Target Information

Target General Infomation
Target ID
T97613
Former ID
TTDI01766
Target Name
Melatonin receptor
Gene Name
MTNR1A
Synonyms
Mel1AR; Mel1a receptor; MTNR1A
Target Type
Successful
Disease Anxiety disorder [ICD9: 300, 311; ICD10: F32, F40-F42]
Circadian rhythm sleep disorder [ICD9: 327.3, 780.55; ICD10: G47.2]
Insomnia [ICD9: 307.41, 307.42, 327.0, 780.51, 780.52; ICD10: F51.0, G47.0]
Major depressive disorder [ICD9: 296.2, 296.3, 710.0; ICD10: F32, F33, M32]
Sleep disorders [ICD9: 307.4, 327, 780.5; ICD10: F51, G47]
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.
BioChemical Class
GPCR rhodopsin
Target Validation
T31415
UniProt ID
P48039
Sequence
MQGNGSALPNASQPVLRGDGARPSWLASALACVLIFTIVVDILGNLLVILSVYRNKKLRN
AGNIFVVSLAVADLVVAIYPYPLVLMSIFNNGWNLGYLHCQVSGFLMGLSVIGSIFNITG
IAINRYCYICHSLKYDKLYSSKNSLCYVLLIWLLTLAAVLPNLRAGTLQYDPRIYSCTFA
QSVSSAYTIAVVVFHFLVPMIIVIFCYLRIWILVLQVRQRVKPDRKPKLKPQDFRNFVTM
FVVFVLFAICWAPLNFIGLAVASDPASMVPRIPEWLFVASYYMAYFNSCLNAIIYGLLNQ
NFRKEYRRIIVSLCTARVFFVDSSNDVADRVKWKPSPLMTNNNVVKVDSV
Drugs and Mode of Action
Drug(s) Melatonin Drug Info Approved Insomnia [537181], [539417], [551871]
Ramelteon Drug Info Approved Insomnia [536647], [538833]
Tasimelteon Drug Info Approved Insomnia [542414], [551871]
LY-156735 Drug Info Phase 2 Anxiety disorder [529024], [538829]
Neu-P11 Drug Info Phase 2 Insomnia [523722]
Agomelatine Drug Info Withdrawn from market Major depressive disorder [536580], [539276]
GR-131663 Drug Info Terminated Anxiety disorder [545488]
GR-133347 Drug Info Terminated Anxiety disorder [545477]
Luzindole Drug Info Terminated Sleep disorders [538841], [544715]
Ramelteon Drug Info Terminated Circadian rhythm sleep disorder [536647], [538833]
S-20928 Drug Info Terminated Sleep disorders [538838], [546213]
SL-18.1616 Drug Info Terminated Insomnia [547238]
Antagonist (hydroxymethylphenyl)agomelatine Drug Info [529678]
2-(indolin-1yl)-melatonin Drug Info [529949]
4P-PDOT Drug Info [534706]
DH97 Drug Info [534767]
K185 Drug Info [525729]
S22153 Drug Info [526629]
S26131 Drug Info [526629]
UCM 549 Drug Info [529075]
UCM 724 Drug Info [529075]
Agonist 2-iodo-melatonin Drug Info [533401]
2-methoxy-alpha,beta-didehydro-agomelatine Drug Info [532164]
2-[125I]melatonin Drug Info [534353]
5-HEAT Drug Info [525901]
5-methoxy-luzindole Drug Info [534353]
6-Cl-MLT Drug Info [533401]
6-hydroxymelatonin Drug Info [533401]
AAE-M-PBP-amine Drug Info [532022]
Agomelatine Drug Info [536794]
BOMPPA Drug Info [532148]
CBOBNEA Drug Info [530895]
CIFEA Drug Info [531426]
difluoroagomelatine Drug Info [531787]
EFPPEA Drug Info [531472]
GR 128107 Drug Info [525470]
GR 196429 Drug Info [534642]
IIK7 Drug Info [525729]
isoamyl-agomelatine Drug Info [531787]
LY-156735 Drug Info [536144]
Neu-P11 Drug Info [543744]
S24014 Drug Info [526629]
S24773 Drug Info [526629]
S26284 Drug Info [526629]
SL-18.1616 Drug Info [550889]
Tasimelteon Drug Info [542414]
UCM 765 Drug Info [529190]
UCM 793 Drug Info [529190]
[125I]DIV880 Drug Info [532369]
[125I]S70254 Drug Info [532369]
[125I]SD6 Drug Info [532369]
[3H]melatonin Drug Info [525706]
Inhibitor 4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one Drug Info [531079]
5-methoxycarbonylamino-N-acetyltryptamine Drug Info [529396]
Beta,beta-dimethylmelatonin Drug Info [528234]
Beta-methylmelatonin Drug Info [528234]
IODOMELATONIN Drug Info [526317]
N-(2,3,4,9-Tetrahydro-1H-carbazol-3-yl)-acetamide Drug Info [551266]
N-(2,3-Dihydro-1H-phenalen-2-yl)-acetamide Drug Info [534186]
N-(2-(5-methoxybenzofuran-3-yl)ethyl)acetamide Drug Info [529396]
N-(3-(2,5-dimethoxyphenyl)propyl)acetamide Drug Info [530786]
N-(3-(2-ethoxy-5-methoxyphenyl)propyl)acetamide Drug Info [530786]
N-(3-(2-hydroxy-5-methoxyphenyl)propyl)acetamide Drug Info [530786]
N-(3-(3-methoxyphenyl)-3-phenylallyl)acetamide Drug Info [529949]
N-(3-(3-methoxyphenyl)propyl)acetamide Drug Info [530786]
N-(3-(3-methoxyphenyl)propyl)propionamide Drug Info [530786]
N-(3-(4-hydroxy-3-methoxyphenyl)propyl)acetamide Drug Info [530786]
N-(3-(5-methoxy-2-propoxyphenyl)propyl)acetamide Drug Info [530786]
N-[2-(5-Hydroxy-1H-indol-3-yl)-ethyl]-acetamide Drug Info [534186]
UCM-454 Drug Info [529949]
Modulator GR-131663 Drug Info [525346]
GR-133347 Drug Info [550913]
Luzindole Drug Info [533364]
Ramelteon Drug Info [529337], [532551]
S-20928 Drug Info [534707]
Binder Melatonin Drug Info [536063], [536104]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Neuroactive ligand-receptor interaction
Circadian entrainment
Reactome Class A/1 (Rhodopsin-like receptors)
G alpha (i) signalling events
WikiPathways GPCRs, Class A Rhodopsin-like
Small Ligand GPCRs
GPCR ligand binding
GPCR downstream signaling
References
Ref 523722ClinicalTrials.gov (NCT01489969) Sleep Laboratory Study to Investigate the Safety and Efficacy of Neu-P11 in Primary Insomnia Patients. U.S. National Institutes of Health.
Ref 529024Melatonin and its receptors: a new class of sleep-promoting agents. J Clin Sleep Med. 2007 Aug 15;3(5 Suppl):S17-23.
Ref 536580Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 2008 Aug;33(9):2080-92. Epub 2008 Jan 2.
Ref 536647Emerging therapies for fibromyalgia. Expert Opin Emerg Drugs. 2008 Mar;13(1):53-62.
Ref 537181Melatonin and melatonergic drugs on sleep: possible mechanisms of action. Int J Neurosci. 2009;119(6):821-46.
Ref 538829(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 1351).
Ref 538833(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 1356).
Ref 538838(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 1360).
Ref 538841(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 1363).
Ref 539276(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 198).
Ref 539417(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 224).
Ref 542414(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7393).
Ref 544715Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000705)
Ref 545477Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003420)
Ref 545488Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003455)
Ref 546213Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006913)
Ref 547238Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014349)
Ref 551871Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
Ref 525346Novel non-indolic melatonin receptor agonists differentially entrain endogenous melatonin rhythm and increase its amplitude. Eur J Pharmacol. 1999 Oct 15;382(3):157-66.
Ref 525470The putative melatonin receptor antagonist GR128107 is a partial agonist on Xenopus laevis melanophores. Br J Pharmacol. 1999 Mar;126(5):1237-45.
Ref 525706Pharmacological characterization of human recombinant melatonin mt(1) and MT(2) receptors. Br J Pharmacol. 2000 Mar;129(5):877-86.
Ref 525729Mapping the melatonin receptor. 6. Melatonin agonists and antagonists derived from 6H-isoindolo[2,1-a]indoles, 5,6-dihydroindolo[2,1-a]isoquinolines, and 6,7-dihydro-5H-benzo[c]azepino[2,1-a]indoles.J Med Chem. 2000 Mar 23;43(6):1050-61.
Ref 525901A new melatonin receptor ligand with mt1-agonist and MT2-antagonist properties. J Pineal Res. 2000 Nov;29(4):234-40.
Ref 526317J Med Chem. 2002 Apr 25;45(9):1853-9.Synthesis of nitroindole derivatives with high affinity and selectivity for melatoninergic binding sites MT(3).
Ref 526629New selective ligands of human cloned melatonin MT1 and MT2 receptors. Naunyn Schmiedebergs Arch Pharmacol. 2003 Jun;367(6):553-61. Epub 2003 May 23.
Ref 528234J Med Chem. 2006 Jun 15;49(12):3509-19.Mapping the melatonin receptor. 7. Subtype selective ligands based on beta-substituted N-acyl-5-methoxytryptamines and beta-substituted N-acyl-5-methoxy-1-methyltryptamines.
Ref 529075Synthesis, enantiomeric resolution, and structure-activity relationship study of a series of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene MT2 receptor antagonists. ChemMedChem. 2007 Dec;2(12):1741-9.
Ref 529190N-(substituted-anilinoethyl)amides: design, synthesis, and pharmacological characterization of a new class of melatonin receptor ligands. J Med Chem. 2007 Dec 27;50(26):6618-26. Epub 2007 Dec 6.
Ref 529337Ramelteon: a melatonin receptor agonist for the treatment of insomnia. J Postgrad Med. 2008 Jan-Mar;54(1):45-8.
Ref 529396Bioorg Med Chem. 2008 May 1;16(9):4954-62. Epub 2008 Mar 17.Design and synthesis of benzofuranic derivatives as new ligands at the melatonin-binding site MT3.
Ref 529678Synthesis of 3-phenylnaphthalenic derivatives as new selective MT(2) melatoninergic ligands. Bioorg Med Chem. 2008 Sep 15;16(18):8339-48.
Ref 529949J Med Chem. 2009 Feb 12;52(3):826-33.2-[(2,3-dihydro-1H-indol-1-yl)methyl]melatonin analogues: a novel class of MT2-selective melatonin receptor antagonists.
Ref 530786Bioorg Med Chem Lett. 2010 Apr 15;20(8):2582-5. Epub 2010 Feb 25.Synthesis of substituted N-[3-(3-methoxyphenyl)propyl] amides as highly potent MT(2)-selective melatonin ligands.
Ref 530895Design, synthesis and pharmacological evaluation of novel naphthalenic derivatives as selective MT(1) melatoninergic ligands. Bioorg Med Chem. 2010 May 15;18(10):3426-36.
Ref 531079J Med Chem. 2010 Sep 9;53(17):6386-97.Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential.
Ref 5314261,6-Dihydro-2H-indeno[5,4-b]furan derivatives: design, synthesis, and pharmacological characterization of a novel class of highly potent MT??selective agonists. J Med Chem. 2011 May 12;54(9):3436-44.
Ref 531472Synthesis of a novel series of tricyclic dihydrofuran derivatives: discovery of 8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridines as melatonin receptor (MT1/MT2) ligands. J Med Chem. 2011 Jun 23;54(12):4207-18.
Ref 531787Design, synthesis and pharmacological evaluation of new series of naphthalenic analogues as melatoninergic (MT1/MT2) and serotoninergic 5-HT2C dual ligands (I). Eur J Med Chem. 2012 Mar;49:310-23.
Ref 532022MT1-selective melatonin receptor ligands: synthesis, pharmacological evaluation, and molecular dynamics investigation of N-{[(3-O-substituted)anilino]alkyl}amides. ChemMedChem. 2012 Nov;7(11):1954-64.
Ref 532148Development of substituted N-[3-(3-methoxylphenyl)propyl] amides as MT(2)-selective melatonin agonists: improving metabolic stability. Bioorg Med Chem. 2013 Jan 15;21(2):547-52.
Ref 532164Synthesis of new N-(arylcyclopropyl)acetamides and N-(arylvinyl)acetamides as conformationally-restricted ligands for melatonin receptors. Bioorg Med Chem Lett. 2013 Jan 15;23(2):430-4.
Ref 532369New radioligands for describing the molecular pharmacology of MT1 and MT2 melatonin receptors. Int J Mol Sci. 2013 Apr 25;14(5):8948-62.
Ref 532551MT1 and MT2 melatonin receptors: ligands, models, oligomers, and therapeutic potential. J Med Chem. 2014 Apr 24;57(8):3161-85.
Ref 533364Luzindole (N-0774): a novel melatonin receptor antagonist. J Pharmacol Exp Ther. 1988 Sep;246(3):902-10.
Ref 533401Characterization of a retinal melatonin receptor. J Pharmacol Exp Ther. 1985 Aug;234(2):395-401.
Ref 534186J Med Chem. 1996 Aug 2;39(16):3089-95.Synthesis of 2-amido-2,3-dihydro-1H-phenalene derivatives as new conformationally restricted ligands for melatonin receptors.
Ref 534353Melatonin receptor antagonists that differentiate between the human Mel1a and Mel1b recombinant subtypes are used to assess the pharmacological profile of the rabbit retina ML1 presynaptic heteroreceptor. Naunyn Schmiedebergs Arch Pharmacol. 1997 Mar;355(3):365-75.
Ref 534642GR196429: a nonindolic agonist at high-affinity melatonin receptors. J Pharmacol Exp Ther. 1998 Jun;285(3):1239-45.
Ref 534706Selective MT2 melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms. FASEB J. 1998 Sep;12(12):1211-20.
Ref 534707Effects of two melatonin analogues, S-20098 and S-20928, on melatonin receptors in the pars tuberalis of the rat. J Pineal Res. 1998 Oct;25(3):172-6.
Ref 534767Comparison of the structure-activity relationships of melatonin receptor agonists and antagonists: lengthening the N-acyl side-chain has differing effects on potency on Xenopus melanophores. Naunyn Schmiedebergs Arch Pharmacol. 1998 Nov;358(5):522-8.
Ref 536063The human MT1 melatonin receptor stimulates cAMP production in the human neuroblastoma cell line SH-SY5Y cells via a calcium-calmodulin signal transduction pathway. J Neuroendocrinol. 2005 Mar;17(3):170-8.
Ref 536104Coexpression of MT1 and RORalpha1 melatonin receptors in the Syrian hamster Harderian gland. J Pineal Res. 2005 Aug;39(1):21-6.
Ref 536144Melatonin and sleep in aging population. Exp Gerontol. 2005 Dec;40(12):911-25. Epub 2005 Sep 23.
Ref 536794Melatonin receptor agonists: SAR and applications to the treatment of sleep-wake disorders. Curr Top Med Chem. 2008;8(11):954-68.
Ref 542414(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7393).
Ref 543744(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 288).
Ref 550889US patent application no. 2005,016,4987, Melatonin combination therapy for improving sleep quality.
Ref 550913US patent application no. 5,151,446, Substituted 2-amidotetralins as melatonin agonists and antagonists.
Ref 551266Mapping the melatonin receptor. 2. synthesis and biological activity of indole derived melatonin analogues with restricted conformations of the C-3 amidoethane side chain, Bioorg. Med. Chem. Lett. 4(13):1559-1564 (1994).

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