-[2-[(8S)-2,6,7,8-tetrahydro-1H-cyclopenta[e]benzofuran-8-yl]ethyl]propanamide is a member of indanes.
Ramelteon is the first in a new class of sleep agents that selectively binds to the melatonin receptors in the suprachiasmatic nucleus (SCN). It is used for insomnia, particularly delayed sleep onset. Ramelteon has not been shown to produce dependence and has shown no potential for abuse.
Ramelteon is a Melatonin Receptor Agonist. The mechanism of action of ramelteon is as a Melatonin Receptor Agonist.
Ramelteon is a melatonin receptor agonist that is used for the treatment of insomnia. Ramelteon has not been implicated in causing serum enzyme elevations or clinically apparent liver injury.
Ramelteon is a synthetic melatonin analogue with hypnotic and circadian rhythm-modulating activities. Ramelteon binds to and activates melatonin receptors 1 and 2 in the suprachiasmatic nucleus (SCN) of the brain, thereby promoting the onset of sleep. Unlike the nonbenzodiazepine sedative hypnotics zolpidem and zaleplon, this agent does not activate GABA receptors and, so, produces no GABA receptor-mediated anxiolytic, myorelaxant, and amnesic effects.

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Drug Indication
For the treatment of insomnia characterized by difficulty with sleep onset.
FDA Label

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Mechanism of Action
Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT₁ and MT₂ receptors, and lower selectivity for the MT₃ receptor. Melatonin production is concurrent with nocturnal sleep, meaning that an increase in melatonin levels is related to the onset of self-reported sleepiness and an increase in sleep propensity. MT₁ receptors are believed to be responsible for regulation of sleepiness and facilitation of sleep onset, and MT₂ receptors are believed to mediate phase-shifting effects of melatonin on the circadian rhythm. While MT₁ and MT₂ receptors are associated with the sleep-wake cycle, MT₃ has a completely different profile, and therefore is not likely to be involved in the sleep-wake cycle. Remelteon has no appreciable affinity for the gamma-aminobutyric acid (GABA) receptor complex or receptors that bind neuropeptides, cytokines, serotonin, dopamine, norepinephrine, acetylcholine, or opiates.
Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over the MT3 receptor. Ramelteon demonstrates full agonist activity in vitro in cells expressing human MT1 or MT2 receptors. The activity of ramelteon at the MT1 and MT2 receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle. Ramelteon has no appreciable affinity for the GABA receptor complex or for receptors that bind neuropeptides, cytokines, serotonin, dopamine, noradrenaline, acetylcholine, and opiates. Ramelteon also does not interfere with the activity of a number of selected enzymes in a standard panel. The major metabolite of ramelteon, M-II, is active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT1 and MT2 receptors, respectively, and is 17- to 25-fold less potent than ramelteon in in vitro functional assays. Although the potency of M-II at MT1 and MT2 receptors is lower than the parent drug, M-II circulates at higher concentrations than the parent producing 20- to 100-fold greater mean systemic exposure when compared to ramelteon. M-II has weak affinity for the serotonin 5-HT2B receptor, but no appreciable affinity for other receptors or enzymes. Similar to ramelteon, M-II does not interfere with the activity of a number of endogenous enzymes. All other known metabolites of ramelteon are inactive

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Therapeutic Uses
Ramelteon is used in the management of insomnia characterized by difficulty with sleep onset. /Use Included in US product label/
THERAPEUTIC CATEGORY: Sedative, hypnotic

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Drug Warnings
Ramelteon did not demonstrate a respiratory depressant effect in patients with mild to moderate chronic obstructive pulmonary disease. The effect of ramelteon in patients with severe chronic obstructive pulmonary disease (e.g., those with elevated PCO2, those requiring nocturnal oxygen therapy) has not been studied, and use in these patients is not recommended. In studies in patients with mild to moderate obstructive sleep apnea, ramelteon did not produce differences in measures of apnea indices.1 However, the effect of ramelteon on severe obstructive sleep apnea has not been studied, and use in these patients is not recommended.
In a 35-night randomized study evaluating next-day residual effects of ramelteon, adult patients receiving 8 mg of the drug every night experienced reduced immediate/delayed memory recall and increased sluggishness, fatigue, and irritation at weeks 1 and 3 of treatment compared with those receiving placebo. However, next-day residual effects were not substantially different between ramelteon- and placebo-treated patients at week 5.1 2 A similar study in geriatric patients receiving 4 or 8 mg of ramelteon every night did not produce any substantial differences in measures of residual effects.
Studies employing subjective measures (e.g., questionnaires) did not reveal evidence of a withdrawal syndrome (including rebound insomnia) following discontinuance of long-term ramelteon therapy (4, 8, or 16 mg daily for up to 35 days).
No evidence of abuse potential was detected following administration of relatively high ramelteon doses (up to 20 times the recommended hypnotic dose) in patients with a history of drug (e.g., sedative-hypnotic, anxiolytic) abuse or dependence. Ramelteon does not appear to produce physical dependence.
For more Drug Warnings (Complete) data for Ramelteon (18 total), please visit the HSDB record page.

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Pharmacodynamics
Ramelteon is the first selective melatonin agonist. It works by mimicking melatonin (MT), a naturally occuring hormone that is produced during the sleep period and thought to be responsible for the regulation of circadian rhythm underlying the normal sleep-wake cycle. Ramelteon has a high affinity for the MT₁ and MT₂ receptors. The MT₁ and MT₂ receptors are located in the brain's suprachiasmatic nuclei (SCN),which is known as the body's "master clock" because it regulates the 24-hour sleep-wake cycle. Ramelteon has an active metabolite that is less potent but circulates in higher concentrations than the parent compound. The metabolite also has weak affinity for the 5HT2b receptor.

C16H21NO2

259.34

259.157

C, 74.10; H, 8.16; N, 5.40; O, 12.34

196597-26-9

Ramelteon-d3; 1432057-38-9; Ramelteon-d5; 1134159-63-9

208902

White to off-white solid powder

1.1±0.1 g/cm3

455.3±24.0 °C at 760 mmHg

113-115ºC

229.2±22.9 °C

0.0±1.1 mmHg at 25°C

1.556

2.57

1

2

4

19

331

1

O1C([H])([H])C([H])([H])C2=C1C([H])=C([H])C1C([H])([H])C([H])([H])C([H])(C([H])([H])C([H])([H])N([H])C(C([H])([H])C([H])([H])[H])=O)C=12

YLXDSYKOBKBWJQ-LBPRGKRZSA-N

InChI=1S/C16H21NO2/c1-2-15(18)17-9-7-12-4-3-11-5-6-14-13(16(11)12)8-10-19-14/h5-6,12H,2-4,7-10H2,1H3,(H,17,18)/t12-/m0/s1

N-[2-[(8S)-2,6,7,8-tetrahydro-1H-cyclopenta[e][1]benzofuran-8-yl]ethyl]propanamide

TAK-375; TAK375; trade name: Rozerem; TAK 375

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 (9.64 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 (9.64 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 (9.64 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: 0.5% methylcellulose: 30 mg/mL

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