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Showing drug card for Ramelteon (DB00980)

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Version 2.5
Creation Date 2005-06-13 13:24:05
Update Date 2009-06-23 18:07:34
Primary Accession Number DB00980
Secondary Accession Number
  • APRD01213
Name Ramelteon
Drug Type
  • Approved
  • Investigational
  • Small Molecule
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.
Synonyms
  1. TAK-375
  2. ramelteon
Brand Names
  1. Rozerem
Brand Mixtures Not Available
Chemical IUPAC Name N-[2-[(8S)-2,6,7,8-tetrahydro-1H-cyclopenta[e][1]benzoxol-8-yl]ethyl]propanamide
Chemical Formula C16H21NO2
Chemical Structure Structure
CAS Registry Number 196597-26-9
InChI Identifier InChI=1/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/f/h17H
InChI Key YLXDSYKOBKBWJQ-ZIMDTWQLDG
KEGG Drug Not Available
KEGG Compound Not Available
PubChem Compound 208902 Link Image
PubChem Substance 783731 Link Image
ChEBI ID Not Available
PharmGKB ID Not Available
HET ID Not Available
GenBank ID Not Available
Drug ID Number [DIN] Not Available
RxList Link http://www.rxlist.com/cgi/generic4/rozerem.htm Link Image
PDRhealth Link Not Available
Wikipedia Link http://en.wikipedia.org/wiki/Ramelteon Link Image
FDA Label
Material Safety Data Sheet (MSDS) Not Available
Synthesis Reference Not Available
Average Molecular Weight 259.3434
Monoisotopic Molecular Weight 259.1572
State Solid
Melting Point Not Available
Experimental Water Solubility Not Available Source: PhysProp
Predicted Water Solubility 1.64e-02 mg/mL Calculated using ALOGPS
Experimental LogP/Hydrophobicity 2.4 Source: PhysProp
Predicted LogP 3.03 Calculated using ALOGPS
Experimental LogS Not Available
Predicted LogS -4.20 Calculated using ALOGPS
Experimental Caco2 Permeability Not Available
pKa/Isoelectric Point Not Available
Mass Spectrum Not Available
MOL File Show Link Image | Download Link Image
SDF File Show Link Image | Download Link Image
PDB File Show Link Image | Download Link Image
2D Structure
3D Structure
Experimental PDB ID Not Available
Isomeric SMILES CCC(=O)NCC[C@@H]1CCC2=C1C1=C(OCC1)C=C2
Canonical SMILES CCC(=O)NCCC1CCC2=C1C1=C(OCC1)C=C2
Drug Category
  • Hypnotics and Sedatives
ATC Codes Not Available
AHFS Codes Not Available
Indication For the treatment of insomnia characterized by difficulty with sleep onset.
Pharmacology Ramelton is the first selective melatonin agonist. It works by mimicing melatonin (MT), a naturally occuring hormone that is produced during the sleep period. It has a high affinity for the MT1 and MT2 receptor. The MT1 and MT2 receptors are located in the brain's suprachiasmatic nuclei (SCN). The SCN is known as the body's "master clock" because it regulates the 24-hour sleep-wake cycle. Ramelton 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 Ramelton 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, and high selectivity for human MT 1 and MT2 receptors compared to the MT3 receptor.
Absorption Rapid, total absorption is at least 84%.
Toxicity Not Available
Protein Binding ~82% (in human serum)
Biotransformation Hepatic
Half Life ~1-2.6 hours
Dosage Forms
Form Route
Tablet Oral
Patient Information Show Link Image
Contraindications Show Link Image
Interactions Show Link Image
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 This imidazole increases levels/toxicity of ramelteon
Fluvoxamine Fluvoxamine increases levels/toxicity of ramelteon
Ketoconazole This imidazole increases levels/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
Zileuton Zileuton increases levels/toxicity of ramelteon
Food Interactions
  • Avoid alcohol.
  • Do not take with or immediately after a high-fat meal.
Pathways Not Available
General References
  1. Drugs.com Link Image
  2. Wikipedia Link Image
  3. RxList Link Image
Organisms Affected
  • Humans and other mammals
Phase 1 Metabolizing Enzymes
  1. Cytochrome P450 1A2 (CYP1A2)
Targets
  1. Melatonin receptor type 1B
  2. Melatonin receptor type 1A
Phase 1 Metabolizing Enzyme 1 [top]
Enzyme 1 Name Cytochrome P450 1A2 (CYP1A2)
Enzyme 1 Gene Name CYP1A2
Enzyme 1 SwissProt ID P05177 Link Image
Enzyme 1 SNPs SNPJam Report Link Image
Enzyme 1 Protein Sequence >P05177|CP1A2_HUMAN Cytochrome P450 1A2 - Homo sapiens (Human). 
MALSQSVPFSATELLLASAIFCLVFWVLKGLRPRVPKGLKSPPEPWGWPLLGHVLTLGKN
PHLALSRMSQRYGDVLQIRIGSTPVLVLSRLDTIRQALVRQGDDFKGRPDLYTSTLITDG
QSLTFSTDSGPVWAARRRLAQNALNTFSIASDPASSSSCYLEEHVSKEAKALISRLQELM
AGPGHFDPYNQVVVSVANVIGAMCFGQHFPESSDEMLSLVKNTHEFVETASSGNPLDFFP
ILRYLPNPALQRFKAFNQRFLWFLQKTVQEHYQDFDKNSVRDITGALFKHSKKGPRASGN
LIPQEKIVNLVNDIFGAGFDTVTTAISWSLMYLVTKPEIQRKIQKELDTVIGRERRPRLS
DRPQLPYLEAFILETFRHSSFLPFTIPHSTTRDTTLNGFYIPKKCCVFVNQWQVNHDPEL
WEDPSEFRPERFLTADGTAINKPLSEKMMLFGMGKRRCIGEVLAKWEIFLFLAILLQQLE
FSVPPGVKVDLTPIYGLTMKHARCEHVQARRFSIN
Drug Target 1 [top]
Target 1 ID 362
Target 1 Name Melatonin receptor type 1B
Target 1 Synonyms
  1. Mel-1B-R
  2. Mel1b melatonin receptor
Target 1 Gene Name MTNR1B
Target 1 Protein Sequence >Melatonin receptor type 1B 
MSENGSFANCCEAGGWAVRPGWSGAGSARPSRTPRPPWVAPALSAVLIVTTAVDVVGNLL
VILSVLRNRKLRNAGNLFLVSLALADLVVAFYPYPLILVAIFYDGWALGEEHCKASAFVM
GLSVIGSVFNITAIAINRYCYICHSMAYHRIYRRWHTPLHICLIWLLTVVALLPNFFVGS
LEYDPRIYSCTFIQTASTQYTAAVVVIHFLLPIAVVSFCYLRIWVLVLQARRKAKPESRL
CLKPSDLRSFLTMFVVFVIFAICWAPLNCIGLAVAINPQEMAPQIPEGLFVTSYLLAYFN
SCLNAIVYGLLNQNFRREYKRILLALWNPRHCIQDASKGSHAEGLQSPAPPIIGVQHQAD
AL
Target 1 Number of Residues 368
Target 1 Molecular Weight 40189
Target 1 Theoretical pI 8.91
Target 1 GO Classification
Function
melatonin receptor activity
signal transducer activity
receptor activity
transmembrane receptor activity
G-protein coupled receptor activity
rhodopsin-like receptor activity
Process
cellular process
cell communication
signal transduction
cell surface receptor linked signal transduction
G-protein coupled receptor protein signaling pathway
Component
cell
membrane
intrinsic to membrane
integral to membrane
Target 1 General Function Involved in rhodopsin-like receptor activity
Target 1 Specific Function 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
Target 1 Pathways Not Available
Target 1 Reactions Not Available
Target 1 Pfam Domain Function
Target 1 Signals
  • None
Target 1 Transmembrane Regions
  • 43-63
  • 77-97
  • 116-136
  • 156-176
  • 201-221
  • 254-274
  • 288-308
Target 1 Essentiality Non-Essential
Target 1 GenBank ID Protein 971194 Link Image
Target 1 UniProtKB/Swiss-Prot ID P49286 Link Image
Target 1 UniProtKB/Swiss-Prot Entry Name MTR1B_HUMAN Link Image
Target 1 PDB ID Not Available
Target 1 Cellular Location
  • Membrane
  • multi-pass membrane protein
Target 1 Gene Sequence >1089 bp 
ATGTCAGAGAACGGCTCCTTCGCCAACTGCTGCGAGGCGGGCGGGTGGGCAGTGCGCCCG
GGCTGGTCGGGGGCTGGCAGCGCGCGGCCCTCCAGGACCCCTCGACCTCCCTGGGTGGCT
CCAGCGCTGTCCGCGGTGCTCATCGTCACCACCGCCGTGGACGTCGTGGGCAACCTCCTG
GTGATCCTCTCCGTGCTCAGGAACCGCAAGCTCCGGAACGCAGGTAATTTGTTCTTGGTG
AGTCTGGCATTGGCTGACCTGGTGGTGGCCTTCTACCCCTACCCGCTAATCCTCGTGGCC
ATCTTCTATGACGGCTGGGCCCTGGGGGAGGAGCACTGCAAGGCCAGCGCCTTTGTGATG
GGCCTGAGCGTCATCGGCTCTGTCTTCAATATCACTGCCATCGCCATTAACCGCTACTGC
TACATCTGCCACAGCATGGCCTACCACCGAATCTACCGGCGCTGGCACACCCCTCTGCAC
ATCTGCCTCATCTGGCTCCTCACCGTGGTGGCCTTGCTGCCCAACTTCTTTGTGGGGTCC
CTGGAGTACGACCCACGCATCTATTCCTGCACCTTCATCCAGACCGCCAGCACCCAGTAC
ACGGCGGCAGTGGTGGTCATCCACTTCCTCCTCCCTATCGCTGTCGTGTCCTTCTGCTAC
CTGCGCATCTGGGTGCTGGTGCTTCAGGCCCGCAGGAAAGCCAAGCCAGAGAGCAGGCTG
TGCCTGAAGCCCAGCGACTTGCGGAGCTTTCTAACCATGTTTGTGGTGTTTGTGATCTTT
GCCATCTGCTGGGCTCCACTTAACTGCATCGGCCTCGCTGTGGCCATCAACCCCCAAGAA
ATGGCTCCCCAGATCCCTGAGGGGCTATTTGTCACTAGCTACTTACTGGCTTATTTCAAC
AGCTGCCTGAATGCCATTGTCTATGGGCTCTTGAACCAAAACTTCCGCAGGGAATACAAG
AGGATCCTCTTGGCCCTTTGGAACCCACGGCACTGCATTCAAGATGCTTCCAAGGGCAGC
CACGCGGAGGGGCTGCAGAGCCCAGCTCCACCCATCATTGGTGTGCAGCACCAGGCAGAT
GCTCTCTAG
Target 1 GenBank Gene ID
Target 1 GeneCard ID MTNR1B Link Image
Target 1 GenAtlas ID MTNR1B Link Image
Target 1 HGNC ID HGNC:7464 Link Image
Target 1 Chromosome Location 11
Target 1 Locus 11q21-q22
Target 1 SNPs SNPJam Report Link Image
Target 1 General References
  1. Ebisawa T, Uchiyama M, Kajimura N, Kamei Y, Shibui K, Kim K, Kudo Y, Iwase T, Sugishita M, Jodoi T, Ikeda M, Ozeki Y, Watanabe T, Sekimoto M, Katoh M, Yamada N, Toyoshima R, Okawa M, Takahashi K, Yamauchi T: Genetic polymorphisms of human melatonin 1b receptor gene in circadian rhythm sleep disorders and controls. Neurosci Lett. 2000 Feb 11;280(1):29-32. [PubMed Link Image]
  2. Reppert SM, Godson C, Mahle CD, Weaver DR, Slaugenhaupt SA, Gusella JF: Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8734-8. [PubMed Link Image]
Target 1 Drug 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 Link Image]
  2. 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 Link Image]
  3. 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 Link Image]
  4. 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 Link Image]
  5. 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 Link Image]
Drug Target 2 [top]
Target 2 ID 571
Target 2 Name Melatonin receptor type 1A
Target 2 Synonyms
  1. Mel-1A-R
  2. Mel1a melatonin receptor
Target 2 Gene Name MTNR1A
Target 2 Protein Sequence >Melatonin receptor type 1A 
MQGNGSALPNASQPVLRGDGARPSWLASALACVLIFTIVVDILGNLLVILSVYRNKKLRN
AGNIFVVSLAVADLVVAIYPYPLVLMSIFNNGWNLGYLHCQVSGFLMGLSVIGSIFNITG
IAINRYCYICHSLKYDKLYSSKNSLCYVLLIWLLTLAAVLPNLRAGTLQYDPRIYSCTFA
QSVSSAYTIAVVVFHFLVPMIIVIFCYLRIWILVLQVRQRVKPDRKPKLKPQDFRNFVTM
FVVFVLFAICWAPLNFIGLAVASDPASMVPRIPEWLFVASYYMAYFNSCLNAIIYGLLNQ
NFRKEYRRIIVSLCTARVFFVDSSNDVADRVKWKPSPLMTNNNVVKVDSV
Target 2 Number of Residues 355
Target 2 Molecular Weight 39375
Target 2 Theoretical pI 9.75
Target 2 GO Classification
Function
melatonin receptor activity
signal transducer activity
receptor activity
transmembrane receptor activity
G-protein coupled receptor activity
rhodopsin-like receptor activity
Process
cellular process
cell communication
signal transduction
cell surface receptor linked signal transduction
G-protein coupled receptor protein signaling pathway
Component
cell
membrane
intrinsic to membrane
integral to membrane
Target 2 General Function Involved in rhodopsin-like receptor activity
Target 2 Specific Function 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
Target 2 Pathways Not Available
Target 2 Reactions Not Available
Target 2 Pfam Domain Function
Target 2 Signals
  • None
Target 2 Transmembrane Regions
  • 30-50
  • 64-84
  • 103-123
  • 143-163
  • 188-208
  • 241-261
  • 275-295
Target 2 Essentiality Non-Essential
Target 2 GenBank ID Protein 602130 Link Image
Target 2 UniProtKB/Swiss-Prot ID P48039 Link Image
Target 2 UniProtKB/Swiss-Prot Entry Name MTR1A_HUMAN Link Image
Target 2 PDB ID Not Available
Target 2 Cellular Location
  • Membrane
  • multi-pass membrane protein
Target 2 Gene Sequence >1053 bp 
ATGCAGGGCAACGGCAGCGCGCTGCCCAACGCCTCCCAGCCCGTGCTCCGCGGGGACGGC
GCGCGGCCCTCGTGGCTGGCGTCCGCCCTAGCCTGCGTCCTCATCTTCACCATCGTGGTG
GACATCCTGGGCAACCTCCTGGTCATCCTGTCGGTGTATCGGAACAAGAAGCTCAGGAAC
GCAGGAAACATCTTTGTGGTGAGCTTAGCGGTGGCAGACCTGGTGGTGGCCATTTATCCG
TACCCGTTGGTGCTGATGTCGATATTTAACAACGGGTGGAACCTGGGCTATCTGCACTGC
CAAGTCAGTGGGTTCCTGATGGGCCTGAGCGTCATCGGCTCCATATTCAACATCACCGGC
ATCGCCATCAACCGCTACTGCTACATCTGCCACAGTCTCAAGTACGACAAACTGTACAGC
AGCAAGAACTCCCTCTGCTACGTGCTCCTCATATGGCTCCTGACGCTGGCGGCCGTCCTG
CCCAACCTCCGTGCAGGGACTCTCCAGTACGACCCGAGGATCTACTCGTGCACCTTCGCC
CAGTCCGTCAGCTCCGCCTACACCATCGCCGTGGTGGTTTTCCACTTCCTCGTCCCCATG
ATCATAGTCATCTTCTGTTACCTGAGAATATGGATCCTGGTTCTCCAGGTCAGACAGAGG
GTGAAACCTGACCGCAAACCCAAACTGAAACCACAGGACTTCAGGAATTTTGTCACCATG
TTTGTGGTTTTTGTCCTCTTTGCCATTTGCTGGGCTCCTCTGAACTTCATTGGCCTGGCC
GTGGCCTCTGACCCCGCCAGCATGGTGCCTAGGATCCCAGAGTGGCTGTTTGTGGCCAGT
TACTACATGGCGTATTTCAACAGCTGCCTCAATGCCATTATATACGGGCTACTGAACCAA
AATTTCAGGAAGGAATACAGGAGAATTATAGTCTCGCTCTGTACAGCCAGGGTGTTCTTT
GTGGACAGCTCTAACGACGTGGCCGATAGGGTTAAATGGAAACCGTCTCCACTGATGACC
AACAATAATGTAGTAAAGGTGGACTCCGTTTAA
Target 2 GenBank Gene ID
Target 2 GeneCard ID MTNR1A Link Image
Target 2 GenAtlas ID MTNR1A Link Image
Target 2 HGNC ID HGNC:7463 Link Image
Target 2 Chromosome Location 4
Target 2 Locus 4q35.1
Target 2 SNPs SNPJam Report Link Image
Target 2 General References
  1. Ebisawa T, Kajimura N, Uchiyama M, Katoh M, Sekimoto M, Watanabe T, Ozeki Y, Ikeda M, Jodoi T, Sugishita M, Iwase T, Kamei Y, Kim K, Shibui K, Kudo Y, Yamada N, Toyoshima R, Okawa M, Takahashi K, Yamauchi T: Alleic variants of human melatonin 1a receptor: function and prevalence in subjects with circadian rhythm sleep disorders. Biochem Biophys Res Commun. 1999 Sep 7;262(3):832-7. [PubMed Link Image]
  2. Reppert SM, Weaver DR, Ebisawa T: Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron. 1994 Nov;13(5):1177-85. [PubMed Link Image]
Target 2 Drug 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 Link Image]
  2. 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 Link Image]
  3. 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 Link Image]
  4. 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 Link Image]
  5. 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 Link Image]

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.