GNRHR

Summary

GNRHR (gonadotropin releasing hormone receptor, HGNC:4421) is a protein-coding gene on chromosome 4q13.2, encoding Gonadotropin-releasing hormone receptor (P30968). Receptor for gonadotropin releasing hormone (GnRH) that mediates the action of GnRH to stimulate the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

This gene encodes the receptor for type 1 gonadotropin-releasing hormone. This receptor is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. It is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate. Following binding of gonadotropin-releasing hormone, the receptor associates with G-proteins that activate a phosphatidylinositol-calcium second messenger system. Activation of the receptor ultimately causes the release of gonadotropic luteinizing hormone (LH) and follicle stimulating hormone (FSH). Defects in this gene are a cause of hypogonadotropic hypogonadism (HH). Alternative splicing results in multiple transcript variants encoding different isoforms. More than 18 transcription initiation sites in the 5’ region and multiple polyA signals in the 3’ region have been identified for this gene.

Source: NCBI Gene 2798 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypogonadotropic hypogonadism 7 with or without anosmia (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 219 total — 17 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 44
• Druggable target: yes — 12 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000406

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4421
Approved symbol	GNRHR
Name	gonadotropin releasing hormone receptor
Location	4q13.2
Locus type	gene with protein product
Status	Approved
Aliases	LHRHR
Ensembl gene	ENSG00000109163
Ensembl biotype	protein_coding
OMIM	138850
Entrez	2798

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000226413, ENST00000420975

RefSeq mRNA: 2 — MANE Select: NM_000406 NM_000406, NM_001012763

CCDS: CCDS3517, CCDS47064

Canonical transcript exons

ENST00000226413 — 3 exons

Exon	Start	End
ENSE00000371801	67744568	67744787
ENSE00001597165	67737118	67740724
ENSE00001879116	67753814	67754388

Expression profiles

Bgee: expression breadth ubiquitous, 121 present calls, max score 98.47.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2842 / max 330.8589, expressed in 3 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52316	0.2450	3
52315	0.0322	3
52317	0.0070	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	98.47	gold quality
adenohypophysis	UBERON:0002196	79.83	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.03	gold quality
pituitary gland	UBERON:0000007	78.89	gold quality
cortical plate	UBERON:0005343	68.85	gold quality
pancreatic ductal cell	CL:0002079	68.77	silver quality
cervix squamous epithelium	UBERON:0006922	63.68	gold quality
buccal mucosa cell	CL:0002336	63.40	silver quality
ganglionic eminence	UBERON:0004023	63.01	gold quality
ventricular zone	UBERON:0003053	60.34	gold quality
sural nerve	UBERON:0015488	60.00	silver quality
tibialis anterior	UBERON:0001385	59.55	silver quality
bone marrow cell	CL:0002092	59.09	silver quality
ileal mucosa	UBERON:0000331	58.66	silver quality
embryo	UBERON:0000922	56.99	gold quality
decidua	UBERON:0002450	56.55	gold quality
prefrontal cortex	UBERON:0000451	54.99	gold quality
corpus callosum	UBERON:0002336	54.76	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	54.73	gold quality
colonic epithelium	UBERON:0000397	54.02	silver quality
deltoid	UBERON:0001476	53.69	silver quality
hair follicle	UBERON:0002073	52.94	gold quality
epithelial cell of pancreas	CL:0000083	52.72	gold quality
metanephros	UBERON:0000081	52.39	silver quality
cervix epithelium	UBERON:0004801	52.31	gold quality
calcaneal tendon	UBERON:0003701	50.94	silver quality
quadriceps femoris	UBERON:0001377	50.79	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
lower lobe of lung	UBERON:0008949	50.34	silver quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.07

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ASCL1, CREB1, ESR1, FOXL2, GATA2, GATA3, ISL1, JUN, LHX3, LHX5, LHX9, MSX1, NEUROD1, NFYA, NR3C1, NR4A1, NR5A1, NR5A2, OTX2, PITX1, POU1F1, POU2F1, SP1, TBP

miRNA regulators (miRDB)

140 targeting GNRHR, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-659-3P	99.85	70.69	1620

Literature-anchored findings (GeneRIF, showing 40)

• Site-directed mutagenesis of the C-terminal domain of extracellular loop 2 of the human GnRH receptor showed that a minimum of two mutations is needed in this region for agonist activity of antagonist 135-18 (PMID:11981042)
• the E(90)K mutation impairs hGnRHR-effector coupling; sequence modifications that enhance surface expression of the receptor restore function (PMID:11994356)
• Coupling of GnRH concentration and the GnRH receptor-activated gene program (PMID:12040003)
• Novel homozygous splice acceptor site GnRH receptor (GnRHR) mutation: human GnRHR “knockout”. amenorrhea and absent thelarche and pubarche (PMID:12050282)
• conserved physical linkage in medaka and human genomes (PMID:12054603)
• our results strongly indicate a role of the C/EBP and GATA motifs in regulating GnRHR gene transcription in human granulosa-luteal cells (PMID:12089350)
• Locally expressed LHRH receptors mediate the oncostatic and antimetastatic activity of LHRH agonists on melanoma cells. (PMID:12161512)
• results clearly indicate a role of octamer transcription factor-1 in the transcriptional repression of the human gonadotropin-releasing hormone receptor gene (PMID:12446597)
• A missense mutation in this gene is found in a case of complete hypogonadotropic hypogonadism. (PMID:12568864)
• Genetic analysis has excluded sequence variations in GNRH1 and GNRHR in four families with recessive IHH, suggesting the existence of a novel, as-yet-undiscovered gene for this condition. (PMID:12788881)
• The dominant-negative effect of the naturally occurring receptor mutants for the WT hGnRHR, which has intrinsic low maturation efficiency suggesting that this effect and the diminished plasma membrane expression is a recent evolutionary event. (PMID:12843188)
• Estrogen receptor-alpha represses human GnRH receptor gene transcription via an indirect mechanism involving Creb-binding protein. (PMID:12947046)
• direct role for the GnRHR in mediating antiproliferative events in two cell systems, neither of which was derived from extrapituitary reproductive tumors. (PMID:14551223)
• Neurons express GnRH receptor and responded to GnRH with time- and dose-dependent increases in GnRH gene expression and protein release. (PMID:14565958)
• In hormone-related tumors, type I GnRH receptors are coupled to the Gi-cAMP signal transduction pathway. In melanoma cells, GnRH-I behaves as a negative regulator of tumor growth and progression. (PMID:14726258)
• the dominant-negative effect, which occurs for human GnRHR mutants isolated from patients with hypogonadotropic hypogonadism , results from receptor retention in the endoplasmic reticulum by mislocalized mutants. (PMID:15105440)
• Pro7.33(303) of the human GnRH receptor is required for selective high affinity binding of mammalian GnRH. (PMID:15149726)
• Expression of gonadotropin-releasing hormone receptor in endometrial stromal sarcomas may provide a rationale for a clinical study of gonadotropin-releasing hormone analogs in the treatment of women with endometrial stromal sarcomas. (PMID:15529183)
• Genetic variation in GNRHR is not likely to be a substantial modulator of pubertal timing in the general population. (PMID:15546906)
• the HFRK motif in the membrane-proximal region confers the differential signal transduction pathways between mammalian and nonmammalian GnRHRs (PMID:15563546)
• the GnRHR-II-reliquum plays a modulatory role in GnRHR-I expression (PMID:15761034)
• there are species-specific dominant negative receptor trafficking effects of the GnRHR between human, rat and mouse (PMID:15886197)
• GNRHR mutations account for approximately 3.5% of all normosmic and 7%-11% of presumed autosomal recessive idiopathic hypogonadotropic hypogonadism, suggesting that additional genes play an important role in normal puberty. (PMID:16213849)
• Cryostat and paraffin sections of prostate biopsy samples of 10 untreated patients with prostate carcinoma (T2-T3, Gleason score 5-8) were investigated for Gn-RH receptors (Gn-RHR) and androgen receptors (PMID:16301116)
• No mutations were identified in the male, whereas in the females the mutation Pro146Ser in the GnRHR was identified in heterozygosity in idiopathic hypogonadotropic hypogonadism (PMID:16359986)
• Activation of the GnRHR by interacting with GnRH may transcriptionally down-regulate itself via the protein kinase C pathway in human neuronal cells. (PMID:16364974)
• data suggest the occurrence of a specific LIM-HD pituitary code and designate the GnRH-R gene as the first identified transcriptional target of Isl-1 in the anterior pituitary (PMID:16613990)
• A homozygous R262Q mutation in the gonadotropin-releasing hormone receptor presenting as constitutional delay of growth and puberty with subsequent borderline oligospermia. (PMID:16968799)
• proportion of the human and the rat WT GnRHR appears to be retained in the endoplasmic reticulum by calnexin, an effect that decreases GnRHR signaling capacity (PMID:17170088)
• The R139C mutation almost completely abolished plasma membrane expression while having little effect on GnRH-binding affinity in hypogonadotropic hypoganadism-related mutant. (PMID:17179725)
• These results reveal GnRH ligand and receptor structural elements for conformational selection, and support co-evolution of GnRH ligand and receptor conformations. (PMID:17452338)
• Summarizes the overall structure-function relationships of the human GnRH receptor, with an emphasis on the impact of naturally occurring mutations. (PMID:17710733)
• Arg(38(1.35)) of the GnRH receptor is essential for high-affinity binding of GnRH agonists and stabilizing the receptor active conformation (PMID:17942747)
• We have defined the proportion of GnRHRs at the cell surface. (PMID:18252959)
• Two endogenous forms of GnRH ligand but only one functional form of full-length GnRH receptor in humans elecits specific functions of the receptor. (PMID:18356273)
• 12% of Kallman syndrome males have KAL1 deletions, but intragenic deletions of the FGFR1, GNRH1, GNRHR, GPR54 and NELF genes are uncommon in Idiopathic hypogonadotropic hypogonadism/Kallman syndrome. (PMID:18463157)
• Transient co-transfection of HEK293 cells with human WT GnRHR and with stimulatory and inhibitory G proteins led to either production or inhibition of total inositol phosphate production, depending on the G protein that was over-expressed (PMID:18541137)
• Data show that over half of meningiomas may be regulated by GnRH-GnRH-R expression in an autocrine fashion. (PMID:18980792)
• Results reveal important pharmacophoric features of the GnRH receptor, and then identify a novel chemical ligand, able to rescue a D(98) mutant of the human GnRHR that could not be rescued as effectively by previously known pharmacoperones. (PMID:19095769)
• the antitumor effect of gonadotropin-releasing hormone type i is mediated by the activation of type I (but not of type II) GnRH-R (PMID:19190109)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gnrhr1	ENSDARG00000100593
danio_rerio		ENSDARG00000102438
mus_musculus	Gnrhr	ENSMUSG00000029255
drosophila_melanogaster	AkhR	FBGN0025595
caenorhabditis_elegans	gnrr-1	WBGENE00018798

Paralogs (16): NPFFR2 (ENSG00000056291), CCKBR (ENSG00000110148), HCRTR1 (ENSG00000121764), AVPR2 (ENSG00000126895), GALR3 (ENSG00000128310), HCRTR2 (ENSG00000137252), NPFFR1 (ENSG00000148734), CCKAR (ENSG00000163394), AVPR1A (ENSG00000166148), GALR1 (ENSG00000166573), GPR22 (ENSG00000172209), GPR150 (ENSG00000178015), OXTR (ENSG00000180914), FFAR4 (ENSG00000186188), QRFPR (ENSG00000186867), AVPR1B (ENSG00000198049)

Protein

Protein identifiers

Gonadotropin-releasing hormone receptor — P30968 (reviewed: P30968)

All UniProt accessions (1): P30968

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for gonadotropin releasing hormone (GnRH) that mediates the action of GnRH to stimulate the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This receptor mediates its action by association with G-proteins that activate a phosphatidylinositol-calcium second messenger system. Isoform 2 may act as an inhibitor of GnRH-R signaling.

Subcellular location. Cell membrane.

Tissue specificity. Pituitary, ovary, testis, breast and prostate but not in liver and spleen.

Disease relevance. Hypogonadotropic hypogonadism 7 with or without anosmia (HH7) [MIM:146110] A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. In some cases, it is associated with non-reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in GNRHR as well as in other HH-associated genes including FGFR1.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P30968-1	1	yes
P30968-2	2, Truncated

RefSeq proteins (2): NP_000397, NP_001012781 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR001658	GphnRH_fam_rcpt	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (53 total): sequence variant 16, helix 10, topological domain 8, transmembrane region 7, strand 4, glycosylation site 2, turn 2, chain 1, disulfide bond 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7BR3	X-RAY DIFFRACTION	2.79

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P30968-F1	84.63	0.52

Functional residue map

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

Disulfide bonds (1): 114–196

Glycosylation sites (2): 18, 102

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-375281	Hormone ligand-binding receptors
R-HSA-416476	G alpha (q) signalling events

MSigDB gene sets: 212 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOZGIT_ESR1_TARGETS_DN, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, GAUSSMANN_MLL_AF4_FUSION_TARGETS_E_UP, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELL_CELL_SIGNALING, chr4q13, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, REACTOME_HORMONE_LIGAND_BINDING_RECEPTORS, KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION, HFH4_01

GO Biological Process (5): G protein-coupled receptor signaling pathway (GO:0007186), gonadotropin secretion (GO:0032274), cellular response to hormone stimulus (GO:0032870), signal transduction (GO:0007165), cellular response to gonadotropin-releasing hormone (GO:0097211)

GO Molecular Function (3): gonadotropin-releasing hormone receptor activity (GO:0004968), G protein-coupled receptor activity (GO:0004930), protein-hormone receptor activity (GO:0016500)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor activity	2
signal transduction	1
hormone secretion	1
response to hormone	1
cellular response to chemical stimulus	1
cellular response to endogenous stimulus	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cellular response to peptide hormone stimulus	1
response to gonadotropin-releasing hormone	1
protein-hormone receptor activity	1
gonadotropin-releasing hormone binding	1
cellular response to gonadotropin-releasing hormone	1
transmembrane signaling receptor activity	1
G protein-coupled receptor signaling pathway	1
signaling receptor activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1330 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GNRHR	GNRH1	P01148	999
GNRHR	KISS1R	Q969F8	975
GNRHR	GNRH2	O43555	971
GNRHR	KISS1	Q15726	951
GNRHR	FSHB	P01225	897
GNRHR	TAC3	Q9UHF0	890
GNRHR	GNAQ	P50148	826
GNRHR	ANOS1	P23352	820
GNRHR	NSMF	Q6X4W1	818
GNRHR	PROK2	Q9HC23	789
GNRHR	GHRHR	Q02643	771
GNRHR	FGFR1	P11362	758
GNRHR	CHD7	Q9P2D1	744
GNRHR	LHCGR	P22888	723
GNRHR	FSHR	P23945	688

IntAct

9 interactions, top by confidence:

A	B	Type	Score
GNRHR	CAMK1D	psi-mi:“MI:0915”(physical association)	0.400
GNRHR	RAMP1	psi-mi:“MI:0915”(physical association)	0.400
RAMP2	GNRHR	psi-mi:“MI:0915”(physical association)	0.400
GNRHR	RAMP3	psi-mi:“MI:0915”(physical association)	0.400
GPAA1	GNRHR	psi-mi:“MI:0915”(physical association)	0.370
TSPAN7	GNRHR	psi-mi:“MI:0915”(physical association)	0.370
TMEM161A	GNRHR	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (7): CAMK1D (Affinity Capture-MS), SET (Affinity Capture-Western), GPAA1 (Two-hybrid), TSPAN7 (Two-hybrid), TMEM161A (Two-hybrid), CAMK1D (Affinity Capture-MS), GNRHR (Dosage Lethality)

ESM2 similar proteins: O02300, O14804, O18821, O42329, O54798, O97967, P0C0L6, P30560, P30968, P30969, P32236, P32237, P32247, P35371, P37288, P48974, P49922, Q01776, Q19PY9, Q56H79, Q58CW4, Q5QD16, Q5QD17, Q5QD24, Q5QD25, Q5QD28, Q5QNP2, Q62463, Q6H2Y3, Q6W5P4, Q7T3Q7, Q7YW31, Q8BZ39, Q8BZP8, Q8CH60, Q8K418, Q90252, Q90334, Q90352, Q95JG1

Diamond homologs: A0A2L0VBG2, E7EM37, E9QJ73, O18821, O18935, O19012, O19014, O19025, O19032, O42329, O62169, O75388, O77700, O77713, O77715, O77721, O77830, O88634, P16395, P30968, P30969, P32236, P32237, P32251, P49651, P49922, P97288, Q01776, Q15722, Q19PY9, Q29003, Q2V2K5, Q6UNA4, Q6XKD3, Q8CH60, Q8JG69, Q8JG70, Q8MJ88, Q8NGA4, Q8SPZ1

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
GNRHR	“up-regulates activity”	GNAS	binding
GNRHR	“up-regulates activity”	GNAL	binding
GNRHR	“up-regulates activity”	GNAI1	binding
GNRHR	“up-regulates activity”	GNAI3	binding
GNRHR	“up-regulates activity”	GNAQ	binding
GNRHR	“up-regulates activity”	GNA14	binding
leuprolide	“up-regulates activity”	GNRHR	“chemical activation”
abarelix	“down-regulates activity”	GNRHR	“chemical inhibition”
degarelix	“down-regulates activity”	GNRHR	“chemical inhibition”
Goserelin	“up-regulates activity”	GNRHR	“chemical activation”
“leuprolide acetate”	“up-regulates activity”	GNRHR	“chemical activation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	14
Uncertain significance	123
Likely benign	18
Benign	22

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
126540	NM_000406.3(GNRHR):c.842C>T (p.Thr281Ile)	Pathogenic
140610	NM_000406.3(GNRHR):c.392T>C (p.Met131Thr)	Pathogenic
140611	NM_000406.3(GNRHR):c.806C>T (p.Thr269Met)	Pathogenic
1458023	NM_000406.3(GNRHR):c.401T>G (p.Val134Gly)	Pathogenic
16026	NM_000406.3(GNRHR):c.386C>A (p.Ala129Asp)	Pathogenic
16027	NM_000406.3(GNRHR):c.651C>A (p.Ser217Arg)	Pathogenic
16028	NM_000406.3(GNRHR):c.504T>A (p.Ser168Arg)	Pathogenic
16029	NM_000406.3(GNRHR):c.941T>A (p.Leu314Ter)	Pathogenic
16030	NM_000406.3(GNRHR):c.416G>A (p.Arg139His)	Pathogenic
16033	NM_000406.3(GNRHR):c.523-1G>A	Pathogenic
16034	NM_000406.3(GNRHR):c.511G>A (p.Ala171Thr)	Pathogenic
16036	NM_000406.3(GNRHR):c.959C>T (p.Pro320Leu)	Pathogenic
1675193	NM_000406.3(GNRHR):c.415C>T (p.Arg139Cys)	Pathogenic
2577284	NM_000406.3(GNRHR):c.35del (p.Asn12fs)	Pathogenic
2581289	NM_000406.3(GNRHR):c.521A>G (p.Gln174Arg)	Pathogenic
3590757	NM_000406.3(GNRHR):c.113dup (p.Val39fs)	Pathogenic
379859	NM_000406.3(GNRHR):c.633T>A (p.Tyr211Ter)	Pathogenic
1338680	NM_000406.3(GNRHR):c.156del (p.Phe52fs)	Likely pathogenic
16025	NM_000406.3(GNRHR):c.851A>G (p.Tyr284Cys)	Likely pathogenic
16031	NM_000406.3(GNRHR):c.30T>A (p.Asn10Lys)	Likely pathogenic
1709893	NM_000406.3(GNRHR):c.845C>T (p.Pro282Leu)	Likely pathogenic
2681146	NM_000406.3(GNRHR):c.248del (p.Leu83fs)	Likely pathogenic
3004558	NM_000406.3(GNRHR):c.113G>A (p.Arg38Gln)	Likely pathogenic
3337153	NM_000406.3(GNRHR):c.488C>A (p.Ala163Asp)	Likely pathogenic
3351455	NM_000406.3(GNRHR):c.777A>T (p.Pro259=)	Likely pathogenic
3590753	NM_000406.3(GNRHR):c.583C>T (p.Gln195Ter)	Likely pathogenic
3590755	NM_000406.3(GNRHR):c.497T>C (p.Leu166Pro)	Likely pathogenic
3590756	NM_000406.3(GNRHR):c.469C>T (p.Gln157Ter)	Likely pathogenic
3660422	NM_000406.3(GNRHR):c.512C>T (p.Ala171Val)	Likely pathogenic
418236	NM_000406.3(GNRHR):c.413A>G (p.Asp138Gly)	Likely pathogenic

SpliceAI

268 predictions. Top by Δscore:

Variant	Effect	Δscore
4:67740725:C:CC	acceptor_gain	1.0000
4:67753808:GCTTA:G	donor_loss	1.0000
4:67753809:CTTAC:C	donor_loss	1.0000
4:67753810:TTAC:T	donor_loss	1.0000
4:67753811:TACCT:T	donor_loss	1.0000
4:67753812:A:T	donor_loss	1.0000
4:67740721:AGTTC:A	acceptor_loss	0.9900
4:67740722:GTT:G	acceptor_gain	0.9900
4:67740722:GTTC:G	acceptor_loss	0.9900
4:67740723:TT:T	acceptor_gain	0.9900
4:67740723:TTCT:T	acceptor_loss	0.9900
4:67740724:TC:T	acceptor_loss	0.9900
4:67740725:CTGTT:C	acceptor_loss	0.9900
4:67740726:T:G	acceptor_loss	0.9900
4:67744562:ACAT:A	donor_loss	0.9900
4:67744563:CATA:C	donor_loss	0.9900
4:67744564:ATAC:A	donor_loss	0.9900
4:67744565:T:TG	donor_loss	0.9900
4:67744566:ACC:A	donor_loss	0.9900
4:67744567:C:CG	donor_loss	0.9900
4:67744785:TAA:T	acceptor_gain	0.9900
4:67744788:C:CC	acceptor_gain	0.9900
4:67753812:A:AC	donor_gain	0.9900
4:67753813:C:CC	donor_gain	0.9900
4:67740720:TAGTT:T	acceptor_gain	0.9800
4:67744566:A:AC	donor_gain	0.9800
4:67744567:C:CC	donor_gain	0.9800
4:67744783:TATAA:T	acceptor_gain	0.9700
4:67740728:T:TC	acceptor_gain	0.9600
4:67744559:AATAC:A	donor_loss	0.9500

AlphaMissense

2172 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:67754015:C:A	W107C	0.997
4:67754015:C:G	W107C	0.997
4:67754017:A:G	W107R	0.997
4:67754017:A:T	W107R	0.997
4:67740639:A:C	F276L	0.995
4:67740639:A:T	F276L	0.995
4:67740641:A:G	F276L	0.995
4:67753835:A:C	S167R	0.995
4:67753835:A:T	S167R	0.995
4:67753837:T:G	S167R	0.995
4:67753995:C:G	C114S	0.995
4:67753996:A:T	C114S	0.995
4:67744776:G:C	F178L	0.994
4:67744776:G:T	F178L	0.994
4:67744778:A:G	F178L	0.994
4:67753928:G:C	S136R	0.994
4:67753928:G:T	S136R	0.994
4:67753930:T:G	S136R	0.994
4:67753846:A:G	W164R	0.992
4:67753846:A:T	W164R	0.992
4:67753995:C:T	C114Y	0.991
4:67740629:A:G	W280R	0.990
4:67740629:A:T	W280R	0.990
4:67753994:G:C	C114W	0.990
4:67744723:C:G	C196S	0.989
4:67744724:A:T	C196S	0.989
4:67753824:G:T	A171E	0.989
4:67753920:C:G	R139P	0.989
4:67753996:A:G	C114R	0.989
4:67740622:G:T	P282H	0.988

dbSNP variants (sampled 300 via entrez): RS1000206339 (4:67752207 CT>C,CTT,CTTTT), RS1000362799 (4:67750034 A>G), RS1000491341 (4:67752362 T>C), RS1000546473 (4:67753646 G>A,C), RS1000603986 (4:67737516 C>T), RS1000668448 (4:67748059 A>T), RS1000728551 (4:67744522 A>G), RS1000839536 (4:67746041 A>G), RS1000951841 (4:67740754 A>C), RS1001054611 (4:67737943 T>A), RS1001204592 (4:67756015 A>G), RS1001609227 (4:67742527 A>C), RS1001661358 (4:67742762 A>G), RS1001789463 (4:67749388 A>C), RS1001993645 (4:67744311 G>A)

Disease associations

OMIM: gene MIM:138850 | disease phenotypes: MIM:146110, MIM:147950

GenCC curated gene-disease

Disease	Classification	Inheritance
hypogonadotropic hypogonadism 7 with or without anosmia	Strong	Autosomal recessive
hypogonadotropic hypogonadism	Supportive	Autosomal dominant

Mondo (5): hypogonadotropic hypogonadism 7 with or without anosmia (MONDO:0007794), infertility disorder (MONDO:0005047), isolated congenital hypogonadotropic hypogonadism (MONDO:0016553), hypogonadotropic hypogonadism (MONDO:0018555), amenorrhea (MONDO:0001836)

Orphanet (3): Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432), Rare disorder with multisystemic involvement and congenital hypogonadotropic hypogonadism (Orphanet:181387), Isolated congenital hypogonadotropic hypogonadism (Orphanet:238666)

HPO phenotypes

44 total (30 of 44 shown, HPO-id order):

HPO	Term
HP:0000002	Abnormality of body height
HP:0000007	Autosomal recessive inheritance
HP:0000013	Hypoplasia of the uterus
HP:0000026	Male hypogonadism
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000054	Micropenis
HP:0000118	Phenotypic abnormality
HP:0000134	Female hypogonadism
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000316	Hypertelorism
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000771	Gynecomastia
HP:0000786	Primary amenorrhea
HP:0000789	Infertility
HP:0000802	Impotence
HP:0000823	Delayed puberty
HP:0000869	Secondary amenorrhea
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0001608	Abnormality of the voice
HP:0002215	Sparse axillary hair
HP:0002225	Sparse pubic hair
HP:0002231	Sparse body hair
HP:0002750	Delayed skeletal maturation
HP:0002761	Generalized joint hypermobility
HP:0003187	Breast hypoplasia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006921_13	Regular attendance at a pub or social club	7.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009592	social interaction measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D000568	Amenorrhea	C23.550.568.500
D007246	Infertility	C12.100.750
C562785	Idiopathic Hypogonadotropic Hypogonadism (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1855 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

12 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 154,273 (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
CHEMBL1007	GONADORELIN	4	8,578
CHEMBL1200490	CETRORELIX	4	16,775
CHEMBL1201199	LEUPROLIDE	4	95,230
CHEMBL1208155	ELAGOLIX	4	879
CHEMBL1252	ABARELIX	4	25,996
CHEMBL1800159	RELUGOLIX	4	984
CHEMBL3668014	LINZAGOLIX	4	222
CHEMBL415606	DEGARELIX	4	5,217
CHEMBL502182	ELAGOLIX SODIUM	4	214
CHEMBL5314377	GANIRELIX ACETATE	4	17
CHEMBL22055	SUFUGOLIX	2	82
CHEMBL262747	ACYLINE	2	79

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Gonadotrophin-releasing hormone receptors

Most potent curated ligand interactions (46 total), top 25:

Ligand	Action	Affinity	Parameter
histerelin	Full agonist	10.4	pKd
GnRH I	Full agonist	10.0	pEC50
D-23487	Antagonist	10.0	pKi
sufugolix	Antagonist	10.0	pKi
buserelin	Full agonist	10.0	pKi
deslorelin	Full agonist	10.0	pKd
[des-Gly10,D-Ala6]GnRH N-ethylamide	Full agonist	9.9	pIC50
T-98475	Antagonist	9.7	pIC50
[3H]NBI-49202	Antagonist	9.7	pKd
[125I]cetrorelix	Antagonist	9.7	pKd
merigolix	Antagonist	9.6	pIC50
antarelix	Antagonist	9.6	pKi
triptorelin	Full agonist	9.49	pKi
abarelix	Antagonist	9.49	pKi
relugolix	Antagonist	9.48	pIC50
[125I]triptorelin	Full agonist	9.3	pKd
alarelin	Full agonist	9.3	pKi
[125I][des-Gly10,D-Ala6]GnRH N-ethylamide	Full agonist	9.3	pKd
NBI-42902	Antagonist	9.3	pKi
IN-3	Antagonist	9.22	pIC50
[Ac-D-2Nal1,D4CPA2,D-3Pal3,6,Leu8, D-Ala10]GnRH-II	Antagonist	9.18	pIC50
leuprolide	Full agonist	9.1	pKi
fertirelin	Full agonist	9.1	pKd
elagolix	Antagonist	9.05	pKi
iturelix	Antagonist	8.98	pIC50

Binding affinities (BindingDB)

79 measured of 79 human assays (84 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[4-[7-[(2,6-difluorophenyl)methyl]-3-[(dimethylamino)methyl]-5-(2-fluoro-3-methoxyphenyl)-4,6-dioxo-1,7a-dihydropyrazolo[3,4-d]pyrimidin-2-yl]phenyl]-3-methylurea	IC50	0.11 nM	US-10344034: Pyrazolopyrimidone or Pyrrolotriazone derivatives, method of preparing same, and pharmaceutical applications thereof
5-(2-{(S)-2-[5-[2-(2-Aza-bicyclo[2.2.2]oct-2-yl)-1,1-dimethyl-2-oxo-ethyl]-2-(3,5-dimethyl-phenyl)-1H-indol-3-yl]-propylamino}-ethyl)-1H-pyridin-2-one	IC50	0.3 nM
1-(7-Aza-bicyclo[2.2.1]hept-7-yl)-2-[3-[(S)-2-(2-benzooxazol-5-yl-ethylamino)-1-methyl-ethyl]-2-(3,5-dimethyl-phenyl)-1H-indol-5-yl]-2-methyl-propan-1-one	IC50	0.3 nM
1-(2-Aza-bicyclo[2.2.2]oct-2-yl)-2-(2-(3,5-dimethyl-phenyl)-3-{(S)-2-[2-(3H-imidazo[4,5-b]pyridin-6-yl)-ethylamino]-1-methyl-ethyl}-1H-indol-5-yl)-2-methyl-propan-1-one	IC50	0.3 nM
1-(2-Aza-bicyclo[2.2.2]oct-2-yl)-2-(2-(3,5-dimethyl-phenyl)-3-{(S)-1-methyl-2-[2-(1-oxy-pyridin-4-yl)-ethylamino]-ethyl}-1H-indol-5-yl)-2-methyl-propan-1-one	IC50	0.3 nM
1-(7-Aza-bicyclo[2.2.1]hept-7-yl)-2-[3-[(S)-2-(2-benzooxazol-6-yl-ethylamino)-1-methyl-ethyl]-2-(3,5-dimethyl-phenyl)-1H-indol-5-yl]-2-methyl-propan-1-one	IC50	0.4 nM
1-(2-Aza-bicyclo[2.2.2]oct-2-yl)-2-(2-(3,5-dimethyl-phenyl)-3-{(S)-2-[2-(2-hydroxymethyl-pyridin-4-yl)-ethylamino]-1-methyl-ethyl}-1H-indol-5-yl)-2-methyl-propan-1-one	IC50	0.4 nM
1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(2-fluoro-3-methoxyphenyl)-2,4-dioxopyrrolo[2,1-f][1,2,4]triazin-6-yl]phenyl]-3-methoxyurea	IC50	0.43 nM	US-10344034: Pyrazolopyrimidone or Pyrrolotriazone derivatives, method of preparing same, and pharmaceutical applications thereof
1-[4-[3-[(dimethylamino)methyl]-5-(2-fluoro-3-methoxyphenyl)-7-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-4,6-dioxo-1,7a-dihydropyrazolo[3,4-d]pyrimidin-2-yl]phenyl]-3-methoxyurea	IC50	0.49 nM	US-10344034: Pyrazolopyrimidone or Pyrrolotriazone derivatives, method of preparing same, and pharmaceutical applications thereof
1-(2-Aza-bicyclo[2.2.2]oct-2-yl)-2-[3-[(S)-2-(2-benzooxazol-6-yl-ethylamino)-1-methyl-ethyl]-2-(3,5-dimethyl-phenyl)-1H-indol-5-yl]-2-methyl-propan-1-one	IC50	0.6 nM
1-(7-Aza-bicyclo[2.2.1]hept-7-yl)-2-{2-(3,5-dimethyl-phenyl)-3-[(S)-2-(2-isoquinolin-5-yl-ethylamino)-1-methyl-ethyl]-1H-indol-5-yl}-2-methyl-propan-1-one	IC50	0.6 nM
1-(2-Aza-bicyclo[2.2.2]oct-2-yl)-2-[2-(3,5-dimethyl-phenyl)-3-((S)-2-{2-[2-(1-hydroxy-ethyl)-pyridin-4-yl]-ethylamino}-1-methyl-ethyl)-1H-indol-5-yl]-2-methyl-propan-1-one	IC50	0.6 nM
1-[4-[7-[(2,6-difluorophenyl)methyl]-3-[(dimethylamino)methyl]-5-(6-methoxypyridazin-3-yl)-4,6-dioxo-1,7a-dihydropyrazolo[3,4-d]pyrimidin-2-yl]phenyl]-3-ethylurea	IC50	0.66 nM	US-10344034: Pyrazolopyrimidone or Pyrrolotriazone derivatives, method of preparing same, and pharmaceutical applications thereof
CHEMBL408746	KI	0.7 nM
1-(7-Aza-bicyclo[2.2.1]hept-7-yl)-2-{2-(3,5-dimethyl-phenyl)-3-[(S)-1-methyl-2-(2-pyridin-4-yl-ethylamino)-ethyl]-1H-indol-5-yl}-2-methyl-propan-1-one	IC50	0.8 nM
1-[4-[7-[(2,6-difluorophenyl)methyl]-3-[(dimethylamino)methyl]-5-(2-fluoro-3-methoxyphenyl)-4,6-dioxo-1,7a-dihydropyrazolo[3,4-d]pyrimidin-2-yl]phenyl]-3-ethylurea	IC50	0.9 nM	US-10344034: Pyrazolopyrimidone or Pyrrolotriazone derivatives, method of preparing same, and pharmaceutical applications thereof
1-(7-Aza-bicyclo[2.2.1]hept-7-yl)-2-{2-(3,5-dimethyl-phenyl)-3-[(S)-2-(3-isoquinolin-5-yl-propylamino)-1-methyl-ethyl]-1H-indol-5-yl}-2-methyl-propan-1-one	IC50	0.9 nM
1-(2-Aza-bicyclo[2.2.2]oct-2-yl)-2-(2-(3,5-dimethyl-phenyl)-3-{(S)-1-methyl-2-[2-(2-methyl-pyridin-4-yl)-ethylamino]-ethyl}-1H-indol-5-yl)-2-methyl-propan-1-one	IC50	0.9 nM
1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(2-fluoro-3-methoxyphenyl)-2,4-dioxopyrrolo[2,1-f][1,2,4]triazin-6-yl]phenyl]-3-ethylurea	IC50	0.92 nM	US-10344034: Pyrazolopyrimidone or Pyrrolotriazone derivatives, method of preparing same, and pharmaceutical applications thereof
1-[4-[3-[(dimethylamino)methyl]-5-(2-fluoro-3-methoxyphenyl)-7-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-4,6-dioxo-1,7a-dihydropyrazolo[3,4-d]pyrimidin-2-yl]phenyl]-3-ethylurea	IC50	0.96 nM	US-10344034: Pyrazolopyrimidone or Pyrrolotriazone derivatives, method of preparing same, and pharmaceutical applications thereof
1-(2-Aza-bicyclo[2.2.2]oct-2-yl)-2-{2-(3,5-dimethyl-phenyl)-3-[(S)-1-methyl-2-(4-pyridin-4-yl-butylamino)-ethyl]-1H-indol-5-yl}-2-methyl-propan-1-one	IC50	1 nM
1-(7-Aza-bicyclo[2.2.1]hept-7-yl)-2-{2-(3,5-dimethyl-phenyl)-3-[2-(4-pyridin-4-yl-butylamino)-ethyl]-1H-indol-5-yl}-2-methyl-propan-1-one	IC50	1.4 nM
1-[4-[7-[(2,6-difluorophenyl)methyl]-3-[(dimethylamino)methyl]-5-(2-fluoro-3-methoxyphenyl)-4,6-dioxo-1,7a-dihydropyrazolo[3,4-d]pyrimidin-2-yl]phenyl]-3-methoxyurea	IC50	1.46 nM	US-10344034: Pyrazolopyrimidone or Pyrrolotriazone derivatives, method of preparing same, and pharmaceutical applications thereof
3-[2-chloro-5-(3,4-dihydro-2H-quinolin-1-ylsulfonyl)phenyl]-2,4-dioxo-1H-thieno[3,4-d]pyrimidine-5-carboxylic acid	IC50	2 nM	US-9040693: Fused heterocyclic derivative, medicinal composition containing the same, and medicinal use thereof
1-[4-[3-[(dimethylamino)methyl]-7-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-5-(6-methoxypyridazin-3-yl)-4,6-dioxo-1,7a-dihydropyrazolo[3,4-d]pyrimidin-2-yl]phenyl]-3-methylurea	IC50	2.24 nM	US-10344034: Pyrazolopyrimidone or Pyrrolotriazone derivatives, method of preparing same, and pharmaceutical applications thereof
1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxopyrrolo[2,1-f][1,2,4]triazin-6-yl]phenyl]-3-methylurea	IC50	2.32 nM	US-10344034: Pyrazolopyrimidone or Pyrrolotriazone derivatives, method of preparing same, and pharmaceutical applications thereof
1-(7-Aza-bicyclo[2.2.1]hept-7-yl)-2-[3-{(S)-2-[2-(1H-benzoimidazol-5-yl)-ethylamino]-1-methyl-ethyl}-2-(3,5-dimethyl-phenyl)-1H-indol-5-yl]-2-methyl-propan-1-one	IC50	2.6 nM
methyl ((S)-2-(2-(1-(7-aza-bicyclo[2.2.1]heptan-7-yl)-2-methyl-1-oxopropan-2-yl)-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrol-4-yl)propylamino)(3-(pyridin-4-yl)pyrrolidin-1-yl)methylenecarbamate	IC50	3 nM
1-(2-Aza-bicyclo[2.2.2]oct-2-yl)-2-(2-(3,5-dimethyl-phenyl)-3-{(S)-2-[2-(2-ethyl-pyridin-4-yl)-ethylamino]-1-methyl-ethyl}-1H-indol-5-yl)-2-methyl-propan-1-one	IC50	3.3 nM
1-(2-Aza-bicyclo[2.2.2]oct-2-yl)-2-[3-{(S)-2-[2-(1H-benzoimidazol-5-yl)-ethylamino]-1-methyl-ethyl}-2-(3,5-dimethyl-phenyl)-1H-indol-5-yl]-2-methyl-propan-1-one	IC50	4.5 nM
1-(2-Aza-bicyclo[2.2.2]oct-2-yl)-2-(2-(3,5-dimethyl-phenyl)-3-{(S)-1-methyl-2-[2-(2-propyl-pyridin-4-yl)-ethylamino]-ethyl}-1H-indol-5-yl)-2-methyl-propan-1-one	IC50	4.6 nM
2-{2-(3,5-Dimethyl-phenyl)-3-[(S)-1-methyl-2-(4-pyridin-4-yl-butylamino)-ethyl]-1H-indol-5-yl}-2-methyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-propan-1-one	IC50	6.4 nM
1-(6-Aza-bicyclo[3.2.1]oct-6-yl)-2-{2-(3,5-dimethyl-phenyl)-3-[(S)-1-methyl-2-(4-pyridin-4-yl-butylamino)-ethyl]-1H-indol-5-yl}-2-methyl-propan-1-one	IC50	6.8 nM
1-(7-Aza-bicyclo[2.2.1]hept-7-yl)-2-{2-(3,5-dimethyl-phenyl)-3-[(S)-2-(4-isoquinolin-5-yl-butylamino)-1-methyl-ethyl]-1H-indol-5-yl}-2-methyl-propan-1-one	IC50	6.8 nM
4-(2-{(S)-2-[5-[2-(2-Aza-bicyclo[2.2.2]oct-2-yl)-1,1-dimethyl-2-oxo-ethyl]-2-(3,5-dimethyl-phenyl)-1H-indol-3-yl]-propylamino}-ethyl)-pyridine-2-carboxylic acid	IC50	8.2 nM
1-(8-Aza-bicyclo[3.2.1]oct-8-yl)-2-{2-(3,5-dimethyl-phenyl)-3-[(S)-1-methyl-2-(4-pyridin-4-yl-butylamino)-ethyl]-1H-indol-5-yl}-2-methyl-propan-1-one	IC50	8.8 nM
3-[2-chloro-5-(2-methyl-2-phenylpropanoyl)phenyl]-2,4-dioxo-1H-thieno[3,4-d]pyrimidine-5-carboxylic acid	IC50	10 nM	US-9040693: Fused heterocyclic derivative, medicinal composition containing the same, and medicinal use thereof
4-(2-{(S)-2-[5-[2-(2-Aza-bicyclo[2.2.2]oct-2-yl)-1,1-dimethyl-2-oxo-ethyl]-2-(3,5-dimethyl-phenyl)-1H-indol-3-yl]-propylamino}-ethyl)-pyridine-2-carbonitrile	IC50	11 nM
(S)-isopropyl (2-(2-(1-(7-aza-bicyclo[2.2.1]heptan-7-yl)-2-methyl-1-oxopropan-2-yl)-5-(3,5-dimethylphenyl)-6H-thieno[2,3-b]pyrrol-4-yl)propylamino)(4-(pyridin-4-yl)piperidin-1-yl)methylenecarbamate	IC50	12 nM
Linzagolix	IC50	15 nM	US-9040693: Fused heterocyclic derivative, medicinal composition containing the same, and medicinal use thereof
3-[5-[[2,3-difluoro-6-(2-methoxyethoxy)phenyl]methoxy]-2-fluorophenyl]-2,4-dioxo-1H-thieno[3,4-d]pyrimidine-5-carboxylic acid	IC50	15 nM	US-9040693: Fused heterocyclic derivative, medicinal composition containing the same, and medicinal use thereof
3-[2-fluoro-5-[2-(5-fluoro-2-methoxyphenyl)propan-2-ylsulfanyl]phenyl]-2,4-dioxo-1H-thieno[3,4-d]pyrimidine-5-carboxylic acid	IC50	17 nM	US-9040693: Fused heterocyclic derivative, medicinal composition containing the same, and medicinal use thereof
3-[2-chloro-5-[methyl(phenyl)carbamoyl]phenyl]-2,4-dioxo-1H-thieno[3,4-d]pyrimidine-5-carboxylic acid	IC50	19 nM	US-9040693: Fused heterocyclic derivative, medicinal composition containing the same, and medicinal use thereof
3-[2-fluoro-5-(2-phenylpropan-2-ylsulfonyl)phenyl]-2,4-dioxo-1H-thieno[3,4-d]pyrimidine-5-carboxylic acid	IC50	20 nM	US-9040693: Fused heterocyclic derivative, medicinal composition containing the same, and medicinal use thereof
Acetic acid 4-(2-{(S)-2-[5-[2-(2-aza-bicyclo[2.2.2]oct-2-yl)-1,1-dimethyl-2-oxo-ethyl]-2-(3,5-dimethyl-phenyl)-1H-indol-3-yl]-propylamino}-ethyl)-pyridin-2-ylmethyl ester	IC50	22 nM
1-(2-Aza-bicyclo[2.2.2]oct-2-yl)-2-(2-(3,5-dimethyl-phenyl)-3-{(S)-2-[2-(2,6-dimethyl-pyridin-4-yl)-ethylamino]-1-methyl-ethyl}-1H-indol-5-yl)-2-methyl-propan-1-one	IC50	24 nM
4-(2-{(S)-2-[5-[2-(2-Aza-bicyclo[2.2.2]oct-2-yl)-1,1-dimethyl-2-oxo-ethyl]-2-(3,5-dimethyl-phenyl)-1H-indol-3-yl]-propylamino}-ethyl)-pyridine-2-carboxylic acid methyl ester	IC50	25 nM
3-[2-fluoro-5-[1-(2-fluoro-6-methoxyphenyl)ethoxy]phenyl]-2,4-dioxo-1H-thieno[3,4-d]pyrimidine-5-carboxylic acid	IC50	29 nM	US-9040693: Fused heterocyclic derivative, medicinal composition containing the same, and medicinal use thereof
3-[5-[(2,6-difluoro-N-methylanilino)methyl]-2-fluoro-4-methoxyphenyl]-2,4-dioxo-1H-thieno[3,4-d]pyrimidine-5-carboxylic acid	IC50	29 nM	US-9040693: Fused heterocyclic derivative, medicinal composition containing the same, and medicinal use thereof
(7-Aza-bicyclo[2.2.1]hept-7-yl)-{2-(3,5-dimethyl-phenyl)-3-[2-(4-pyridin-4-yl-butylamino)-ethyl]-1H-indol-5-yl}-methanone	IC50	32 nM

ChEMBL bioactivities

2794 potent at pChembl≥5 of 2817 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.22	IC50	0.06	nM	CHEMBL379629
10.22	IC50	0.06	nM	SUFUGOLIX
10.15	IC50	0.07	nM	CHEMBL377396
10.15	IC50	0.07	nM	CHEMBL210294
10.15	IC50	0.07	nM	CHEMBL1800156
10.15	IC50	0.07	nM	CHEMBL1800663
10.15	IC50	0.07	nM	CHEMBL1800155
10.15	IC50	0.07	nM	CHEMBL435167
10.10	IC50	0.08	nM	CHEMBL1800668
10.10	IC50	0.08	nM	CHEMBL1800661
10.10	IC50	0.08	nM	RELUGOLIX
10.10	IC50	0.08	nM	CHEMBL1800157
10.05	IC50	0.09	nM	CHEMBL1800666
10.05	IC50	0.09	nM	CHEMBL1800661
10.00	IC50	0.1	nM	CHEMBL441676
10.00	IC50	0.1	nM	CHEMBL211485
10.00	IC50	0.1	nM	CHEMBL377396
10.00	IC50	0.1	nM	CHEMBL208812
10.00	IC50	0.1	nM	CHEMBL210709
10.00	IC50	0.1	nM	CHEMBL3977463
10.00	Ki	0.1	nM	CHEMBL71917
10.00	IC50	0.1	nM	SUFUGOLIX
10.00	IC50	0.1	nM	CHEMBL1800153
10.00	IC50	0.1	nM	CHEMBL1800668
10.00	IC50	0.1	nM	CHEMBL1800664
10.00	IC50	0.1	nM	CHEMBL435167
10.00	IC50	0.1	nM	CHEMBL2092994
9.96	IC50	0.11	nM	CHEMBL4454362
9.96	IC50	0.11	nM	CHEMBL5895782
9.96	IC50	0.11	nM	CHEMBL5867597
9.92	IC50	0.12	nM	CHEMBL1800158
9.87	Kd	0.135	nM	CETRORELIX
9.85	IC50	0.14	nM	CHEMBL4585638
9.85	Ki	0.14	nM	CHEMBL405548
9.80	IC50	0.16	nM	CHEMBL4474379
9.77	IC50	0.17	nM	CHEMBL4566719
9.77	IC50	0.17	nM	CHEMBL4516712
9.77	IC50	0.17	nM	CHEMBL1800155
9.74	IC50	0.18	nM	CHEMBL1800153
9.70	IC50	0.2	nM	CHEMBL544440
9.70	IC50	0.2	nM	CHEMBL71917
9.70	IC50	0.2	nM	CHEMBL377396
9.70	IC50	0.2	nM	CHEMBL212121
9.70	IC50	0.2	nM	CHEMBL377015
9.70	IC50	0.2	nM	CHEMBL211503
9.70	IC50	0.2	nM	CHEMBL540109
9.70	IC50	0.2	nM	CHEMBL1800152
9.70	Ki	0.2	nM	CHEMBL71917
9.70	Ki	0.2	nM	CHEMBL466731
9.70	IC50	0.2	nM	CHEMBL261979

PubChem BioAssay actives

2743 with measured affinity, of 3396 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
1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[2-methoxyethyl(methyl)amino]methyl]-3-(4-methoxyphenyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea	606109: Displacement of [125I]leuprorelin from recombinant human GnRH receptor expressed in CHO cells after 60 mins by X-ray counter	ic50	0.0001	uM
Relugolix	606109: Displacement of [125I]leuprorelin from recombinant human GnRH receptor expressed in CHO cells after 60 mins by X-ray counter	ic50	0.0001	uM
1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxy-3-pyridinyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea	606109: Displacement of [125I]leuprorelin from recombinant human GnRH receptor expressed in CHO cells after 60 mins by X-ray counter	ic50	0.0001	uM
1-[4-[3-[[benzyl(methyl)amino]methyl]-7-[(2,6-difluorophenyl)methyl]-5-(2-methylpropanoyl)-4-oxothieno[2,3-b]pyridin-2-yl]phenyl]-3-methylurea	267082: Inhibition of [125I]leuprorelin binding to human recombinant LHRH receptor expressed in CHO cells	ic50	0.0001	uM
ethyl 3-[[benzyl(methyl)amino]methyl]-7-[(2,6-difluorophenyl)methyl]-2-[4-(methylcarbamoylamino)phenyl]-4-oxothieno[2,3-b]pyridine-5-carboxylate	267082: Inhibition of [125I]leuprorelin binding to human recombinant LHRH receptor expressed in CHO cells	ic50	0.0001	uM
ethyl 3-[[benzyl(methyl)amino]methyl]-7-[(2-fluorophenyl)methyl]-2-[4-(methylcarbamoylamino)phenyl]-4-oxothieno[2,3-b]pyridine-5-carboxylate	267082: Inhibition of [125I]leuprorelin binding to human recombinant LHRH receptor expressed in CHO cells	ic50	0.0001	uM
N-[4-[5-benzoyl-3-[[benzyl(methyl)amino]methyl]-7-[(2,6-difluorophenyl)methyl]-4-oxothieno[2,3-b]pyridin-2-yl]phenyl]-2-methylpropanamide	267082: Inhibition of [125I]leuprorelin binding to human recombinant LHRH receptor expressed in CHO cells	ic50	0.0001	uM
ethyl 3-[[benzyl(methyl)amino]methyl]-7-[(2,6-difluorophenyl)methyl]-4-oxo-2-[4-(propanoylamino)phenyl]thieno[2,3-b]pyridine-5-carboxylate	267082: Inhibition of [125I]leuprorelin binding to human recombinant LHRH receptor expressed in CHO cells	ic50	0.0001	uM
[(2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-4,4-difluoro-2-(hydroxymethyl)oxolan-3-yl] N-[(5R)-6-[[(2S)-1-[[(2S)-1-[(2S)-2-[(2-amino-2-oxoethyl)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-[[(2S)-2-[[(2S)-3-hydroxy-2-[[(2S)-2-[[(2S)-3-(1H-imidazol-5-yl)-2-[[(2S)-5-oxopyrrolidine-2-carbonyl]amino]propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]propanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-oxohexyl]carbamate	1602090: Displacement of [125I]-D-Tyr6-His5-GnRH from recombinant human GnRH receptor expressed in HEK293 cell membrane measured after 16 to 19 hrs by gamma counting method	ic50	0.0001	uM
1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[2-methoxyethyl(methyl)amino]methyl]-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea	606109: Displacement of [125I]leuprorelin from recombinant human GnRH receptor expressed in CHO cells after 60 mins by X-ray counter	ic50	0.0001	uM
N-[4-[3-[[benzyl(methyl)amino]methyl]-7-[(2,6-difluorophenyl)methyl]-5-(2-methylpropanoyl)-4-oxothieno[2,3-b]pyridin-2-yl]phenyl]-2-hydroxybutanamide	267082: Inhibition of [125I]leuprorelin binding to human recombinant LHRH receptor expressed in CHO cells	ic50	0.0001	uM
Cetrorelix	1681581: Inhibition of Tag-lite green-labeled agonist binding to terbium fluorophore-labeled human N-terminal SNAP-tag GnRh receptor expressed in HEK293 cells assessed as equilibrium dissociation constant by TR-FRET assay	kd	0.0001	uM
1-[4-[5-[[benzyl(methyl)amino]methyl]-1-[(2,6-difluorophenyl)methyl]-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea	102817: Antagonist concentration required to inhibit specific binding of [125I]leuprorelin to human luteinizing releasing hormone receptor in cloned chinese hamster ovary (CHO) cells.	ic50	0.0001	uM
(1R,7S,10S,15S,18S,30S,33R)-15-[[(2R)-2-[[(2R)-2-[[(2R)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-33-[3-(diaminomethylideneamino)propyl]-30-(2-methylpropyl)-2,8,13,16,21,24,29,32,35-nonaoxo-3,9,12,17,22,25,28,31,34-nonazatricyclo[16.9.8.03,7]pentatriacontane-10-carboxamide	74696: Binding affinity towards Gonadotropin-releasing hormone receptor	ki	0.0001	uM
7-chloro-2-oxo-4-[2-[(2S)-4-oxoazetidin-2-yl]ethoxy]-N-(1,2,5-thiadiazol-3-yl)-3-(3,4,5-trimethylphenyl)-1H-quinoline-6-carboxamide	242633: Binding affinity towards human gonadotropin releasing hormone receptor expressed in CHO cells was determined by using [125I]-buserelin as radioligand	ic50	0.0001	uM
1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[2-methoxyethyl(methyl)amino]methyl]-3-(5-methyl-2-pyridinyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea	606109: Displacement of [125I]leuprorelin from recombinant human GnRH receptor expressed in CHO cells after 60 mins by X-ray counter	ic50	0.0001	uM
1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[2-methoxyethyl(methyl)amino]methyl]-3-(6-methoxy-3-pyridinyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea	606111: Antagonist activity at human GnRH receptor expressed in CHO cells assessed as inhibition of GnRH-induced arachidonic acid release using [5,6,8,9,11,12,14,15-3H]arachidonic acid preincubated for 15 mins measured after 45 mins by scintillation counting	ic50	0.0001	uM
1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[2-methoxyethyl(methyl)amino]methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea	606109: Displacement of [125I]leuprorelin from recombinant human GnRH receptor expressed in CHO cells after 60 mins by X-ray counter	ic50	0.0001	uM
1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[methyl(pyridin-2-ylmethyl)amino]methyl]-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea	606109: Displacement of [125I]leuprorelin from recombinant human GnRH receptor expressed in CHO cells after 60 mins by X-ray counter	ic50	0.0001	uM
1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[methyl(2-pyridin-2-ylethyl)amino]methyl]-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea	606109: Displacement of [125I]leuprorelin from recombinant human GnRH receptor expressed in CHO cells after 60 mins by X-ray counter	ic50	0.0001	uM
1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[[6-(hydroxymethyl)-2-pyridinyl]methyl-methylamino]methyl]-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea	606109: Displacement of [125I]leuprorelin from recombinant human GnRH receptor expressed in CHO cells after 60 mins by X-ray counter	ic50	0.0001	uM
1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[methyl-[2-(2-oxopyrrolidin-1-yl)ethyl]amino]methyl]-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea	606109: Displacement of [125I]leuprorelin from recombinant human GnRH receptor expressed in CHO cells after 60 mins by X-ray counter	ic50	0.0001	uM
4-[2-[(1R)-1-amino-2-[3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-4-methyl-5-[4-[(3-nitrophenyl)methyl]piperazin-1-yl]-2,6-dioxopyrimidin-1-yl]ethyl]phenoxy]butanoic acid	1630533: Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cell membranes incubated for 1 hr by competitive binding assay	ic50	0.0001	uM
propan-2-yl 3-[[benzyl(methyl)amino]methyl]-7-[(2,6-difluorophenyl)methyl]-2-[4-(2-methylpropanoylamino)phenyl]-4-oxothieno[2,3-b]pyridine-5-carboxylate	1416689: Antagonist activity at N-terminal FLAG-tagged human full-length GnRHR expressed in HEK293T cells assessed as inhibition of GnRH-induced calcium mobilization preincubated for 15 mins followed by agonist addition by FLIPR assay	ki	0.0001	uM
1-[4-[5-[[benzyl(methyl)amino]methyl]-1-[(2,6-difluorophenyl)methyl]-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methylurea	102817: Antagonist concentration required to inhibit specific binding of [125I]leuprorelin to human luteinizing releasing hormone receptor in cloned chinese hamster ovary (CHO) cells.	ic50	0.0001	uM
1-[4-[5-[[benzyl(methyl)amino]methyl]-1-[(2,6-difluorophenyl)methyl]-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-ethylurea	102817: Antagonist concentration required to inhibit specific binding of [125I]leuprorelin to human luteinizing releasing hormone receptor in cloned chinese hamster ovary (CHO) cells.	ic50	0.0001	uM
3-[(2R)-2-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[(2-fluoro-6-methylsulfonylphenyl)methyl]-6-methylpyrimidine-2,4-dione	407893: Binding affinity at human GnRH receptor	ki	0.0002	uM
ethyl 3-[[benzyl(methyl)amino]methyl]-7-[(2,6-difluorophenyl)methyl]-2-[4-(2-methylpropanoylamino)phenyl]-4-oxothieno[2,3-b]pyridine-5-carboxylate;hydrochloride	267082: Inhibition of [125I]leuprorelin binding to human recombinant LHRH receptor expressed in CHO cells	ic50	0.0002	uM
N-[4-[3-[[benzyl(methyl)amino]methyl]-7-[(2,6-difluorophenyl)methyl]-5-(2-methylpropanoyl)-4-oxothieno[2,3-b]pyridin-2-yl]phenyl]-2-hydroxyacetamide	267082: Inhibition of [125I]leuprorelin binding to human recombinant LHRH receptor expressed in CHO cells	ic50	0.0002	uM
N-[4-[3-[[benzyl(methyl)amino]methyl]-7-[(2,6-difluorophenyl)methyl]-5-(2-methylpropanoyl)-4-oxothieno[2,3-b]pyridin-2-yl]phenyl]-2-hydroxy-2-methylpropanamide	267082: Inhibition of [125I]leuprorelin binding to human recombinant LHRH receptor expressed in CHO cells	ic50	0.0002	uM
2-[2-[(1R)-1-amino-2-[3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-4-methyl-5-[4-[(3-nitrophenyl)methyl]piperazin-1-yl]-2,6-dioxopyrimidin-1-yl]ethyl]phenoxy]acetic acid	1630533: Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cell membranes incubated for 1 hr by competitive binding assay	ic50	0.0002	uM
1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-2,4-dioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]thieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea	1994054: Displacement of [1251][D-Trp6]-LH-RH from human GnRH-R expressed in Chem-1 cells incubated for 60 mins by liquid scintillation counting analysis	ic50	0.0002	uM
1-(2,2-difluoroethoxy)-3-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]urea	1994054: Displacement of [1251][D-Trp6]-LH-RH from human GnRH-R expressed in Chem-1 cells incubated for 60 mins by liquid scintillation counting analysis	ic50	0.0002	uM
5-[2-[[(2S)-2-[5-[1-(2-azabicyclo[2.2.2]octan-2-yl)-2-methyl-1-oxopropan-2-yl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]propyl]amino]ethyl]-1-methylpyridin-2-one	74284: Binding inhibition towards human pituitary gonadotropin-releasing hormone receptor using [125I]buserelin.	ic50	0.0002	uM
(2R)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2R)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]-N-[(2S)-1-amino-1-oxopropan-2-yl]pyrrolidine-2-carboxamide	74412: The binding affinity towards Gonadotropin-releasing hormone receptor	kd	0.0002	uM
(1R,6R,9R,15S,18R,21R,24R,34R,37S,40R)-34-acetamido-37-[(4-chlorophenyl)methyl]-15-[3-(diaminomethylideneamino)propyl]-40-(1H-indol-3-ylmethyl)-18-(2-methylpropyl)-21-(naphthalen-2-ylmethyl)-3,8,14,17,20,23,28,31,35,38,41,43-dodecaoxo-4,7,13,16,19,22,27,30,36,39,42,44-dodecazatricyclo[22.18.2.09,13]tetratetracontane-6-carboxamide	74696: Binding affinity towards Gonadotropin-releasing hormone receptor	ki	0.0002	uM
1-[4-[1-[(2,6-difluorophenyl)methyl]-3-(2-methoxyethyl)-5-[[2-methoxyethyl(methyl)amino]methyl]-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea	606109: Displacement of [125I]leuprorelin from recombinant human GnRH receptor expressed in CHO cells after 60 mins by X-ray counter	ic50	0.0002	uM
1-[4-[1-[(2,6-difluorophenyl)methyl]-3-(2-ethoxyethyl)-5-[[2-methoxyethyl(methyl)amino]methyl]-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea	606109: Displacement of [125I]leuprorelin from recombinant human GnRH receptor expressed in CHO cells after 60 mins by X-ray counter	ic50	0.0002	uM
1-[4-[1-[(2,6-difluorophenyl)methyl]-3-(5-fluoro-2-pyridinyl)-5-[[2-methoxyethyl(methyl)amino]methyl]-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea	606109: Displacement of [125I]leuprorelin from recombinant human GnRH receptor expressed in CHO cells after 60 mins by X-ray counter	ic50	0.0002	uM
1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[methyl(pyridin-3-ylmethyl)amino]methyl]-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea	606109: Displacement of [125I]leuprorelin from recombinant human GnRH receptor expressed in CHO cells after 60 mins by X-ray counter	ic50	0.0002	uM
1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[methyl-[2-[methyl(methylsulfonyl)amino]ethyl]amino]methyl]-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea	606109: Displacement of [125I]leuprorelin from recombinant human GnRH receptor expressed in CHO cells after 60 mins by X-ray counter	ic50	0.0002	uM
3-[(2R)-2-amino-2-(2-hydroxyphenyl)ethyl]-1-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-6-methyl-5-[4-[(3-nitrophenyl)methyl]piperazin-1-yl]pyrimidine-2,4-dione	1630533: Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cell membranes incubated for 1 hr by competitive binding assay	ic50	0.0002	uM
5-[[4-[1-[(2R)-2-amino-2-phenylethyl]-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-4-methyl-2,6-dioxopyrimidin-5-yl]piperazin-1-yl]methyl]furan-2-carbonitrile	1630533: Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cell membranes incubated for 1 hr by competitive binding assay	ic50	0.0002	uM
5-[4-[(3-acetylphenyl)methyl]piperazin-1-yl]-3-[(2R)-2-amino-2-phenylethyl]-1-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-6-methylpyrimidine-2,4-dione	1630533: Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cell membranes incubated for 1 hr by competitive binding assay	ic50	0.0002	uM
(2R)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2R)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-5-[(5-amino-1H-1,2,4-triazol-3-yl)amino]pentanoyl]amino]-5-[(5-amino-1H-1,2,4-triazol-3-yl)amino]pentanoyl]amino]-4-methylpentanoyl]amino]-6-(propan-2-ylamino)hexanoyl]-N-[(2S)-1-amino-1-oxopropan-2-yl]pyrrolidine-2-carboxamide	74412: The binding affinity towards Gonadotropin-releasing hormone receptor	kd	0.0002	uM
N-[4-[3-[[benzyl(methyl)amino]methyl]-7-[(2,6-difluorophenyl)methyl]-5-(2-methylpropanoyl)-4-oxothieno[2,3-b]pyridin-2-yl]phenyl]-2-methylpropanamide	267082: Inhibition of [125I]leuprorelin binding to human recombinant LHRH receptor expressed in CHO cells	ic50	0.0002	uM
1-[4-[5-[[benzyl(methyl)amino]methyl]-1-[(2,6-difluorophenyl)methyl]-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-propan-2-ylurea	102817: Antagonist concentration required to inhibit specific binding of [125I]leuprorelin to human luteinizing releasing hormone receptor in cloned chinese hamster ovary (CHO) cells.	ic50	0.0002	uM
1-[4-[5-[[benzyl(methyl)amino]methyl]-1-[(2,6-difluorophenyl)methyl]-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-ethoxyurea	102817: Antagonist concentration required to inhibit specific binding of [125I]leuprorelin to human luteinizing releasing hormone receptor in cloned chinese hamster ovary (CHO) cells.	ic50	0.0002	uM
propan-2-yl 3-[[benzyl(methyl)amino]methyl]-7-[(2,6-difluorophenyl)methyl]-2-[4-(2-methylpropanoylamino)phenyl]-4-oxothieno[2,3-b]pyridine-5-carboxylate;hydrochloride	102817: Antagonist concentration required to inhibit specific binding of [125I]leuprorelin to human luteinizing releasing hormone receptor in cloned chinese hamster ovary (CHO) cells.	ic50	0.0002	uM
N-[4-[5-[[benzyl(methyl)amino]methyl]-1-[(2,6-difluorophenyl)methyl]-3-(3-methoxyphenyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]propanamide	102817: Antagonist concentration required to inhibit specific binding of [125I]leuprorelin to human luteinizing releasing hormone receptor in cloned chinese hamster ovary (CHO) cells.	ic50	0.0002	uM

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
potassium perchlorate	increases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
trichostatin A	affects expression, decreases reaction	1
1,6-hexamethylene diisocyanate	affects expression	1
trimellitic anhydride	affects expression	1
ammonium hexachloroplatinate	affects expression	1
maleic acid	increases expression	1
deslorelin	decreases reaction, increases transport	1
CGP 52608	increases reaction, affects binding	1
bifenthrin	increases expression	1
5-(N-benzyl-N-methylaminomethyl)-1–(2,6-difluorobenzyl)-6-(4-(3-methoxyureido)phenyl)-3-phenylthieno(2,3-d)pyrimidine-2,4(1H,3H)-dione	affects binding, decreases activity	1
quinocetone	increases expression	1
bisphenol S	affects expression	1
relugolix	affects binding, decreases activity	1
Benzene	affects binding, decreases activity	1
Benzo(a)pyrene	increases expression	1
Buserelin	affects binding, increases activity, decreases reaction, increases transport	1
Carmustine	increases expression	1
Doxorubicin	affects response to substance	1
Estradiol	decreases reaction, increases expression, increases reaction, increases phosphorylation	1
Nickel	affects expression, decreases reaction	1
Tetradecanoylphorbol Acetate	affects cotreatment, affects expression	1
Zinc	affects cotreatment, affects expression	1
2,4-Dinitrophenol	decreases reaction, increases transport	1
Lactic Acid	decreases expression	1

ChEMBL screening assays

302 unique, capped per target: 248 binding, 54 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1008930	Binding	Displacement of [125I-Tyr5,DLeu6,NMeLeu7,Pro9-NEt-]GnRH from human GnRH receptor expressed in HEK293 cells by liquid scintillation counting	Discovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor. — J Med Chem
CHEMBL1008931	Functional	Antagonist activity at human GnRH receptor expressed in RBL1 cells assessed as inhibition of GnRH-stimulated inositol phosphate production	Discovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor. — 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_H440	CHO-K1/GNRHR/Galpha15	Spontaneously immortalized cell line	Female
CVCL_KA76	293/GNRHR/Galpha15	Transformed cell line	Female
CVCL_KU59	CHO-K1 GNRHR Gq	Spontaneously immortalized cell line	Female
CVCL_VR08	MCF7-h14	Cancer cell line	Female
CVCL_ZI70	GeneBLAzer GnRHR-NFAT-bla CHO-K1	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00328926	PHASE4	TERMINATED	Luveris® (Lutropin Alfa for Injection) in Women With Hypogonadotropic Hypogonadism (Luteinizing Hormone [LH] Less Than [<] 1.2 International Unit Per Liter [IU/L])
NCT01403532	PHASE4	COMPLETED	Sequential Therapy for Hypogonadotropic Hypogonadism
NCT01454011	PHASE4	COMPLETED	The Effect of Testosterone Replacement on the High Density Lipoprotein Cholesterol Subgroups
NCT01601327	PHASE4	COMPLETED	Effects of Medications in Patients With Hypogonadism
NCT02310074	PHASE4	UNKNOWN	Efficacy and Safety of Pulsatile Gonadotropin Releasing Hormone Pump Treatment in Patients With Idiopathic Hypogonadotropic Hypogonadism
NCT02880280	PHASE4	UNKNOWN	Human Menopausal Gonadotropin Combining With Human Chorionic Gonadotropin Treat Congenital Hypogonadotropic Hypogonadism
NCT03490513	PHASE4	COMPLETED	Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism
NCT04456296	PHASE4	COMPLETED	A Study of the Effect of Testosterone Replacement Therapy on Blood Pressure in Adult Male Participants With Hypogonadism
NCT05205837	PHASE4	TERMINATED	A Randomized, Double-blinded, Clinical, Placebo-controlled Trial on the Effects of Therapy With Letrozole and hUman Choriongonadotropin in Male Hypogonadism Induced by Illicit Use of Anabolic Androgenic Steroids- The LUCAS Trial
NCT01388907	PHASE4	COMPLETED	Efficacity Assessment of PREVADH® in Adhesion Prevention in Gynaecologic Surgery
NCT01430650	PHASE4	COMPLETED	Endometrial Priming for Embryo Transfer
NCT02607319	PHASE4	COMPLETED	Low Molecular Weight Heparin to Improve Pregnancy Outcome in Patients With Recurrent Implantation Failure
NCT03169166	PHASE4	COMPLETED	The Use of GnRH Agonist Trigger for Final Follicle Maturation in Women Undergoing Assisted Reproductive Technologies
NCT03177122	PHASE4	UNKNOWN	Myo-Inositol- Based Co-treatment in Women With PCOS Undergoing Assisted Reproductive Technology
NCT03477929	PHASE4	UNKNOWN	Cetrorelix and Ganirelix Flexible Protocol for (IVF)
NCT03619707	PHASE4	COMPLETED	Oral Versus Vaginal Progesterone in the Luteal Support in Cryo-warmed Embryo Transfer Cycles
NCT03846544	PHASE4	COMPLETED	Double Pick up in Poor Prognosis Women
NCT05725512	PHASE4	RECRUITING	Prednisolone Administration in Patients With Unexplained REcurrent MIscarriages
NCT06195163	PHASE4	NOT_YET_RECRUITING	TRAP Study: Testosterone for Androgen Receptor Polymorphism
NCT06763926	PHASE4	NOT_YET_RECRUITING	Intranasal Nafarelin For Triggering Oocyte Maturation
NCT01103518	PHASE4	UNKNOWN	Ethinyl Estradiol and Cyproterone Acetate in Irregular Menstruation
NCT01206153	PHASE4	COMPLETED	Metformin for Treatment Antipsychotic Induced Amenorrhea in Female Schizophrenic Patients
NCT02393482	PHASE4	UNKNOWN	Psychological Impact of Amenorrhea in Women With Endometriosis
NCT00467870	PHASE3	COMPLETED	Long-term Safety Study of Intramuscular Injections of 750 mg and 1000 mg Testosterone Undecanoate in Hypogonadal Men
NCT00962637	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal™ Treatment in Men With Secondary Hypogonadism
NCT01067365	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal Treatment in Men With Secondary Hypogonadism
NCT01532414	PHASE3	COMPLETED	Phase III Study to Evaluated Morning Testosterone Normalization in Men With Secondary Hypogonadism
NCT01534208	PHASE3	COMPLETED	Safety Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01709331	PHASE3	COMPLETED	A Study of the Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adult Men With Hypogonadotropic Hypogonadism (HH) (P07937)
NCT01739582	PHASE3	COMPLETED	An Extension Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01739595	PHASE3	COMPLETED	Phase III Study to Evaluate Morning Testosterone Normalization in Overweight Men With Secondary Hypogonadism
NCT01993212	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT01993225	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT02110368	PHASE3	COMPLETED	Bioequivalence Study of Test and Reference Testosterone Topical Gel, 1.62% Metered Pump in Testosterone Deficient Adult Male Subjects Under Fasting Conditions
NCT03019575	PHASE3	COMPLETED	Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adolescent Males With Hypogonadotropic Hypogonadism (HH) (MK-8962-043)
NCT06561594	PHASE3	NOT_YET_RECRUITING	To Evaluate Recombinant Human Follicle Stimulating Hormone-CTP Fusion Protein Injection or Placebo Combined With Chorionic Gonadotropin for Injection
NCT00749853	PHASE3	SUSPENDED	Efficacy of Ovarian Stimulation Based on FSHR Genotype Status
NCT03238092	PHASE3	UNKNOWN	Comparison Between Testosterone and Estradiol Over the Homogenization of Follicular Cohort
NCT03803228	PHASE3	COMPLETED	Dual Ovarian Stimulation (DUOSTIM) for Poor Ovarian Responders
NCT00827151	PHASE3	WITHDRAWN	Bone Mass Accrual in Adolescent Athletes