MTNR1A

Summary

MTNR1A (melatonin receptor 1A, HGNC:7463) is a protein-coding gene on chromosome 4q35.2, encoding Melatonin receptor type 1A (P48039). High affinity receptor for melatonin.

This gene encodes one of two high affinity forms of a receptor for melatonin, the primary hormone secreted by the pineal gland. This receptor is a G-protein coupled, 7-transmembrane receptor that is responsible for melatonin effects on mammalian circadian rhythm and reproductive alterations affected by day length. The receptor is an integral membrane protein that is readily detectable and localized to two specific regions of the brain. The hypothalamic suprachiasmatic nucleus appears to be involved in circadian rhythm while the hypophysial pars tuberalis may be responsible for the reproductive effects of melatonin.

Source: NCBI Gene 4543 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 52 total — 1 pathogenic
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005958

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7463
Approved symbol	MTNR1A
Name	melatonin receptor 1A
Location	4q35.2
Locus type	gene with protein product
Status	Approved
Aliases	MEL-1A-R
Ensembl gene	ENSG00000168412
Ensembl biotype	protein_coding
OMIM	600665
Entrez	4543

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000307161, ENST00000703170

RefSeq mRNA: 1 — MANE Select: NM_005958 NM_005958

CCDS: CCDS3848

Canonical transcript exons

ENST00000307161 — 2 exons

Exon	Start	End
ENSE00001149248	186555182	186555567
ENSE00003988239	186533655	186534557

Expression profiles

Bgee: expression breadth broad, 50 present calls, max score 88.90.

Top tissues by expression

234 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.90	gold quality
palpebral conjunctiva	UBERON:0001812	67.74	gold quality
hair follicle	UBERON:0002073	61.06	gold quality
rectum	UBERON:0001052	58.67	gold quality
islet of Langerhans	UBERON:0000006	57.50	gold quality
decidua	UBERON:0002450	56.55	gold quality
adult mammalian kidney	UBERON:0000082	54.75	gold quality
nasal cavity epithelium	UBERON:0005384	51.93	gold quality
colonic epithelium	UBERON:0000397	51.71	gold quality
vermiform appendix	UBERON:0001154	51.36	gold quality
gall bladder	UBERON:0002110	51.29	gold quality
cerebellar cortex	UBERON:0002129	50.24	gold quality
cerebellar hemisphere	UBERON:0002245	49.86	gold quality
cerebellum	UBERON:0002037	49.80	gold quality
caecum	UBERON:0001153	48.82	gold quality
kidney	UBERON:0002113	48.66	gold quality
mucosa of transverse colon	UBERON:0004991	48.36	gold quality
right hemisphere of cerebellum	UBERON:0014890	48.23	gold quality
pancreas	UBERON:0001264	48.13	gold quality
buccal mucosa cell	CL:0002336	48.08	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	44.71	gold quality
nasal cavity mucosa	UBERON:0001826	44.57	gold quality
transverse colon	UBERON:0001157	44.14	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
body of pancreas	UBERON:0001150	42.40	silver quality
duodenum	UBERON:0002114	41.98	gold quality
cortex of kidney	UBERON:0001225	41.58	gold quality
vastus lateralis	UBERON:0001379	41.41	gold quality
quadriceps femoris	UBERON:0001377	41.37	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.95

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 40)

• Increased melatonin 1a-receptor immunoreactivity in the hippocampus of Alzheimer’s disease patients. (PMID:11841602)
• Monitoring of ligand-independent dimerization and ligand-induced conformational changes of melatonin receptors in living cells by bioluminescence resonance energy transfer (melatonin receptor 2) (PMID:11940583)
• Melatonin inhibited ERalpha mRNA expression & enhanced induction of pancreatic spasmolytic polypeptide in MT(1)-transfected breast cancer cells, suggesting a role for the MT(1) receptor in melatonin-regulated growth-suppression & gene-modulation. (PMID:12088876)
• Expression in cultured skin cells. (PMID:12767050)
• Identification of variants in the human melatonin receptor could provide a useful tool for testing the gene in the predisposition to various other melatonin-related disorders and for clarifying the role of melatonin in adolescent idiopathic scoliosis. (PMID:12973153)
• the first evidence for the presence of MT1 receptor in human gallbladder epithelia; might be involved in the regulation of gallbladder function (PMID:14675129)
• The colocalization of MT1 and CRH suggests that melatonin might directly modulate the hypothalamus-pituitary-adrenal axis in the PVN, which may have implications for stress conditions such as depression (PMID:17072839)
• Human osteoblasts expressed melatonin 1a receptor and its expression levels decreased gradually with the age of the hosts. (PMID:17349020)
• on the abundant expression of MT1-mRNA in human bone tumors and osteosarcoma cells lines suggest an important role for MT1 in bone pathology (PMID:17645699)
• Luzindole also stimulates downregulation of the MT1 receptor protein, interfering with the synthesis and/or degradation of the receptor (PMID:17803522)
• Truncation of the C-terminal tail of both receptors (MT(1)Y7.64 and MT(2)Y7.64) inhibited internalization as well as the cAMP response, suggesting the importance of the C-terminal tail in these receptor functions. (PMID:18341518)
• MUPP1 binds to the G protein-coupled MT(1) melatonin receptor and directly regulates its G(i)-dependent signal transduction (PMID:18378672)
• MTNR1A is the most likely target for epigenetic silencing at 4q35 and to play a pivotal role during oral carcinogenesis. (PMID:18452558)
• Promoter polymorphism of the MTNR1A gene was not associated with the occurrence or curve severity of adolescent idiopathic scoliosis. (PMID:18794763)
• These studies suggest amplification of the MT1 gene in some breast tumors (PMID:18979234)
• Melatonin synergizes with oxytocin to promote myometrial cell contractions in vitro, which in vivo would promote coordinated and forceful contractions of the late term pregnant uterus necessary for parturition. (PMID:19001515)
• MT1 receptor is a major transducer of melatonin’s actions in the breast, suppressing mammary gland development and mediating the anticancer actions of melatonin through multiple pathways. (PMID:20050373)
• The results demonstrate a down-regulation of melatonin receptors in regions affected by Parkinson disease, suggesting their possible involvement in the disease process. (PMID:20110911)
• Immunohistochemical analysis revealed that during tooth development Mel1aR was expressed in secretory ameloblasts, the cells of the stratum intermedium and stellate reticulum, external dental epithelial cells, odontoblasts, and dental sac cells. (PMID:20372918)
• Study identified six non-synonymous mutations for MTNR1A and ten for MTNR1B in autism spectrum disorders patients . The majority of these variations altered receptor function. (PMID:20657642)
• Melatonin has a modulating effect on dopaminergic neurotransmission in the brain. (PMID:20726823)
• The single nucleotide polymorphism rs2119882 is associated with polycystic ovary syndrome (PMID:21474908)
• Melatonin protects human spermatozoa from apoptosis via melatonin receptor- and extracellular signal-regulated kinase-mediated pathways. (PMID:21497337)
• Results suggest that MTNR1A may be a susceptibility gene for schizophrenia and may be associated with insomnia symptoms exhibited in schizophrenia patients. (PMID:21526376)
• Data found a splice site mutation in ASMT (IVS5+2T>C) and one stop mutation in MTNR1A (Y170X) - detected exclusively in patients with ADHD - for which biochemical analyses indicated that they abolish the activity of ASMT and MTNR1A. (PMID:21615493)
• The finding suggests a synergism effect between the unfavourable genotype (CT) of the MELIA receptor SNP and the vascular disease in this subgroup of patients. (PMID:21635358)
• Single nucleotide polymorphisms in the melatonin receptor 1A gene is associated with calcium nephrolithiasis. (PMID:21652546)
• Data indicate that melatonin receptors MT1 and MT2 expression levels decreased in both early and advanced stages of tumors in males. (PMID:21809392)
• piRNA_015520 negatively regulates MTNR1A gene expression by binding to its genomic region (PMID:21818375)
• This study delineated a pathologic process whereby mutant htt-induced loss of the mitochondrial MT1 receptor enhances neuronal vulnerability and potentially accelerates the neurodegenerative process. (PMID:21994366)
• Description of the constitutive activity of cloned human melatonin receptors hMT(1) and hMT(2) and discovery of inverse agonists. (PMID:22017484)
• Results suggest that common genetic variation in the MTNR1a and 1b genes may contribute to breast cancer susceptibility, and that associations may vary by menopausal status. (PMID:22138747)
• the decreased expression of MT1 in human colorectal cancer could point to a role of melatonin in this disease. (PMID:22217986)
• MT1 and MT2 expression is significantly reduced in preeclamptic compared with normotensive pregnancy placentas. (PMID:22686298)
• intracytoplasmic positivity for the MTNR1A receptor in the excretory ducts of human major and minor salivary glands and Warthin’s tumor was found (PMID:23155241)
• MT1 negative TNBC in all cases regardless of race showed a significantly higher hazard ratio for disease progression, shorter progression free survival, and disease-related death, and shorter OS. (PMID:23250547)
• Genetic inactivation of both transgenic MT1 and MT2 receptors produces an increase of wakefulness, likely as a result of reduced NREMS due to the lack of MT2 transgene receptors, and reduced REMS induced by the lack of MT1 transgene receptors. (PMID:23333399)
• MR-1A placental expression is elevated in all types of hypertensive syndromes in pregnancy (PMID:23725077)
• Suggest that physiological regulation of the melatonin receptors may result from complex and subtle mechanisms, a small difference in affinity between the active and inactive states of the receptor, and spontaneous coupling to G-proteins. (PMID:24117008)
• genetic polymorphisms rs2119882 in melatonin receptor 1A (MTNR1A) and rs10830963 in melatonin receptor 1B (MTNR1B) are associated with an increased risk of developing gestational diabetes mellitus and insulin resistance in Han Chinese women (PMID:24157813)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mtnr1ab	ENSDARG00000055852
mus_musculus	Mtnr1a	ENSMUSG00000054764
rattus_norvegicus	Mtnr1a	ENSRNOG00000028744

Paralogs (33): TACR2 (ENSG00000075073), PROKR2 (ENSG00000101292), GPR50 (ENSG00000102195), TACR1 (ENSG00000115353), GPR75 (ENSG00000119737), PRLHR (ENSG00000119973), GPR83 (ENSG00000123901), MCHR1 (ENSG00000128285), OR11H1 (ENSG00000130538), MTNR1B (ENSG00000134640), MCHR2 (ENSG00000152034), NPY1R (ENSG00000164128), NPY5R (ENSG00000164129), PROKR1 (ENSG00000169618), TACR3 (ENSG00000169836), OR9G1 (ENSG00000174914), OR11H4 (ENSG00000176198), OR11H6 (ENSG00000176219), OR9A2 (ENSG00000179468), GPR88 (ENSG00000181656), GPR19 (ENSG00000183150), NPY2R (ENSG00000185149), OR11G2 (ENSG00000196832), NPY4R (ENSG00000204174), OR11A1 (ENSG00000204694), OR9A1P (ENSG00000237621), OR11H12 (ENSG00000257115), OR9A4 (ENSG00000258083), OR11H2 (ENSG00000258453), OR11H7 (ENSG00000258806), NPY4R2 (ENSG00000264717), OR10X1 (ENSG00000279111), OR51F1 (ENSG00000280021)

Protein

Protein identifiers

Melatonin receptor type 1A — P48039 (reviewed: P48039)

All UniProt accessions (1): P48039

UniProt curated annotations — full annotation on UniProt →

Function. High affinity receptor for melatonin. 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. Possibly involved in sleep induction, by melatonin activation of the potassium channel KCNMA1/BK and the dissociation of G-beta and G-gamma subunits, thereby decreasing synaptic transmission.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in hypophyseal pars tuberalis and hypothalamic suprachiasmatic nuclei (SCN). Hippocampus.

Similarity. Belongs to the G-protein coupled receptor 1 family.

RefSeq proteins (1): NP_005949* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000025	Melatonin_rcpt	Family
IPR000276	GPCR_Rhodpsn	Family
IPR002278	Mel_1A/1B_rcpt	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (46 total): helix 16, topological domain 8, transmembrane region 7, turn 4, sequence variant 3, binding site 2, glycosylation site 2, strand 2, chain 1, disulfide bond 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
6ME2	X-RAY DIFFRACTION	2.8
6ME3	X-RAY DIFFRACTION	2.9
7VGY	ELECTRON MICROSCOPY	3.1
6ME4	X-RAY DIFFRACTION	3.2
6ME5	X-RAY DIFFRACTION	3.2
6PS8	X-RAY DIFFRACTION	3.3
7DB6	ELECTRON MICROSCOPY	3.3
7VGZ	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48039-F1	86.16	0.69

Antibody-complex structures (SAbDab): 3 — 7DB6, 7VGY, 7VGZ

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (2): 162; 181

Disulfide bonds (1): 100–177

Glycosylation sites (2): 4, 10

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-418594	G alpha (i) signalling events
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-388396	GPCR downstream signalling
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 57 (showing top): GOBP_CIRCADIAN_RHYTHM, GOBP_BEHAVIOR, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_REPRODUCTIVE_BEHAVIOR, KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION, chr4q35, AFFAR_YY1_TARGETS_DN, GOBP_ADENYLATE_CYCLASE_INHIBITING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, LEE_AGING_NEOCORTEX_DN, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, GOCC_RECEPTOR_COMPLEX, REACTOME_CLASS_A_1_RHODOPSIN_LIKE_RECEPTORS, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GOBP_RHYTHMIC_PROCESS, YOSHIMURA_MAPK8_TARGETS_UP

GO Biological Process (6): G protein-coupled receptor signaling pathway (GO:0007186), G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger (GO:0007187), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), mating behavior (GO:0007617), circadian rhythm (GO:0007623), signal transduction (GO:0007165)

GO Molecular Function (4): G protein-coupled receptor activity (GO:0004930), melatonin receptor activity (GO:0008502), hormone binding (GO:0042562), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), signaling receptor complex (GO:0043235), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Signaling by GPCR	2
GPCR ligand binding	1
GPCR downstream signalling	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor activity	2
G protein-coupled receptor signaling pathway	2
binding	2
signal transduction	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase inhibitor activity	1
reproductive behavior	1
rhythmic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transmembrane signaling receptor activity	1
membrane	1
cell periphery	1
protein-containing complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

724 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MTNR1A	FAT1	Q14517	871
MTNR1A	FAT3	Q8TDW7	804
MTNR1A	AANAT	Q16613	654
MTNR1A	ASMT	P46597	648
MTNR1A	PRL	P01236	520
MTNR1A	PCDHGB7	Q9Y5F8	477
MTNR1A	VAPB	O95292	473
MTNR1A	PER3	P56645	470
MTNR1A	TNFSF11	O14788	454
MTNR1A	NQO2	P16083	446
MTNR1A	ADRA2B	P18089	438
MTNR1A	GPR52	Q9Y2T5	437
MTNR1A	NPAS2	Q99743	433
MTNR1A	VGLL1	Q99990	431
MTNR1A	PER2	O15055	426

IntAct

305 interactions, top by confidence:

A	B	Type	Score
MTNR1A	CALR	psi-mi:“MI:0915”(physical association)	0.660
TMEM33	MTNR1A	psi-mi:“MI:0915”(physical association)	0.660
KRTAP1-3	MTNR1A	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	MTNR1A	psi-mi:“MI:0915”(physical association)	0.560
MTNR1A	PGRMC1	psi-mi:“MI:0914”(association)	0.530
MTNR1A	HTR2C	psi-mi:“MI:0915”(physical association)	0.470
HTR2C	MTNR1A	psi-mi:“MI:2364”(proximity)	0.470
MTNR1A	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
MTNR1A	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
MTNR1A	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
MTNR1A	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
MTNR1A	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
MTNR1A	APBA1	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	MTNR1A	psi-mi:“MI:0407”(direct interaction)	0.440
MTNR1A	GIPC2	psi-mi:“MI:0407”(direct interaction)	0.440
MTNR1A	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
MTNR1A	MPP2	psi-mi:“MI:0407”(direct interaction)	0.440
DLG4	MTNR1A	psi-mi:“MI:0407”(direct interaction)	0.440
MTNR1A	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
MTNR1A	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.440
MTNR1A	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
MTNR1A	NHERF4	psi-mi:“MI:0407”(direct interaction)	0.440
MTNR1A	PDZRN4	psi-mi:“MI:0407”(direct interaction)	0.440
MTNR1A	PALS2	psi-mi:“MI:0407”(direct interaction)	0.440
MTNR1A	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
MTNR1A	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
MTNR1A	RHPN1	psi-mi:“MI:0407”(direct interaction)	0.440
MTNR1A	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
MTNR1A	TJP3	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (298): MTNR1A (Synthetic Growth Defect), Snap25 (Reconstituted Complex), Syn1 (Reconstituted Complex), Syn2 (Reconstituted Complex), Stxbp1 (Reconstituted Complex), Cacna1b (Reconstituted Complex), CACNA1B (Affinity Capture-Western), Slc4a4 (Reconstituted Complex), Ywhab (Reconstituted Complex), Ak1 (Reconstituted Complex), Cops4 (Reconstituted Complex), Prkcz (Reconstituted Complex), Dusp3 (Reconstituted Complex), Ppp2cb (Reconstituted Complex), Rph3al (Reconstituted Complex)

ESM2 similar proteins: A6QLE7, O02769, O02781, O12000, O15974, O17899, O70528, P23820, P30966, P32251, P35364, P47898, P48039, P48040, P49217, P49218, P49219, P49285, P49286, P49287, P49288, P51046, P51047, P51048, P51049, P51050, P51051, P51052, P97288, Q03566, Q03613, Q13639, Q16950, Q16951, Q2KI97, Q59E83, Q61184, Q62758, Q62953, Q86ME6

Diamond homologs: O02213, O02769, O02781, O08892, O42384, O42385, O88495, P08913, P18089, P18825, P18871, P19328, P20905, P22086, P22909, P24628, P28285, P30545, P30729, P32251, P34973, P35405, P48039, P48040, P49217, P49218, P49219, P49285, P49286, P49287, P49288, P51046, P51047, P51048, P51049, P51050, P51051, P51052, P51436, Q01337

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
MTNR1A	“up-regulates activity”	GNAI1	binding
MTNR1A	“up-regulates activity”	GNAI3	binding
MTNR1A	“up-regulates activity”	GNAO1	binding
MTNR1A	“up-regulates activity”	GNAZ	binding
melatonin	“up-regulates activity”	MTNR1A	“chemical activation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 174 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
receptor clustering	5	19.8×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

52 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	38
Likely benign	4
Benign	6

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
831567	NC_000004.12:g.(?186149141)(186709827_?)del	Pathogenic

SpliceAI

402 predictions. Top by Δscore:

Variant	Effect	Δscore
4:186555176:CCCTA:C	donor_loss	1.0000
4:186555177:CCTA:C	donor_loss	1.0000
4:186555178:CTAC:C	donor_loss	1.0000
4:186555178:CTACC:C	donor_loss	1.0000
4:186555179:TA:T	donor_loss	1.0000
4:186555179:TACCT:T	donor_loss	1.0000
4:186555180:A:T	donor_loss	1.0000
4:186555181:C:CA	donor_loss	1.0000
4:186555181:C:CG	donor_loss	1.0000
4:186555188:T:A	donor_gain	1.0000
4:186534554:TTTC:T	acceptor_gain	0.9900
4:186534554:TTTCC:T	acceptor_loss	0.9900
4:186534555:TTC:T	acceptor_gain	0.9900
4:186534555:TTCCT:T	acceptor_loss	0.9900
4:186534558:C:CA	acceptor_loss	0.9900
4:186534558:C:CC	acceptor_gain	0.9900
4:186534559:T:A	acceptor_loss	0.9900
4:186534556:TC:T	acceptor_gain	0.9800
4:186534557:CC:C	acceptor_gain	0.9800
4:186555181:CCTG:C	donor_gain	0.9800
4:186534553:GTTTC:G	acceptor_gain	0.9600
4:186549963:A:C	donor_gain	0.9600
4:186555180:A:AC	donor_gain	0.9600
4:186555181:C:CC	donor_gain	0.9600
4:186534555:TTCC:T	acceptor_loss	0.9400
4:186534560:G:C	acceptor_loss	0.9400
4:186549962:A:AC	donor_gain	0.9200
4:186533563:G:C	donor_gain	0.9000
4:186555197:T:TA	donor_gain	0.8800
4:186534570:CG:C	acceptor_loss	0.8700

AlphaMissense

2299 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:186534538:G:C	S68R	0.999
4:186534538:G:T	S68R	0.999
4:186534540:T:G	S68R	0.999
4:186534001:A:C	F247L	0.998
4:186534001:A:T	F247L	0.998
4:186534003:A:G	F247L	0.998
4:186534368:C:G	R125P	0.998
4:186534524:T:G	D73A	0.998
4:186533836:G:C	F302L	0.997
4:186533836:G:T	F302L	0.997
4:186533837:A:C	F302C	0.997
4:186533837:A:G	F302S	0.997
4:186533838:A:G	F302L	0.997
4:186534523:G:C	D73E	0.997
4:186534523:G:T	D73E	0.997
4:186534524:T:C	D73G	0.997
4:186534525:C:G	D73H	0.997
4:186555236:C:G	G44R	0.997
4:186533855:C:T	G296E	0.996
4:186533902:A:C	S280R	0.996
4:186533902:A:T	S280R	0.996
4:186533904:T:G	S280R	0.996
4:186534211:G:C	C177W	0.996
4:186534212:C:G	C177S	0.996
4:186534212:C:T	C177Y	0.996
4:186534213:A:T	C177S	0.996
4:186534288:A:G	W152R	0.996
4:186534288:A:T	W152R	0.996
4:186534463:C:A	W93C	0.996
4:186534463:C:G	W93C	0.996

dbSNP variants (sampled 300 via entrez): RS1000129983 (4:186548124 A>G), RS1000252876 (4:186552736 C>T), RS1000338457 (4:186542364 C>G,T), RS1000436471 (4:186554232 G>A), RS1000831486 (4:186534713 G>A), RS1000882472 (4:186534939 A>G), RS1001022974 (4:186536919 C>T), RS1001036017 (4:186537313 G>T), RS1001065378 (4:186547784 G>A), RS1001356524 (4:186535753 T>A), RS1001366354 (4:186536000 A>G), RS1001413994 (4:186540198 A>C,G), RS1001504465 (4:186546817 T>C), RS1001634516 (4:186537512 C>A), RS1001707631 (4:186552838 G>A)

Disease associations

OMIM: gene MIM:600665 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001057_1	Obesity	7.000000e-06
GCST003667_1	Depressive symptoms measurement (somatic complaints domain)	1.000000e-06
GCST003868_1	Job-related exhaustion in shift workers	5.000000e-08
GCST90026415_13	Mild obesity-related type 2 diabetes	3.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007006	depressive symptom measurement
EFO:0007881	job-related exhaustion measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1945 (SINGLE PROTEIN), CHEMBL2094268 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 344,432 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL10878	AGOMELATINE	4	4,528
CHEMBL1218	RAMELTEON	4	5,217
CHEMBL311498	CIANIDANOL	4	59,647
CHEMBL45	MELATONIN	4	56,417
CHEMBL59	DOPAMINE	4	217,028
CHEMBL7257	MEBUFOTENIN	2	1,595

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Melatonin receptors

Most potent curated ligand interactions (38 total), top 25:

Ligand	Action	Affinity	Parameter
2-iodo-melatonin	Full agonist	11.0	pKi
[125I]SD6	Full agonist	10.96	pKd
ramelteon	Full agonist	10.9	pKi
2-[125I]melatonin	Full agonist	10.7	pKd
2-methoxy-α,β-didehydro-agomelatine	Full agonist	10.5	pKi
difluoroagomelatine	Full agonist	10.5	pKi
agomelatine	Full agonist	10.4	pKi
EFPPEA	Full agonist	10.2	pKi
LY 156735	Full agonist	10.1	pKi
GR 196429	Full agonist	9.9	pKi
[3H]melatonin	Full agonist	9.9	pKd
melatonin	Full agonist	9.7	pKi
tasimelteon	Full agonist	9.5	pKi
CBOBNEA	Partial agonist	9.3	pKi
S26131	Antagonist	9.3	pKi
S26284	Partial agonist	9.2	pKi
6-Cl-MLT	Full agonist	9.2	pKi
6-hydroxymelatonin	Full agonist	9.2	pKi
UCM1341	Agonist	9.11	pKi
UCM 793	Full agonist	9.1	pKi
AAE-M-PBP-amine	Partial agonist	8.9	pKi
IIK7	Full agonist	8.3	pKi
UCM 549	Antagonist	8.2	pKi
S22153	Antagonist	8.1	pKi
UCSF3384	Inverse agonist	7.9	pEC50

Binding affinities (BindingDB)

78 measured of 81 human assays (83 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
Melatonin,2-Iodo	KI	0.01 nM
Melatonin,2-Phenyl	KI	0.02 nM
Melatonin,2-Bromo	KI	0.02 nM
N-[2-[2-(4-phenylbutyl)-7,8-dihydro-6H-cyclopenta[g][1,3]benzoxazol-8-yl]ethyl]acetamide	IC50	0.022 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
N-[2-[(8S)-2-methyl-7,8-dihydro-6H-cyclopenta[g][1,3]benzoxazol-8-yl]ethyl]propanamide	IC50	0.03 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
N-[2-[(8S)-2-methyl-7,8-dihydro-6H-cyclopenta[g][1,3]benzothiazol-8-yl]ethyl]acetamide	IC50	0.038 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
N-[2-[(8S)-2-methyl-7,8-dihydro-6H-cyclopenta[g][1,3]benzoxazol-8-yl]ethyl]acetamide	IC50	0.057 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
N-[2-(2-methyl-6H-cyclopenta[g][1,3]benzoxazol-8-yl)ethyl]acetamide	IC50	0.068 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
N-[(2E)-2-[2-(4-phenylbutyl)-6,7-dihydrocyclopenta[g][1,3]benzoxazol-8-ylidene]ethyl]acetamide	IC50	0.079 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
2,2,2-trifluoro-N-[2-(2-methyl-7,8-dihydro-6H-cyclopenta[g][1,3]benzoxazol-8-yl)ethyl]acetamide	IC50	0.095 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
N-[2-(2-methyl-7,8-dihydro-6H-cyclopenta[g][1,3]benzoxazol-8-yl)ethyl]propanamide	IC50	0.13 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
NSC_5311134	KI	0.14 nM
N-[2-(2-methyl-7,8-dihydro-6H-cyclopenta[g][1,3]benzoxazol-8-yl)ethyl]acetamide	IC50	0.15 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
N-[2-(2-methyl-7,8-dihydro-6H-cyclopenta[g][1,3]benzothiazol-8-yl)ethyl]acetamide	IC50	0.15 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
N-[(2E)-2-(2-methyl-6,7-dihydrocyclopenta[g][1,3]benzothiazol-8-ylidene)ethyl]acetamide	IC50	0.19 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
Melatonin,2-Chloro	KI	0.2 nM
N-[(2E)-2-(2-methyl-6,7-dihydrocyclopenta[g][1,3]benzoxazol-8-ylidene)ethyl]propanamide	IC50	0.25 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
N-[2-(2-methyl-7,8-dihydro-6H-cyclopenta[g][1,3]benzoxazol-8-yl)ethyl]cyclopropanecarboxamide	IC50	0.25 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
5-MeOT-N-propionyl	KI	0.26 nM
CAS_121-75-5	KI	0.29 nM
N-[(2E)-2-(2-methyl-6,7-dihydrocyclopenta[g][1,3]benzoxazol-8-ylidene)ethyl]acetamide	IC50	0.33 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
N-[2-(2-ethyl-7,8-dihydro-6H-cyclopenta[g][1,3]benzoxazol-8-yl)ethyl]acetamide	IC50	0.36 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
5-MeOT-N-butanyl	KI	0.45 nM
N-[2-(2-methoxy-7,8-dihydro-6H-cyclopenta[g][1,3]benzoxazol-8-yl)ethyl]acetamide	IC50	0.54 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
melatonin, 6-Hydroxy	KI	0.54 nM
N-[2-(2-cyclopropyl-7,8-dihydro-6H-cyclopenta[g][1,3]benzoxazol-8-yl)ethyl]acetamide	IC50	0.66 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
N-[2-(6-Chloro-5-methoxy-1H-indol-3-yl)-ethyl]-acetamide	KI	0.67 nM
N-[2-(7,8-dihydro-6H-cyclopenta[g][1,3]benzoxazol-8-yl)ethyl]acetamide	IC50	0.88 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
CAS_73-31-4	KI	1.34 nM
CAS_73-31-4	KI	4.8 nM
8-M-CADOT	KI	5.4 nM
5-MeOT-N-pentanyl	KI	5.88 nM
N-[2-[(8R)-2-methyl-7,8-dihydro-6H-cyclopenta[g][1,3]benzoxazol-8-yl]ethyl]propanamide	IC50	11 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
Melatonin,6-Cl	KI	11.4 nM
N-[2-[(8R)-2-methyl-7,8-dihydro-6H-cyclopenta[g][1,3]benzoxazol-8-yl]ethyl]acetamide	IC50	15 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
N-[2-[(8R)-2-methyl-7,8-dihydro-6H-cyclopenta[g][1,3]benzothiazol-8-yl]ethyl]acetamide	IC50	19 nM	US-8552037: Tricyclic compound and pharmaceutical use thereof
Luzindole,5-Methoxy	KI	32.7 nM
8-M-ADOT	KI	46.9 nM
8-M-PDOT	KI	60.2 nM
N-[(1H-Indol-2-yl)alkyl]acylamino Derivatives 5h	KI	63.1 nM
N-[(1H-Indol-2-yl)alkyl]acylamino Derivatives 5f	KI	87.1 nM
1-[3-(5-Methoxy-1H-indol-3-yl)piperidino]ethanone	KI	90.4 nM
N-Acetyltryptamine,5-Benzyloxy	KI	118 nM
N-[(1H-Indol-2-yl)alkyl]acylamino Derivatives 5g	KI	135 nM
Luzindole,N-propanoyl	KI	154 nM
N-Acetyltryptamine,5-Methyl	KI	156 nM
CAS_117946-91-5	KI	158 nM
N-Acetyltryptamine	KI	196 nM
N-CBCPT	KI	200 nM
Melatonin,6-Methoxy	KI	207 nM

ChEMBL bioactivities

1743 potent at pChembl≥5 of 1782 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	Ki	0.01	nM	CHEMBL132802
11.00	Ki	0.01	nM	CHEMBL287560
11.00	IC50	0.01	nM	CHEMBL421013
11.00	Ki	0.01	nM	CHEMBL330137
10.96	Ki	0.011	nM	CHEMBL1774529
10.92	Ki	0.012	nM	CHEMBL336054
10.91	Ki	0.0123	nM	CHEMBL134874
10.90	IC50	0.01259	nM	CHEMBL139855
10.89	Ki	0.013	nM	IODOMELATONIN
10.89	Ki	0.013	nM	CHEMBL1774514
10.86	Ki	0.0138	nM	RAMELTEON
10.85	Ki	0.014	nM	CHEMBL64664
10.85	Ki	0.014	nM	RAMELTEON
10.85	Ki	0.014	nM	CHEMBL433237
10.82	Ki	0.015	nM	CHEMBL336509
10.82	EC50	0.015	nM	CHEMBL3648356
10.82	IC50	0.0153	nM	CHEMBL320267
10.80	Ki	0.016	nM	CHEMBL340832
10.80	IC50	0.01585	nM	CHEMBL329263
10.77	IC50	0.017	nM	MELATONIN
10.77	Ki	0.017	nM	CHEMBL15060
10.76	Ki	0.0174	nM	CHEMBL134330
10.70	Ki	0.02	nM	CHEMBL314512
10.68	Ki	0.021	nM	IODOMELATONIN
10.68	EC50	0.021	nM	CHEMBL1802025
10.67	Ki	0.0214	nM	CHEMBL135072
10.66	IC50	0.022	nM	CHEMBL3648361
10.66	EC50	0.022	nM	MELATONIN
10.66	Ki	0.02188	nM	CHEMBL15060
10.65	Ki	0.0225	nM	CHEMBL134295
10.64	Ki	0.0231	nM	CHEMBL334645
10.62	Ki	0.024	nM	CHEMBL1774513
10.62	Ki	0.0241	nM	CHEMBL336960
10.59	Ki	0.026	nM	CHEMBL133416
10.59	EC50	0.0257	nM	MELATONIN
10.59	EC50	0.026	nM	MELATONIN
10.59	Ki	0.026	nM	CHEMBL1802028
10.57	Ki	0.027	nM	CHEMBL4868554
10.52	Ki	0.03	nM	CHEMBL130214
10.52	Ki	0.03	nM	CHEMBL2314259
10.52	Ki	0.03	nM	CHEMBL3612603
10.52	IC50	0.03	nM	CHEMBL3648359
10.52	Ki	0.03	nM	CHEMBL14417
10.51	Ki	0.031	nM	CHEMBL3648356
10.49	Ki	0.0321	nM	CHEMBL334404
10.49	Ki	0.032	nM	CHEMBL1774516
10.46	EC50	0.035	nM	CHEMBL4852096
10.44	EC50	0.036	nM	CHEMBL4848885
10.44	Ki	0.036	nM	CHEMBL394273
10.44	Ki	0.036	nM	CHEMBL33415

PubChem BioAssay actives

1645 with measured affinity, of 3485 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[2-(2-bromo-6-methoxyindol-1-yl)ethyl]propanamide	107564: Binding affinity against melatonin receptor in the quail optica tecta using 2-[125] iodomelatonin (100 pM) as labelled ligand	ki	<0.0001	uM
2,2,2-trifluoro-N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide	107706: Monophasic inhibitory concentration against melatonin receptor was measured on ovine pars tuberalis membrane.	ic50	<0.0001	uM
N-[2-(6-methoxy-2-phenylindol-1-yl)ethyl]propanamide	107564: Binding affinity against melatonin receptor in the quail optica tecta using 2-[125] iodomelatonin (100 pM) as labelled ligand	ki	<0.0001	uM
N-[2-(2-phenylindol-1-yl)ethyl]propanamide	1527843: Displacement of 2-[125I]iodomelatonin from melatonin receptor (unknown origin)	ki	<0.0001	uM
1-[2-(5-methoxy-2-phenyl-1-benzofuran-3-yl)ethyl]-3-methylurea	107881: Binding affinity on human melatonin receptor type 1A stably transfected in human embryonic kidney (HEK 293) using 2-[125I]iodomelatonin as radioligand.	ki	<0.0001	uM
N-[2-(5-methoxy-2-phenyl-1-benzofuran-3-yl)ethyl]but-3-enamide	107881: Binding affinity on human melatonin receptor type 1A stably transfected in human embryonic kidney (HEK 293) using 2-[125I]iodomelatonin as radioligand.	ki	<0.0001	uM
N-[2-(7,8-dihydro-6H-cyclopenta[g][1,3]benzodioxol-8-yl)ethyl]propanamide	107729: Binding affinity against human Melatonin receptor type 1A (MT1) in CHO cells	ki	<0.0001	uM
2,2,2-trifluoro-N-[2-(6-methoxy-3H-inden-1-yl)ethyl]acetamide	107728: Ability to inhibit 2-[125I]iodomelatonin specific binding to human melatonin receptor type 1A (MT1) expressed in CHO cells.	ki	<0.0001	uM
2,2,2-trifluoro-N-[2-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)ethyl]acetamide	107728: Ability to inhibit 2-[125I]iodomelatonin specific binding to human melatonin receptor type 1A (MT1) expressed in CHO cells.	ki	<0.0001	uM
N-[2-(6-methoxy-3H-inden-1-yl)ethyl]propanamide	107728: Ability to inhibit 2-[125I]iodomelatonin specific binding to human melatonin receptor type 1A (MT1) expressed in CHO cells.	ki	<0.0001	uM
N-[2-(2-iodo-5-methoxy-1H-indol-3-yl)ethyl]acetamide	107567: Inhibition of 2-[125I]iodomelatonin binding to melatonin receptor in quail brain as 1/Ka	ki	<0.0001	uM
N-[2-(5-methoxy-2-phenyl-1-benzofuran-3-yl)ethyl]prop-2-enamide	107881: Binding affinity on human melatonin receptor type 1A stably transfected in human embryonic kidney (HEK 293) using 2-[125I]iodomelatonin as radioligand.	ki	<0.0001	uM
N-[2-(2,6,7,8-tetrahydro-1H-cyclopenta[e][1]benzofuran-8-yl)ethyl]butanamide	107729: Binding affinity against human Melatonin receptor type 1A (MT1) in CHO cells	ki	<0.0001	uM
N-[2-[(1S)-6-methoxy-2,3-dihydro-1H-inden-1-yl]ethyl]butanamide	107728: Ability to inhibit 2-[125I]iodomelatonin specific binding to human melatonin receptor type 1A (MT1) expressed in CHO cells.	ki	<0.0001	uM
N-[(5-methoxy-1-methyl-3,4-dihydro-2H-quinolin-2-yl)methyl]propanamide	1245366: Displacement of 2-[125I]-Iodomelatonin from human MT1 receptor transfected in CHO cell membranes after 120 mins	ki	<0.0001	uM
N-[2-(2-bromo-5-methoxy-1H-indol-3-yl)ethyl]acetamide	107564: Binding affinity against melatonin receptor in the quail optica tecta using 2-[125] iodomelatonin (100 pM) as labelled ligand	ki	<0.0001	uM
N-[2-(5-methoxy-2-phenylfuro[3,2-b]pyridin-3-yl)ethyl]acetamide	1277515: Displacement of [125I]2-Iodomelatonin from human MT1 receptor expressed in HEK293 cells after 120 mins by radioligand competition assay	ki	<0.0001	uM
N-[2-(6,7-dichloro-5-methoxy-2-methyl-1H-indol-3-yl)ethyl]acetamide	165366: Inhibition of 2-[125I]iodomelatonin stimulated calcium dependent dopamine release from the rabbit retina.	ic50	<0.0001	uM
N-[2-(5-chloro-2-ethoxy-6-methoxybenzimidazol-1-yl)ethyl]acetamide	1775347: Agonist activity at human MT1 receptor expressed in CHO cells assessed as increase in forskolin induced cAMP production incubated at 37 degreeC by HitHunter-cAMP assay	ec50	<0.0001	uM
N-[3-(2-ethoxy-6-methoxybenzimidazol-1-yl)propyl]acetamide	1775347: Agonist activity at human MT1 receptor expressed in CHO cells assessed as increase in forskolin induced cAMP production incubated at 37 degreeC by HitHunter-cAMP assay	ec50	<0.0001	uM
N-[2-(2-methoxy-7,8-dihydrofuro[2,3-g]benzimidazol-1-yl)ethyl]acetamide	1775347: Agonist activity at human MT1 receptor expressed in CHO cells assessed as increase in forskolin induced cAMP production incubated at 37 degreeC by HitHunter-cAMP assay	ec50	<0.0001	uM
N-[2-(2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide	1775347: Agonist activity at human MT1 receptor expressed in CHO cells assessed as increase in forskolin induced cAMP production incubated at 37 degreeC by HitHunter-cAMP assay	ec50	<0.0001	uM
N-[2-(2-ethoxy-7,8-dihydrofuro[2,3-g]benzimidazol-1-yl)ethyl]acetamide	1775347: Agonist activity at human MT1 receptor expressed in CHO cells assessed as increase in forskolin induced cAMP production incubated at 37 degreeC by HitHunter-cAMP assay	ec50	<0.0001	uM
N-[2-(2-ethoxy-6-methoxybenzimidazol-1-yl)ethyl]acetamide	1775347: Agonist activity at human MT1 receptor expressed in CHO cells assessed as increase in forskolin induced cAMP production incubated at 37 degreeC by HitHunter-cAMP assay	ec50	<0.0001	uM
N-[2-(2-bromoindol-1-yl)ethyl]propanamide	1527843: Displacement of 2-[125I]iodomelatonin from melatonin receptor (unknown origin)	ki	<0.0001	uM
N-[2-(2-methyl-7,8-dihydro-6H-cyclopenta[g][1,3]benzothiazol-8-yl)ethyl]propanamide	1775660: Displacement of 2-[125l]-lodomelatonin from human MT1 expressed in CHO cell membrane incubated for 150 mins by radioligand binding assay	ki	<0.0001	uM
N-[(8-methoxy-1,2-dihydroacenaphthylen-1-yl)methyl]butanamide	107726: Binding affinity for human melatonin receptor type 1A, expressed in HEK293 cells (2-[125I]iodomelatonin is used as radioligand)	ki	<0.0001	uM
N-[2-(6-chloro-5-methoxy-1H-indol-3-yl)ethyl]acetamide	165366: Inhibition of 2-[125I]iodomelatonin stimulated calcium dependent dopamine release from the rabbit retina.	ic50	<0.0001	uM
N-[2-(5-methoxy-2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]acetamide	107890: Melatonin receptor type 1A binding affinity measured using 2-[125I]iodomelatonin on ovine pars tuberalis membrane homogenates.	ic50	<0.0001	uM
Ramelteon	107729: Binding affinity against human Melatonin receptor type 1A (MT1) in CHO cells	ki	<0.0001	uM
2,2,2-trifluoro-N-[2-(6-methoxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide	107728: Ability to inhibit 2-[125I]iodomelatonin specific binding to human melatonin receptor type 1A (MT1) expressed in CHO cells.	ki	<0.0001	uM
N-[2-(2,6-dihydro-1H-cyclopenta[e][1]benzofuran-8-yl)ethyl]acetamide	595896: Displacement of [125I]-2-iodomelatonin from human MT1 receptor expressed on CHO cells by microscintillation counting	ki	<0.0001	uM
N-[2-(7-phenyl-2,6-dihydro-1H-cyclopenta[e][1]benzofuran-8-yl)ethyl]acetamide	595896: Displacement of [125I]-2-iodomelatonin from human MT1 receptor expressed on CHO cells by microscintillation counting	ki	<0.0001	uM
N-[2-(2-methyl-7,8-dihydro-6H-cyclopenta[g][1,3]benzothiazol-8-yl)ethyl]acetamide	1775660: Displacement of 2-[125l]-lodomelatonin from human MT1 expressed in CHO cell membrane incubated for 150 mins by radioligand binding assay	ki	<0.0001	uM
N-[2-(3-methoxy-N-(3-methoxyphenyl)anilino)ethyl]acetamide	2073504: Binding affinity to MT1 receptor (unknown origin) expressed in HEK293 cells assessed as inhibition constant	ki	<0.0001	uM
N-[2-(4-ethyl-10-oxa-5,6-diazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7-tetraen-3-yl)ethyl]acetamide	605977: Agonist activity at human MT1 receptor expressed in CHO cells assessed as decrease in forskolin-stimulated cAMP release after 30 mins by multilabel plate reader	ec50	<0.0001	uM
N-[2-(4-ethyl-10-oxa-5,6-diazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7-tetraen-3-yl)ethyl]propanamide	605960: Displacement of 2-[125I]iodomelatonin from human MT1 receptor expressed in CHO cells	ki	<0.0001	uM
N-[2-(5-methoxy-1H-indol-3-yl)ethyl]cyclopropanecarboxamide	107706: Monophasic inhibitory concentration against melatonin receptor was measured on ovine pars tuberalis membrane.	ic50	<0.0001	uM
4-chloro-N-[2-(7-methoxynaphthalen-1-yl)ethyl]butanamide	107706: Monophasic inhibitory concentration against melatonin receptor was measured on ovine pars tuberalis membrane.	ic50	<0.0001	uM
2-bromo-N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide	107706: Monophasic inhibitory concentration against melatonin receptor was measured on ovine pars tuberalis membrane.	ic50	<0.0001	uM
N-[2-(7-methoxynaphthalen-1-yl)ethyl]butanamide	107706: Monophasic inhibitory concentration against melatonin receptor was measured on ovine pars tuberalis membrane.	ic50	<0.0001	uM
N-[2-(5-methoxy-2-phenyl-1H-indol-3-yl)ethyl]acetamide	107564: Binding affinity against melatonin receptor in the quail optica tecta using 2-[125] iodomelatonin (100 pM) as labelled ligand	ki	<0.0001	uM
N-[2-(7-propan-2-yl-2,6-dihydro-1H-cyclopenta[e][1]benzofuran-8-yl)ethyl]acetamide	595896: Displacement of [125I]-2-iodomelatonin from human MT1 receptor expressed on CHO cells by microscintillation counting	ki	<0.0001	uM
N-[2-(7-propan-2-yl-2,6-dihydro-1H-cyclopenta[e][1]benzofuran-8-yl)ethyl]propanamide	595896: Displacement of [125I]-2-iodomelatonin from human MT1 receptor expressed on CHO cells by microscintillation counting	ki	<0.0001	uM
2,2,2-trifluoro-N-[2-(7-propan-2-yl-2,6-dihydro-1H-cyclopenta[e][1]benzofuran-8-yl)ethyl]acetamide	595896: Displacement of [125I]-2-iodomelatonin from human MT1 receptor expressed on CHO cells by microscintillation counting	ki	<0.0001	uM
N-[2-(7-bromo-2,6-dihydro-1H-cyclopenta[e][1]benzofuran-8-yl)ethyl]acetamide	595896: Displacement of [125I]-2-iodomelatonin from human MT1 receptor expressed on CHO cells by microscintillation counting	ki	<0.0001	uM
N-[2-[7-(furan-3-yl)-2,6-dihydro-1H-cyclopenta[e][1]benzofuran-8-yl]ethyl]acetamide	595896: Displacement of [125I]-2-iodomelatonin from human MT1 receptor expressed on CHO cells by microscintillation counting	ki	<0.0001	uM
N-[2-[7-(3-propan-2-ylphenyl)-2,6-dihydro-1H-cyclopenta[e][1]benzofuran-8-yl]ethyl]acetamide	2073508: Binding affinity to human MT1 receptor assessed as inhibition constant	ki	<0.0001	uM
N-[2-(4-cyclopropyl-10-oxa-5,6-diazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7-tetraen-3-yl)ethyl]acetamide	605960: Displacement of 2-[125I]iodomelatonin from human MT1 receptor expressed in CHO cells	ki	<0.0001	uM
N-[2-(4-cyclopropyl-10-oxa-5,6-diazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7-tetraen-3-yl)ethyl]propanamide	605960: Displacement of 2-[125I]iodomelatonin from human MT1 receptor expressed in CHO cells	ki	<0.0001	uM

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Melatonin	affects binding, decreases reaction, increases expression	5
agomelatine	affects binding, increases activity	2
bisphenol A	increases methylation, affects cotreatment	1
chrysoeriol	affects binding	1
terbufos	increases methylation	1
2-iodomelatonin	decreases reaction, affects binding, increases activity	1
4-phenyl-2-propionamidotetraline	affects binding	1
bisphenol S	decreases methylation	1
N-(2-(2-methoxy-6H-dipyrido(2,3-a-3,2-e)pyrrolizin-11-yl)ethyl)-2-furamide	affects binding	1
N-(2-(2-ethyl-8,9-dihydrofuro(3,2-c)pyrazolo(1,5-a)pyridin-1-yl)ethyl)acetamide	affects binding	1
Acenaphthenes	affects binding	1
Resveratrol	affects binding	1
Fulvestrant	increases methylation, affects cotreatment	1
Allergens	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Carbofuran	affects binding, decreases reaction	1
Fonofos	increases methylation	1
Parathion	increases methylation	1
Carbaryl	affects binding, decreases reaction	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects localization, decreases expression	1
Sodium Selenite	decreases expression	1
Cadmium Chloride	increases expression	1
Phenalenes	affects binding	1
Endocannabinoids	affects binding, increases activity, decreases reaction	1

ChEMBL screening assays

396 unique, capped per target: 275 binding, 121 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1022850	Binding	Inhibition of melatonin MT1 receptor at 10 uM	Efficacy, pharmacokinetics, and metabolism of tetrahydroquinoline inhibitors of Plasmodium falciparum protein farnesyltransferase. — Antimicrob Agents Chemother
CHEMBL1031362	Functional	Antagonist activity at human MT1 receptor expressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP formation	2-[(2,3-dihydro-1H-indol-1-yl)methyl]melatonin analogues: a novel class of MT2-selective melatonin receptor antagonists. — J Med Chem

Cellosaurus cell lines

5 cell lines: 3 spontaneously immortalized cell line, 1 transformed cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_F1PB	HyCyte HEK293 KO-hMTNR1A	Transformed cell line	Female
CVCL_H466	CHO-K1/MT1/Galpha15	Spontaneously immortalized cell line	Female
CVCL_KV53	cAMP Hunter CHO-K1 MTNR1A Gi	Spontaneously immortalized cell line	Female
CVCL_KY55	PathHunter CHO-K1 MTNR1A beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_KZ30	PathHunter DLD1 MTNR1A Total GPCR Internalization	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.