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 [1], [2], [3]
Ramelteon Drug Info Approved Insomnia [4], [5]
Tasimelteon Drug Info Approved Insomnia [6], [3]
LY-156735 Drug Info Phase 2 Anxiety disorder [7], [8]
Neu-P11 Drug Info Phase 2 Insomnia [9]
Agomelatine Drug Info Withdrawn from market Major depressive disorder [10], [11]
GR-131663 Drug Info Terminated Anxiety disorder [12]
GR-133347 Drug Info Terminated Anxiety disorder [13]
Luzindole Drug Info Terminated Sleep disorders [14], [15]
Ramelteon Drug Info Terminated Circadian rhythm sleep disorder [4], [5]
S-20928 Drug Info Terminated Sleep disorders [16], [17]
SL-18.1616 Drug Info Terminated Insomnia [18]
Antagonist (hydroxymethylphenyl)agomelatine Drug Info [19]
2-(indolin-1yl)-melatonin Drug Info [20]
4P-PDOT Drug Info [21]
DH97 Drug Info [22]
K185 Drug Info [23]
S22153 Drug Info [24]
S26131 Drug Info [24]
UCM 549 Drug Info [25]
UCM 724 Drug Info [25]
Agonist 2-iodo-melatonin Drug Info [26]
2-methoxy-alpha,beta-didehydro-agomelatine Drug Info [27]
2-[125I]melatonin Drug Info [28]
5-HEAT Drug Info [29]
5-methoxy-luzindole Drug Info [28]
6-Cl-MLT Drug Info [26]
6-hydroxymelatonin Drug Info [26]
AAE-M-PBP-amine Drug Info [30]
Agomelatine Drug Info [31]
BOMPPA Drug Info [32]
CBOBNEA Drug Info [33]
CIFEA Drug Info [34]
difluoroagomelatine Drug Info [35]
EFPPEA Drug Info [36]
GR 128107 Drug Info [37]
GR 196429 Drug Info [38]
IIK7 Drug Info [23]
isoamyl-agomelatine Drug Info [35]
LY-156735 Drug Info [39]
Neu-P11 Drug Info [40]
S24014 Drug Info [24]
S24773 Drug Info [24]
S26284 Drug Info [24]
SL-18.1616 Drug Info [41]
Tasimelteon Drug Info [6]
UCM 765 Drug Info [42]
UCM 793 Drug Info [42]
[125I]DIV880 Drug Info [43]
[125I]S70254 Drug Info [43]
[125I]SD6 Drug Info [43]
[3H]melatonin Drug Info [44]
Inhibitor 4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one Drug Info [45]
5-methoxycarbonylamino-N-acetyltryptamine Drug Info [46]
Beta,beta-dimethylmelatonin Drug Info [47]
Beta-methylmelatonin Drug Info [47]
IODOMELATONIN Drug Info [48]
N-(2,3,4,9-Tetrahydro-1H-carbazol-3-yl)-acetamide Drug Info [49]
N-(2,3-Dihydro-1H-phenalen-2-yl)-acetamide Drug Info [50]
N-(2-(5-methoxybenzofuran-3-yl)ethyl)acetamide Drug Info [46]
N-(3-(2,5-dimethoxyphenyl)propyl)acetamide Drug Info [51]
N-(3-(2-ethoxy-5-methoxyphenyl)propyl)acetamide Drug Info [51]
N-(3-(2-hydroxy-5-methoxyphenyl)propyl)acetamide Drug Info [51]
N-(3-(3-methoxyphenyl)-3-phenylallyl)acetamide Drug Info [20]
N-(3-(3-methoxyphenyl)propyl)acetamide Drug Info [51]
N-(3-(3-methoxyphenyl)propyl)propionamide Drug Info [51]
N-(3-(4-hydroxy-3-methoxyphenyl)propyl)acetamide Drug Info [51]
N-(3-(5-methoxy-2-propoxyphenyl)propyl)acetamide Drug Info [51]
N-[2-(5-Hydroxy-1H-indol-3-yl)-ethyl]-acetamide Drug Info [50]
UCM-454 Drug Info [20]
Modulator GR-131663 Drug Info [52]
GR-133347 Drug Info [53]
Luzindole Drug Info [54]
Ramelteon Drug Info [55], [56]
S-20928 Drug Info [57]
Binder Melatonin Drug Info [58], [59]
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 1Melatonin and melatonergic drugs on sleep: possible mechanisms of action. Int J Neurosci. 2009;119(6):821-46.
REF 2(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 3Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 4Emerging therapies for fibromyalgia. Expert Opin Emerg Drugs. 2008 Mar;13(1):53-62.
REF 5(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 6(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 7Melatonin and its receptors: a new class of sleep-promoting agents. J Clin Sleep Med. 2007 Aug 15;3(5 Suppl):S17-23.
REF 8(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 9ClinicalTrials.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 10Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 2008 Aug;33(9):2080-92. Epub 2008 Jan 2.
REF 11(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 12Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003455)
REF 13Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003420)
REF 14(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 15Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000705)
REF 16(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 17Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006913)
REF 18Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014349)
REF 19Synthesis of 3-phenylnaphthalenic derivatives as new selective MT(2) melatoninergic ligands. Bioorg Med Chem. 2008 Sep 15;16(18):8339-48.
REF 20J 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 21Selective MT2 melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms. FASEB J. 1998 Sep;12(12):1211-20.
REF 22Comparison 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 23Mapping 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 24New 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 25Synthesis, 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 26Characterization of a retinal melatonin receptor. J Pharmacol Exp Ther. 1985 Aug;234(2):395-401.
REF 27Synthesis 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 28Melatonin 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 29A new melatonin receptor ligand with mt1-agonist and MT2-antagonist properties. J Pineal Res. 2000 Nov;29(4):234-40.
REF 30MT1-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 31Melatonin receptor agonists: SAR and applications to the treatment of sleep-wake disorders. Curr Top Med Chem. 2008;8(11):954-68.
REF 32Development 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 33Design, 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 341,6-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 35Design, 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 36Synthesis 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 37The putative melatonin receptor antagonist GR128107 is a partial agonist on Xenopus laevis melanophores. Br J Pharmacol. 1999 Mar;126(5):1237-45.
REF 38GR196429: a nonindolic agonist at high-affinity melatonin receptors. J Pharmacol Exp Ther. 1998 Jun;285(3):1239-45.
REF 39Melatonin and sleep in aging population. Exp Gerontol. 2005 Dec;40(12):911-25. Epub 2005 Sep 23.
REF 40(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 41US patent application no. 2005,016,4987, Melatonin combination therapy for improving sleep quality.
REF 42N-(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 43New radioligands for describing the molecular pharmacology of MT1 and MT2 melatonin receptors. Int J Mol Sci. 2013 Apr 25;14(5):8948-62.
REF 44Pharmacological characterization of human recombinant melatonin mt(1) and MT(2) receptors. Br J Pharmacol. 2000 Mar;129(5):877-86.
REF 45J 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 46Bioorg 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 47J 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 48J 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 49Mapping 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).
REF 50J 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 51Bioorg 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 52Novel 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 53US patent application no. 5,151,446, Substituted 2-amidotetralins as melatonin agonists and antagonists.
REF 54Luzindole (N-0774): a novel melatonin receptor antagonist. J Pharmacol Exp Ther. 1988 Sep;246(3):902-10.
REF 55Ramelteon: a melatonin receptor agonist for the treatment of insomnia. J Postgrad Med. 2008 Jan-Mar;54(1):45-8.
REF 56MT1 and MT2 melatonin receptors: ligands, models, oligomers, and therapeutic potential. J Med Chem. 2014 Apr 24;57(8):3161-85.
REF 57Effects 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 58The 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 59Coexpression of MT1 and RORalpha1 melatonin receptors in the Syrian hamster Harderian gland. J Pineal Res. 2005 Aug;39(1):21-6.

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