Target Information

Target General Information

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Target ID

T97613 (Former ID: TTDI01766)

Target Name

Melatonin receptor type 1A (MTNR1A)

Synonyms

Mel1a receptor; Mel1AR; Mel-1A-R

Gene Name

MTNR1A

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Insomnia [ICD-11: 7A00-7A0Z]

Function

Likely to mediate 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. High affinity receptor for melatonin.

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BioChemical Class

GPCR rhodopsin

UniProt ID

MTR1A_HUMAN

Sequence

MQGNGSALPNASQPVLRGDGARPSWLASALACVLIFTIVVDILGNLLVILSVYRNKKLRN
AGNIFVVSLAVADLVVAIYPYPLVLMSIFNNGWNLGYLHCQVSGFLMGLSVIGSIFNITG
IAINRYCYICHSLKYDKLYSSKNSLCYVLLIWLLTLAAVLPNLRAGTLQYDPRIYSCTFA
QSVSSAYTIAVVVFHFLVPMIIVIFCYLRIWILVLQVRQRVKPDRKPKLKPQDFRNFVTM
FVVFVLFAICWAPLNFIGLAVASDPASMVPRIPEWLFVASYYMAYFNSCLNAIIYGLLNQ
NFRKEYRRIIVSLCTARVFFVDSSNDVADRVKWKPSPLMTNNNVVKVDSV

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3D Structure

Click to Show 3D Structure of This Target

PDB

Drugs and Modes of Action

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Approved Drug(s)

[+] 3 Approved Drugs

Melatonin

Drug Info

Approved

Insomnia

[2], [3], [4]

Ramelteon

Drug Info

Approved

Insomnia

[5], [6]

Tasimelteon

Drug Info

Approved

Insomnia

[7], [3]

Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

LY-156735

Drug Info

Phase 2

Anxiety disorder

[8], [9]

Neu-P11

Drug Info

Phase 2

Insomnia

[10]

Discontinued Drug(s)

[+] 6 Discontinued Drugs

Agomelatine

Drug Info

Withdrawn from market

Major depressive disorder

[11], [12]

GR-131663

Drug Info

Terminated

Anxiety disorder

[13]

GR-133347

Drug Info

Terminated

Anxiety disorder

[14]

Luzindole

Drug Info

Terminated

Sleep-wake disorder

[15], [16]

S-20928

Drug Info

Terminated

Sleep-wake disorder

[17], [18]

SL-18.1616

Drug Info

Terminated

Insomnia

[19]

Mode of Action

[+] 5 Modes of Action

Binder

[+] 1 Binder drugs

Melatonin

Drug Info

[1], [20], [21]

Modulator

[+] 5 Modulator drugs

Ramelteon

Drug Info

[22], [23]

GR-131663

Drug Info

[27]

GR-133347

Drug Info

[28]

Luzindole

Drug Info

[29]

S-20928

Drug Info

[30]

Agonist

[+] 30 Agonist drugs

Tasimelteon

Drug Info

[7]

LY-156735

Drug Info

[24]

Neu-P11

Drug Info

[25]

Agomelatine

Drug Info

[26]

SL-18.1616

Drug Info

[31]

2-iodo-melatonin

Drug Info

[34], [35]

2-methoxy-alpha,beta-didehydro-agomelatine

Drug Info

[36]

2-[125I]melatonin

Drug Info

[37]

5-HEAT

Drug Info

[40]

5-methoxy-luzindole

Drug Info

[37]

6-Cl-MLT

Drug Info

[34]

6-hydroxymelatonin

Drug Info

[34]

AAE-M-PBP-amine

Drug Info

[42]

BOMPPA

Drug Info

[44]

CBOBNEA

Drug Info

[45]

CIFEA

Drug Info

[46]

difluoroagomelatine

Drug Info

[48]

EFPPEA

Drug Info

[49]

GR 128107

Drug Info

[50]

GR 196429

Drug Info

[51]

IIK7

Drug Info

[52]

isoamyl-agomelatine

Drug Info

[48]

S24014

Drug Info

[56]

S24773

Drug Info

[56]

S26284

Drug Info

[56]

UCM 765

Drug Info

[58]

UCM 793

Drug Info

[58]

[125I]DIV880

Drug Info

[59]

[125I]S70254

Drug Info

[59]

[125I]SD6

Drug Info

[59]

Antagonist

[+] 9 Antagonist drugs

(hydroxymethylphenyl)agomelatine

Drug Info

[32]

2-(indolin-1yl)-melatonin

Drug Info

[33]

4P-PDOT

Drug Info

[39]

DH97

Drug Info

[47]

K185

Drug Info

[52]

S22153

Drug Info

[56]

S26131

Drug Info

[56]

UCM 549

Drug Info

[57]

UCM 724

Drug Info

[57]

Inhibitor

[+] 17 Inhibitor drugs

4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one

Drug Info

[38]

5-methoxycarbonylamino-N-acetyltryptamine

Drug Info

[41]

Beta,beta-dimethylmelatonin

Drug Info

[43]

Beta-methylmelatonin

Drug Info

[43]

N-(2,3,4,9-Tetrahydro-1H-carbazol-3-yl)-acetamide

Drug Info

[53]

N-(2,3-Dihydro-1H-phenalen-2-yl)-acetamide

Drug Info

[54]

N-(2-(5-methoxybenzofuran-3-yl)ethyl)acetamide

Drug Info

[41]

N-(3-(2,5-dimethoxyphenyl)propyl)acetamide

Drug Info

[55]

N-(3-(2-ethoxy-5-methoxyphenyl)propyl)acetamide

Drug Info

[55]

N-(3-(2-hydroxy-5-methoxyphenyl)propyl)acetamide

Drug Info

[55]

N-(3-(3-methoxyphenyl)-3-phenylallyl)acetamide

Drug Info

[33]

N-(3-(3-methoxyphenyl)propyl)acetamide

Drug Info

[55]

N-(3-(3-methoxyphenyl)propyl)propionamide

Drug Info

[55]

N-(3-(4-hydroxy-3-methoxyphenyl)propyl)acetamide

Drug Info

[55]

N-(3-(5-methoxy-2-propoxyphenyl)propyl)acetamide

Drug Info

[55]

N-acetylserotonin

Drug Info

[54]

UCM-454

Drug Info

[33]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 2 KEGG Pathways

Neuroactive ligand-receptor interaction

Circadian entrainment

Reactome

[+] 2 Reactome Pathways

Class A/1 (Rhodopsin-like receptors)

G alpha (i) signalling events

WikiPathways

[+] 4 WikiPathways

GPCRs, Class A Rhodopsin-like

Small Ligand GPCRs

GPCR ligand binding

GPCR downstream signaling

Target-Related Models and Studies

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Target Validation

Target Validation Info

Target QSAR Model

References

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REF 1

The 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 2

URL: 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 3

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 4

Melatonin and melatonergic drugs on sleep: possible mechanisms of action. Int J Neurosci. 2009;119(6):821-46.

REF 5

REF 6

Emerging therapies for fibromyalgia. Expert Opin Emerg Drugs. 2008 Mar;13(1):53-62.

REF 7

REF 8

REF 9

Melatonin and its receptors: a new class of sleep-promoting agents. J Clin Sleep Med. 2007 Aug 15;3(5 Suppl):S17-23.

REF 10

ClinicalTrials.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 11

REF 12

Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 2008 Aug;33(9):2080-92.

REF 13

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003455)

REF 14

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003420)

REF 15

REF 16

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000705)

REF 17

REF 18

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006913)

REF 19

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014349)

REF 20

Coexpression of MT1 and RORalpha1 melatonin receptors in the Syrian hamster Harderian gland. J Pineal Res. 2005 Aug;39(1):21-6.

REF 21

Pharmacological characterization of human recombinant melatonin mt(1) and MT(2) receptors. Br J Pharmacol. 2000 Mar;129(5):877-86.

REF 22

MT1 and MT2 melatonin receptors: ligands, models, oligomers, and therapeutic potential. J Med Chem. 2014 Apr 24;57(8):3161-85.

REF 23

Ramelteon: a melatonin receptor agonist for the treatment of insomnia. J Postgrad Med. 2008 Jan-Mar;54(1):45-8.

REF 24

Melatonin and sleep in aging population. Exp Gerontol. 2005 Dec;40(12):911-25.

REF 25

REF 26

Melatonin receptor agonists: SAR and applications to the treatment of sleep-wake disorders. Curr Top Med Chem. 2008;8(11):954-68.

REF 27

Novel 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 28

US patent application no. 5,151,446, Substituted 2-amidotetralins as melatonin agonists and antagonists.

REF 29

Luzindole (N-0774): a novel melatonin receptor antagonist. J Pharmacol Exp Ther. 1988 Sep;246(3):902-10.

REF 30

Effects 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 31

US patent application no. 2005,016,4987, Melatonin combination therapy for improving sleep quality.

REF 32

Synthesis of 3-phenylnaphthalenic derivatives as new selective MT(2) melatoninergic ligands. Bioorg Med Chem. 2008 Sep 15;16(18):8339-48.

REF 33

2-[(2,3-dihydro-1H-indol-1-yl)methyl]melatonin analogues: a novel class of MT2-selective melatonin receptor antagonists. J Med Chem. 2009 Feb 12;52(3):826-33.

REF 34

Characterization of a retinal melatonin receptor. J Pharmacol Exp Ther. 1985 Aug;234(2):395-401.

REF 35

Synthesis of nitroindole derivatives with high affinity and selectivity for melatoninergic binding sites MT(3). J Med Chem. 2002 Apr 25;45(9):1853-9.

REF 36

Synthesis 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 37

Melatonin 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 38

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 rec... J Med Chem. 2010 Sep 9;53(17):6386-97.

REF 39

Selective MT2 melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms. FASEB J. 1998 Sep;12(12):1211-20.

REF 40

A new melatonin receptor ligand with mt1-agonist and MT2-antagonist properties. J Pineal Res. 2000 Nov;29(4):234-40.

REF 41

Design and synthesis of benzofuranic derivatives as new ligands at the melatonin-binding site MT3. Bioorg Med Chem. 2008 May 1;16(9):4954-62.

REF 42

MT1-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 43

Mapping the melatonin receptor. 7. Subtype selective ligands based on beta-substituted N-acyl-5-methoxytryptamines and beta-substituted N-acyl-5-me... J Med Chem. 2006 Jun 15;49(12):3509-19.

REF 44

Development 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 45

Design, 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 46

1,6-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 47

Comparison 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 48

Design, 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 49

Synthesis 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 50

The putative melatonin receptor antagonist GR128107 is a partial agonist on Xenopus laevis melanophores. Br J Pharmacol. 1999 Mar;126(5):1237-45.

REF 51

GR196429: a nonindolic agonist at high-affinity melatonin receptors. J Pharmacol Exp Ther. 1998 Jun;285(3):1239-45.

REF 52

Mapping 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 53

Mapping 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 54

Synthesis of 2-amido-2,3-dihydro-1H-phenalene derivatives as new conformationally restricted ligands for melatonin receptors. J Med Chem. 1996 Aug 2;39(16):3089-95.

REF 55

Synthesis of substituted N-[3-(3-methoxyphenyl)propyl] amides as highly potent MT(2)-selective melatonin ligands. Bioorg Med Chem Lett. 2010 Apr 15;20(8):2582-5.

REF 56

New selective ligands of human cloned melatonin MT1 and MT2 receptors. Naunyn Schmiedebergs Arch Pharmacol. 2003 Jun;367(6):553-61.

REF 57

Synthesis, 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 58

N-(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.

REF 59

New radioligands for describing the molecular pharmacology of MT1 and MT2 melatonin receptors. Int J Mol Sci. 2013 Apr 25;14(5):8948-62.

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