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Identification
Name Ramelteon
Accession Number DB00980 (APRD01213)
Type small molecule
Groups approved
Description

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.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
TAK-375
Salts Not Available
Brand names
Name Company
Rozerem
Brand mixtures Not Available
Categories
  • Hypnotics and Sedatives
CAS number 196597-26-9
Weight Average: 259.3434
Monoisotopic: 259.157228921
Chemical Formula C16H21NO2
InChI Key InChIKey=YLXDSYKOBKBWJQ-LBPRGKRZSA-N
InChI
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
Plain Text
IUPAC Name
N-{2-[(8S)-1H,2H,6H,7H,8H-indeno[5,4-b]furan-8-yl]ethyl}propanamide
SMILES
CCC(=O)NCC[C@@H]1CCC2=C1C1=C(OCC1)C=C2
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Benzofurans
  • Indanes
  • Phenylpropylamines
Substructures
  • Benzofurans
  • Indanes
  • Phenols and Derivatives
  • Amino Ketones
  • Ethers
  • Benzene and Derivatives
  • Carboxylic Acids and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Carboxamides and Derivatives
  • Phenylpropylamines
  • Phenyl Esters
Pharmacology
Indication For the treatment of insomnia characterized by difficulty with sleep onset.
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.
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.
Absorption Rapid, total absorption is at least 84%.
Volume of distribution
  • 73.6 L
Protein binding ~82% (in human serum)
Metabolism
Hepatic
Route of elimination 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.
Half life ~1-2.6 hours
Clearance Not Available
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Takeda global research development center inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Rozerem 8 mg tablet 5.17 USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 6034239 1999-07-22 2019-07-22
Properties
State solid
Experimental Properties
Property Value Source
logP 2.4 Not Available
Predicted Properties
Property Value Source
water solubility 1.64e-02 g/l ALOGPS
logP 3.03 ALOGPS
logP 2.57 ChemAxon
logS -4.2 ALOGPS
pKa (strongest acidic) 15.82 ChemAxon
pKa (strongest basic) -0.4 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 2 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 38.33 ChemAxon
rotatable bond count 4 ChemAxon
refractivity 75.52 ChemAxon
polarizability 29.99 ChemAxon
References
Synthesis Reference Not Available
General Reference
  1. Karim A, Tolbert D, Cao C: Disposition kinetics and tolerance of escalating single doses of ramelteon, a high-affinity MT1 and MT2 melatonin receptor agonist indicated for treatment of insomnia. J Clin Pharmacol. 2006 Feb;46(2):140-8. Pubmed
  2. Miyamoto M: Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders. CNS Neurosci Ther. 2009 Winter;15(1):32-51. Pubmed
  3. Pandi-Perumal SR, Srinivasan V, Spence DW, Moscovitch A, Hardeland R, Brown GM, Cardinali DP: Ramelteon: a review of its therapeutic potential in sleep disorders. Adv Ther. 2009 Jun;26(6):613-26. Epub 2009 Jun 30. Pubmed
  4. Borja NL, Daniel KL: Ramelteon for the treatment of insomnia. Clin Ther. 2006 Oct;28(10):1540-55. Pubmed
  5. Roth T, Stubbs C, Walsh JK: Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment. Sleep. 2005 Mar 1;28(3):303-7. Pubmed
  6. Simpson D, Curran MP: Ramelteon: a review of its use in insomnia. Drugs. 2008;68(13):1901-19. Pubmed
External Links
Resource Link
PubChem Compound 208902 Link_out
PubChem Substance 46505923 Link_out
ChemSpider 181000 Link_out
BindingDB 50118470 Link_out
Therapeutic Targets Database DAP000070 Link_out
PharmGKB PA164744896 Link_out
IUPHAR 1356 Link_out
Guide to Pharmacology 1356 Link_out
RxList http://www.rxlist.com/cgi/generic4/rozerem.htm Link_out
Drugs.com http://www.drugs.com/cdi/ramelteon.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Ramelteon Link_out
ATC Codes Not Available
AHFS Codes Not Available
PDB Entries Not Available
FDA label show (2.36 MB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Atazanavir Atazanavir increases levels/toxicity of ramelteon
Ciprofloxacin Ciprofloxacin increases levels/toxicity of ramelteon
Enoxacin Enoxacin increases levels/toxicity of ramelteon
Fluconazole Fluconazole may increase the serum levels and toxcity of ramelteon.
Fluvoxamine Fluvoxamine may increase the serum level and toxicity of ramelteon.
Ketoconazole Ketoconazole may increase the serum levels and toxicity of ramelteon.
Mexiletine Mexiletine increases levels/toxicity of ramelteon
Rifampin Rifampin reduces the levels/effect of ramelteon
Tacrine Tacrine increases levels/toxicity of ramelteon
Thiabendazole Thiabendazole increases levels/toxicity of ramelteon
Triprolidine The CNS depressants, Triprolidine and Ramelteon, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
Zileuton Zileuton increases levels/toxicity of ramelteon
Food Interactions
  • Avoid alcohol.
  • Do not take with or immediately after a high-fat meal.
Targets

1. Melatonin receptor type 1A

Pharmacological action: yes
Actions: multitarget

High affinity receptor for melatonin. Likely to mediates the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that inhibit adenylate cyclase activity

Organism class: human
UniProt ID: P48039 Link_out
Gene: MTNR1A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kato K, Hirai K, Nishiyama K, Uchikawa O, Fukatsu K, Ohkawa S, Kawamata Y, Hinuma S, Miyamoto M: Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology. 2005 Feb;48(2):301-10. Pubmed
  2. Karim A, Tolbert D, Cao C: Disposition kinetics and tolerance of escalating single doses of ramelteon, a high-affinity MT1 and MT2 melatonin receptor agonist indicated for treatment of insomnia. J Clin Pharmacol. 2006 Feb;46(2):140-8. Pubmed
  3. Greenblatt DJ, Harmatz JS, Karim A: Age and gender effects on the pharmacokinetics and pharmacodynamics of ramelteon, a hypnotic agent acting via melatonin receptors MT1 and MT2. J Clin Pharmacol. 2007 Apr;47(4):485-96. Pubmed
  4. Roth T, Stubbs C, Walsh JK: Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment. Sleep. 2005 Mar 1;28(3):303-7. Pubmed
  5. Miyamoto M: Effect of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist, on motor performance in mice. Neurosci Lett. 2006 Jul 24;402(3):201-4. Epub 2006 May 24. Pubmed
  6. Ramelteon: TAK 375. Drugs R D. 2005;6(3):186-8. Pubmed
  7. Miyamoto M: Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders. CNS Neurosci Ther. 2009 Winter;15(1):32-51. Pubmed
  8. Miyamoto M: [A novel therapeutic drug: ramelteon] Nippon Rinsho. 2009 Aug;67(8):1595-600. Pubmed
  9. Pandi-Perumal SR, Srinivasan V, Spence DW, Moscovitch A, Hardeland R, Brown GM, Cardinali DP: Ramelteon: a review of its therapeutic potential in sleep disorders. Adv Ther. 2009 Jun;26(6):613-26. Epub 2009 Jun 30. Pubmed
  10. Borja NL, Daniel KL: Ramelteon for the treatment of insomnia. Clin Ther. 2006 Oct;28(10):1540-55. Pubmed
  11. Johnson MW, Suess PE, Griffiths RR: Ramelteon: a novel hypnotic lacking abuse liability and sedative adverse effects. Arch Gen Psychiatry. 2006 Oct;63(10):1149-57. Pubmed
  12. Zammit G, Erman M, Wang-Weigand S, Sainati S, Zhang J, Roth T: Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia. J Clin Sleep Med. 2007 Aug 15;3(5):495-504. Pubmed
  13. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Melatonin receptor type 1B

Pharmacological action: yes
Actions: multitarget

High affinity receptor for melatonin. Likely to mediates the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that inhibit adenylate cyclase activity

Organism class: human
UniProt ID: P49286 Link_out
Gene: MTNR1B Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kato K, Hirai K, Nishiyama K, Uchikawa O, Fukatsu K, Ohkawa S, Kawamata Y, Hinuma S, Miyamoto M: Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology. 2005 Feb;48(2):301-10. Pubmed
  2. Karim A, Tolbert D, Cao C: Disposition kinetics and tolerance of escalating single doses of ramelteon, a high-affinity MT1 and MT2 melatonin receptor agonist indicated for treatment of insomnia. J Clin Pharmacol. 2006 Feb;46(2):140-8. Pubmed
  3. Greenblatt DJ, Harmatz JS, Karim A: Age and gender effects on the pharmacokinetics and pharmacodynamics of ramelteon, a hypnotic agent acting via melatonin receptors MT1 and MT2. J Clin Pharmacol. 2007 Apr;47(4):485-96. Pubmed
  4. Roth T, Stubbs C, Walsh JK: Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment. Sleep. 2005 Mar 1;28(3):303-7. Pubmed
  5. Miyamoto M: Effect of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist, on motor performance in mice. Neurosci Lett. 2006 Jul 24;402(3):201-4. Epub 2006 May 24. Pubmed
  6. Ramelteon: TAK 375. Drugs R D. 2005;6(3):186-8. Pubmed
  7. Miyamoto M: Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders. CNS Neurosci Ther. 2009 Winter;15(1):32-51. Pubmed
  8. Miyamoto M: [A novel therapeutic drug: ramelteon] Nippon Rinsho. 2009 Aug;67(8):1595-600. Pubmed
  9. Pandi-Perumal SR, Srinivasan V, Spence DW, Moscovitch A, Hardeland R, Brown GM, Cardinali DP: Ramelteon: a review of its therapeutic potential in sleep disorders. Adv Ther. 2009 Jun;26(6):613-26. Epub 2009 Jun 30. Pubmed
  10. Borja NL, Daniel KL: Ramelteon for the treatment of insomnia. Clin Ther. 2006 Oct;28(10):1540-55. Pubmed
  11. Johnson MW, Suess PE, Griffiths RR: Ramelteon: a novel hypnotic lacking abuse liability and sedative adverse effects. Arch Gen Psychiatry. 2006 Oct;63(10):1149-57. Pubmed
  12. Zammit G, Erman M, Wang-Weigand S, Sainati S, Zhang J, Roth T: Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia. J Clin Sleep Med. 2007 Aug 15;3(5):495-504. Pubmed
  13. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Enzymes

1. Cytochrome P450 1A2

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Obach RS, Ryder TF: Metabolism of ramelteon in human liver microsomes and correlation with the effect of fluvoxamine on ramelteon pharmacokinetics. Drug Metab Dispos. 2010 Aug;38(8):1381-91. Epub 2010 May 17. Pubmed
  2. Obach RS, Ryder TF: Metabolism of ramelteon in human liver microsomes and correlation with the effect of fluvoxamine on ramelteon pharmacokinetics. Drug Metab Dispos. 2010 Aug;38(8):1381-91. Epub 2010 May 17. Pubmed

2. Cytochrome P450 2C19

Actions: substrate

Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine

UniProt ID: P33261 Link_out
Gene: CYP2C19 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Obach RS, Ryder TF: Metabolism of ramelteon in human liver microsomes and correlation with the effect of fluvoxamine on ramelteon pharmacokinetics. Drug Metab Dispos. 2010 Aug;38(8):1381-91. Epub 2010 May 17. Pubmed

3. Cytochrome P450 3A4

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Obach RS, Ryder TF: Metabolism of ramelteon in human liver microsomes and correlation with the effect of fluvoxamine on ramelteon pharmacokinetics. Drug Metab Dispos. 2010 Aug;38(8):1381-91. Epub 2010 May 17. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19