KISS1R

Summary

KISS1R (KISS1 receptor, HGNC:4510) is a protein-coding gene on chromosome 19p13.3, encoding KiSS-1 receptor (Q969F8). Receptor for kisspeptins (kisspeptin-10, kisspeptin-13, kisspeptin-14 and metastin/kisspeptin-54).

The protein encoded by this gene is a galanin-like G protein-coupled receptor that binds metastin, a peptide encoded by the metastasis suppressor gene KISS1. The tissue distribution of the expressed gene suggests that it is involved in the regulation of endocrine function, and this is supported by the finding that this gene appears to play a role in the onset of puberty. Mutations in this gene have been associated with hypogonadotropic hypogonadism and central precocious puberty.

Source: NCBI Gene 84634 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypogonadotropic hypogonadism 8 with or without anosmia (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 198 total — 9 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 53
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_032551

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4510
Approved symbol	KISS1R
Name	KISS1 receptor
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	HOT7T175, AXOR12
Ensembl gene	ENSG00000116014
Ensembl biotype	protein_coding
OMIM	604161
Entrez	84634

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000234371, ENST00000592648, ENST00000606939, ENST00000909146

RefSeq mRNA: 1 — MANE Select: NM_032551 NM_032551

CCDS: CCDS12049

Canonical transcript exons

ENST00000234371 — 5 exons

Exon	Start	End
ENSE00000769028	918544	918668
ENSE00000892192	919490	919625
ENSE00000892193	919874	920106
ENSE00000892194	920290	921005
ENSE00003695928	917333	917746

Expression profiles

Bgee: expression breadth ubiquitous, 109 present calls, max score 72.35.

FANTOM5 (CAGE): breadth broad, TPM avg 2.0780 / max 120.7106, expressed in 195 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172806	2.0780	195

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pons	UBERON:0000988	72.35	silver quality
buccal mucosa cell	CL:0002336	67.48	gold quality
endothelial cell	CL:0000115	67.17	silver quality
hypothalamus	UBERON:0001898	66.41	gold quality
Brodmann (1909) area 23	UBERON:0013554	64.00	silver quality
pancreatic ductal cell	CL:0002079	63.26	silver quality
cartilage tissue	UBERON:0002418	63.09	silver quality
superior vestibular nucleus	UBERON:0007227	62.70	silver quality
middle temporal gyrus	UBERON:0002771	61.82	gold quality
nucleus accumbens	UBERON:0001882	60.62	gold quality
blood	UBERON:0000178	59.68	gold quality
ileal mucosa	UBERON:0000331	59.12	silver quality
anterior cingulate cortex	UBERON:0009835	57.56	gold quality
granulocyte	CL:0000094	57.12	gold quality
tibialis anterior	UBERON:0001385	56.28	silver quality
entorhinal cortex	UBERON:0002728	56.00	silver quality
amygdala	UBERON:0001876	55.98	gold quality
pituitary gland	UBERON:0000007	55.67	gold quality
Brodmann (1909) area 9	UBERON:0013540	55.53	gold quality
temporal lobe	UBERON:0001871	55.35	gold quality
tendon of biceps brachii	UBERON:0008188	55.28	gold quality
adenohypophysis	UBERON:0002196	54.48	gold quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
superior frontal gyrus	UBERON:0002661	54.14	silver quality
kidney epithelium	UBERON:0004819	53.93	gold quality
upper arm skin	UBERON:0004263	53.52	gold quality
forebrain	UBERON:0001890	52.95	gold quality
deltoid	UBERON:0001476	52.82	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	52.80	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.24

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, RUNX2, SP1

miRNA regulators (miRDB)

15 targeting KISS1R, 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-513B-5P	99.99	69.96	2150
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-4645-3P	99.76	69.33	993
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-4520-3P	98.75	66.55	963
HSA-MIR-4782-5P	98.35	69.33	1474
HSA-MIR-5706	98.35	69.33	1463
HSA-MIR-4786-5P	97.45	67.89	924
HSA-MIR-6730-3P	97.03	67.54	889
HSA-MIR-514A-3P	96.43	67.77	1048
HSA-MIR-514B-3P	96.43	67.77	1048

Literature-anchored findings (GeneRIF, showing 40)

• Overexpression of hOT7T175 gene was frequently observed and correlated with HCC progression; thus, the possibility that overexpressed hOT7T175 peptides mediate growth signals into cancer cells in HCCs is suggested. (PMID:12898236)
• Mutations in GPR54 cause autosomal recessive idiopathic hypogonadotropic hypogonadism in humans and mice, suggesting that this receptor is essential for normal gonadotropin-releasing hormone physiology and for puberty. (PMID:14573733)
• KiSS-1 and hOT7T175 gene expression have roles in preventing progression of lymph node metastasis in esophageal squamous cell carcinoma (PMID:14977840)
• This review focuses on the role of the kisspeptin-GPR54 system in the activation of GnRH neurons at the time of pubertal awakening of the reproductive axis. (PMID:16034182)
• Recent identification of loss-of-function mutations in GPR54, a receptor for kisspeptin-1, has highlighted a new pathway for the timing of puberty and reproductive control. (PMID:16309735)
• KiSS-1/GPR54 system has been proven as an essential gatekeeper of GnRH neurons, involved in their activation at puberty and their regulation by gonadal steroids. (PMID:16731583)
• role for GPR54 and KP in the cardiovascular system (PMID:17023533)
• Human genetics studies of GPR54. (PMID:17334928)
• One polymorphism in GPR54 gene might be correlated with some cases of central precocious puberty, likely by changes in expression of the receptor (PMID:17700012)
• KiSS1 and its receptor tumoral mRNA levels could be new interesting markers of the tumoral resistance to anti-estrogen treatment. (PMID:17914099)
• Kisspeptin and GPR54 immunoreactivity are significantly associated with favourable prognosis in both disease specific and overall survival. (PMID:18005407)
• Metastin and its receptor are probable targets for suppressing rernal cell carcinoma migration and invasion and proliferation. (PMID:18395325)
• 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)
• Herein we review the evidence which support the role of KiSS-1/GPR54 system in cancer biology. (PMID:18583061)
• Disease-causing mutation in GPR54 reveals the importance of the second intracellular loop for class A G-protein-coupled receptor function. (PMID:18772143)
• The catalytic subunit of protein phosphatase 2A (PP2A-C) is the protein interacting with GPR54. (PMID:18977201)
• Review discusses KP/GPR54 signalling as the principal trigger for activation of GnRH neurons and subsequent ovulation; modulation of this pathway could bring novel pharmacologic strategies for fertility treatment (and contraception) within reach [review] (PMID:19112386)
• Activation of GPR54 resulted in the ERK-dependent expression of tumor necrosis factor-alpha and FasL in a lymphoid cell line, the latter being the main trigger of apoptosis. (PMID:19201817)
• The activation of GPR54 induced immediate and profound changes of cell morphology, including cytoplasmic condensation and formation of unpolarized plasma membrane protrusions. (PMID:19286835)
• Combination of metastin and AXOR12 gene expression also had significant impact on patient prognosis in ovarian cancer. (PMID:19331211)
• the studied LEP, NPY1R and GPR54 variants do not have a major influence upon pubertal timing in Caucasian women. (PMID:19506390)
• Data show that GRK2 stimulates the desensitization of GPR54 in HEK 293 cells and that beta-arrestin-2 mediates GPR54 activation of ERK1/2 in MDA-MB-231 cells. (PMID:19846537)
• Inactivating mutations of the KISS1 receptor cause isolated hypogonadotropic hypogonadism. (PMID:20237166)
• One novel homozygous KISS1R mutation was identified in two siblings with normosmic isolated hypogonadotropic hypogonadism. (PMID:20371656)
• This chapter describes the kisspeptin-GPR54 complex physiology and its current role in human diseases. (PMID:20374724)
• Results provide primary evidence that KISS1 and KISS1R expression can be differentially lost in pituitary tumor subtypes. (PMID:21169415)
• A novel loss-of-function mutation in the GPR54 gene is associated with familial normosmic idiopathic hypogonadotropic hypogonadism (PMID:21193544)
• Data show that endometrial cancer overall survival is improved with high expression of GPR54 and that GPR54 expression is associated with known prognostic factors. (PMID:21282360)
• The Arg386Pro mutation does not affect the rate of KISS1R trafficking–instead, it prolongs responsiveness to kisspeptin by decreasing KISS1R degradation, resulting in the net increase on mutant receptor recycled back to the plasma membrane. (PMID:21285314)
• Studies indicate that KISS1R is degraded by the proteasome, as opposed to the classic lysosomal degradation described for most G protein-coupled receptors. (PMID:21912371)
• Compared to Kiss-1 protein, GPR54 expression was mainly present in syncytiotrophoblasts and deciduas, but not in cytotrophoblasts of women with recurrent pregnancy loss. (PMID:21996032)
• Kisspeptin and its receptor are expressed in the human, rat and mouse heart and kisspeptins possess potent positive inotropic activity. (PMID:22132116)
• KISS1 and KISS1R expression in the human and rat carotid body and superior cervical ganglion. (PMID:22193294)
• Data suggest that the KISS1/KISS1R system may play a role in the pathophysiology of endometriosis only for a particular group of patients. (PMID:22210725)
• NKB/NK(3)R and kisspeptin/KISS1R are present in female peripheral reproductive tissues with colocalization of both systems in some non-neuronal cell populations of the human female genital tract. (PMID:22424618)
• Results suggest that findings of increased kisspeptin receptor (KISS1R) expression may represent a mechanism by which functional activity of kisspeptin (KISS1) is higher in pre-eclampsia (PE) than in normal pregnancy. (PMID:22526494)
• The subnormal gonadal response to hCG in patients may implicate a direct role of KISS1R in gonadal function and fetal development of male external genitalia. (PMID:22619348)
• Negative fetal FSH/LH regulation in late pregnancy is associated with declined kisspeptin/KISS1R expression in the tuberal hypothalamus. (PMID:23015653)
• KISS1R-expressing cells undergo sustained kisspeptin-induced signaling that is dependent upon an influx of extracellular Ca2+ (PMID:23070548)
• study suggests that negative expression of metastin receptor in clear cell RCC is significantly related to metastasis (PMID:23277422)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	kiss1rb	ENSDARG00000067563
mus_musculus	Kiss1r	ENSMUSG00000035773
rattus_norvegicus	Kiss1r	ENSRNOG00000011954
drosophila_melanogaster	AstC-R1	FBGN0036790
caenorhabditis_elegans		WBGENE00006864
caenorhabditis_elegans		WBGENE00013782
caenorhabditis_elegans		WBGENE00020086

Paralogs (17): OPRK1 (ENSG00000082556), OPRM1 (ENSG00000112038), OPRD1 (ENSG00000116329), OPRL1 (ENSG00000125510), NPBWR2 (ENSG00000125522), SSTR4 (ENSG00000132671), SSTR1 (ENSG00000139874), SSTR5 (ENSG00000162009), GPR149 (ENSG00000174948), SSTR2 (ENSG00000180616), UTS2R (ENSG00000181408), PTGDR2 (ENSG00000183134), CMKLR2 (ENSG00000183671), LTB4R (ENSG00000213903), LTB4R2 (ENSG00000213906), SSTR3 (ENSG00000278195), NPBWR1 (ENSG00000288611)

Protein

Protein identifiers

KiSS-1 receptor — Q969F8 (reviewed: Q969F8)

Alternative names: G-protein coupled receptor 54, G-protein coupled receptor OT7T175, Hypogonadotropin-1, Kisspeptins receptor, Metastin receptor

All UniProt accessions (3): Q969F8, K7EQ45, U3KQ86

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for kisspeptins (kisspeptin-10, kisspeptin-13, kisspeptin-14 and metastin/kisspeptin-54). The hypothalamic KISS1/KISS1R signaling system plays a central role in the regulation of the hypothalamic-pituitary-gonadal reproductive axis by modulating the secretion of gonadotropin-releasing hormone (GnRH) from GnRH neurons. In these neurons, kisspeptin binding to its receptor activates G(q)-dependent signaling, leading to phospholipase C (PLC) activation, and hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2). The subsequent rise in intracellular calcium levels results in the inhibition of inward rectifier potassium channels and activation of TRPC-like cation channels, leading to GnRH neurons depolarization and stimulation. In addition to this pathway, kisspeptin also triggers G(q)-independent signaling via beta-arrestin, leading to MAPK cascade activation and ERK1/ERK2 phosphorylation. Furthermore, activation of KISS1R by kisspeptin-10 recruits phosphatase DUSP18 and SRC to the KISS1R C-terminus through a G(q)-dependent signaling pathway, leading to DUSP18-mediated dephosphorylation of SRC. In bone tissue, this results in down-regulation of osteoclast differentiation and activity, and consequently suppression of bone resorption. KISS1R is also involved in the regulation of other processes, including cell proliferation and cell migration.

Subunit / interactions. Interacts with SRC and DUSP18; the interaction depends on receptor activation by kisspeptin-10 and is required for DUSP18-mediated dephosphorylation of SRC. Interaction with SRC and DUSP18 is relevant for down-regulation of osteoclast differentiation and activity, and consequently suppression of bone resorption.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in the pancreas, placenta and spinal cord, with lower-level of expression in peripheral blood leukocytes, kidney, lung, fetal liver, stomach, small intestine, testes, spleen, thymus, adrenal glands and lymph nodes. In the adult brain, expressed in the superior frontal gyrus, putamen, caudate nucleus, cingulate gyrus, nucleus accumbens, hippocampus, pons and amygdala, as well as the hypothalamus and pituitary. Expression levels are higher in early (7-9 weeks) than term placentas. Expression levels were increased in both early placentas and molar pregnancies and were reduced in choriocarcinoma cells. Expressed at higher levels in first trimester trophoblasts than at term of gestation. Also found in the extravillous trophoblast suggesting endocrine/paracrine activation mechanism.

Disease relevance. Hypogonadotropic hypogonadism 8 with or without anosmia (HH8) [MIM:614837] 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). HH8 inheritance pattern is autosomal recessive. 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 KISS1R as well as in other HH-associated genes including FGFR1 and IL17RD. Precocious puberty, central 1 (CPPB1) [MIM:176400] A condition defined as the development of secondary sexual characteristics in boys and girls at a chronological age that is 2.5 standard deviations below the mean age at onset of puberty in the population. Central precocious puberty results from premature activation of the hypothalamic-pituitary-gonadal axis. The disease is caused by variants affecting the gene represented in this entry.

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

RefSeq proteins (1): NP_115940* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR008103	KiSS_1_rcpt	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (67 total): mutagenesis site 15, helix 13, sequence variant 9, topological domain 8, transmembrane region 7, strand 7, glycosylation site 3, turn 2, chain 1, region of interest 1, disulfide bond 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
8XGO	ELECTRON MICROSCOPY	2.68
8XGS	ELECTRON MICROSCOPY	2.95
8XGU	ELECTRON MICROSCOPY	3
8ZJD	ELECTRON MICROSCOPY	3.06
8ZJE	ELECTRON MICROSCOPY	3.07
7YQE	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q969F8-F1	76.22	0.33

Antibody-complex structures (SAbDab): 5 — 8XGO, 8XGS, 8XGU, 8ZJD, 8ZJE

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): 115–191

Glycosylation sites (3): 10, 18, 28

Mutagenesis-validated functional residues (15):

Position	Phenotype
99	decreased sensitivity to activation by kisspeptin-54 and reduced phospholipase c-activating g protein-coupled receptor s
119	decreased sensitivity to activation by kisspeptin-54 and reduced phospholipase c-activating g protein-coupled receptor s
122	decreased sensitivity to activation by kisspeptin-54 and reduced phospholipase c-activating g protein-coupled receptor s
123	decreased sensitivity to activation by kisspeptin-54 and reduced phospholipase c-activating g protein-coupled receptor s
148	mildly decreased phospholipase c-activating g protein-coupled receptor signaling in response to kisspeptin-10.
148	severely decreased phospholipase c-activating g protein-coupled receptor signaling in response to kisspeptin-10.
181	decreased sensitivity to activation by kisspeptin-54 and reduced phospholipase c-activating g protein-coupled receptor s
193	loss of sensitivity to activation by kisspeptin-54 and loss of phospholipase c-activating g protein-coupled receptor sig
297	decreased sensitivity to activation by kisspeptin-54 and reduced phospholipase c-activating g protein-coupled receptor s
302	decreased sensitivity to activation by kisspeptin-54 and reduced phospholipase c-activating g protein-coupled receptor s
305	decreased sensitivity to activation by kisspeptin-54 and reduced phospholipase c-activating g protein-coupled receptor s
309	decreased sensitivity to activation by kisspeptin-54 and reduced phospholipase c-activating g protein-coupled receptor s
313	decreased sensitivity to activation by kisspeptin-54 and reduced phospholipase c-activating g protein-coupled receptor s
336	decreased interaction with src; when associated in cis with a-339. decreased interaction with dusp18; when associated in
339	decreased interaction with src; when associated in cis with a-336. decreased interaction with dusp18; when associated in

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-416476	G alpha (q) signalling events
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-388396	GPCR downstream signalling
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 211 (showing top): BENPORATH_ES_WITH_H3K27ME3, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, PEREZ_TP63_TARGETS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOCC_CELL_SURFACE, SCHLESINGER_METHYLATED_DE_NOVO_IN_CANCER, GOBP_HORMONE_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_NEGATIVE_REGULATION_OF_TISSUE_REMODELING, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, BILD_E2F3_ONCOGENIC_SIGNATURE, KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION, GOBP_REGULATION_OF_BONE_REMODELING, GOBP_SECRETION

GO Biological Process (4): G protein-coupled receptor signaling pathway (GO:0007186), neuropeptide signaling pathway (GO:0007218), positive regulation of hormone secretion (GO:0046887), signal transduction (GO:0007165)

GO Molecular Function (4): neuropeptide receptor activity (GO:0008188), G protein-coupled receptor activity (GO:0004930), protein binding (GO:0005515), G protein-coupled peptide receptor activity (GO:0008528)

GO Cellular Component (4): plasma membrane (GO:0005886), cilium (GO:0005929), cell surface (GO:0009986), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Signaling by GPCR	2
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1
Signal Transduction	1
GPCR ligand binding	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
cellular anatomical structure	2
signal transduction	1
positive regulation of cell communication	1
positive regulation of signaling	1
hormone secretion	1
regulation of hormone secretion	1
positive regulation of secretion by cell	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
neuropeptide signaling pathway	1
G protein-coupled peptide receptor activity	1
neuropeptide binding	1
transmembrane signaling receptor activity	1
binding	1
peptide receptor activity	1
membrane	1
cell periphery	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

790 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KISS1R	KISS1	Q15726	999
KISS1R	GNRHR	P30968	975
KISS1R	GNRH1	P01148	969
KISS1R	TAC3	Q9UHF0	967
KISS1R	NSMF	Q6X4W1	873
KISS1R	NPVF	Q9HCQ7	864
KISS1R	PROK2	Q9HC23	841
KISS1R	GNRH2	O43555	821
KISS1R	CHD7	Q9P2D1	801
KISS1R	FSHB	P01225	767
KISS1R	FGFR1	P11362	756
KISS1R	PDYN	P01213	750
KISS1R	GNAQ	P50148	732
KISS1R	ANOS1	P23352	698
KISS1R	GHRHR	Q02643	686

IntAct

16 interactions, top by confidence:

A	B	Type	Score
PPP2CA	KISS1R	psi-mi:“MI:0915”(physical association)	0.590
KISS1R	PPP2CA	psi-mi:“MI:0915”(physical association)	0.590
KISS1R	PPP2CA	psi-mi:“MI:0407”(direct interaction)	0.590
KISS1R	ERLIN1	psi-mi:“MI:0915”(physical association)	0.400
KISS1R	GNAQ	psi-mi:“MI:0915”(physical association)	0.400
KISS1R	GNA15	psi-mi:“MI:0915”(physical association)	0.400
KISS1R	RAMP1	psi-mi:“MI:0915”(physical association)	0.400
RAMP2	KISS1R	psi-mi:“MI:0915”(physical association)	0.400
KISS1R	RAMP3	psi-mi:“MI:0915”(physical association)	0.400
RAMP3	KISS1R	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (5): KISS1R (Synthetic Growth Defect), PPP2CA (Two-hybrid), PPP2CA (Reconstituted Complex), PPP2R4 (Reconstituted Complex), KISS1 (Protein-peptide)

ESM2 similar proteins: A0A6I8PUB9, O00155, O00270, O08726, O14842, O43603, O60755, O88626, O88634, O88853, O88854, P0C5I1, P13945, P46092, P50406, Q15722, Q28524, Q3T181, Q3ZC80, Q5IS65, Q60483, Q6XKD3, Q76JU8, Q76JU9, Q76JV1, Q80UC6, Q862A8, Q862A9, Q8HYC3, Q8K3T4, Q8MJV2, Q8MJV3, Q8TDU6, Q8TDU9, Q920E0, Q924U0, Q95252, Q969F8, Q96G91, Q96P69

Diamond homologs: A1ZAX0, B2ZI34, E7F7V7, F1MV99, F1R332, O08726, O08786, O43603, O54798, O54799, O62709, O88626, O88854, O97666, O97772, O97967, P05363, P08911, P08912, P21451, P21729, P22270, P24053, P24530, P25101, P26684, P28088, P28336, P28646, P30550, P30551, P30552, P30553, P30796, P30872, P30873, P30937, P30974, P31391, P32238

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
KISS1	up-regulates	KISS1R	binding
KISS1R	“up-regulates activity”	GNAQ	binding
KISS1R	“up-regulates activity”	GNA14	binding
Kisspeptin-10	“up-regulates activity”	KISS1R	“chemical activation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	5
Uncertain significance	113
Likely benign	40
Benign	17

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1176066	NM_032551.5(KISS1R):c.735del (p.Gln246fs)	Pathogenic
1434808	NM_032551.5(KISS1R):c.621del (p.Leu206_Tyr207insTer)	Pathogenic
2637681	NC_000019.9:g.(?917332)(921006_?)del	Pathogenic
2875533	NM_032551.5(KISS1R):c.725del (p.Asp242fs)	Pathogenic
4699538	NM_032551.5(KISS1R):c.324G>A (p.Trp108Ter)	Pathogenic
4720138	NM_032551.5(KISS1R):c.520_738+70del	Pathogenic
5755	NM_032551.5(KISS1R):c.443T>C (p.Leu148Ser)	Pathogenic
5756	NM_032551.5(KISS1R):c.991C>T (p.Arg331Ter)	Pathogenic
5758	NM_032551.5(KISS1R):c.739-6_887del	Pathogenic
1324626	NM_032551.5(KISS1R):c.152del (p.Ala51fs)	Likely pathogenic
1335315	NM_032551.5(KISS1R):c.506-1G>A	Likely pathogenic
1996429	NM_032551.5(KISS1R):c.369+1G>T	Likely pathogenic
4778106	NM_032551.5(KISS1R):c.370-2A>T	Likely pathogenic
978562	NM_032551.5(KISS1R):c.710G>C (p.Arg237Pro)	Likely pathogenic

SpliceAI

701 predictions. Top by Δscore:

Variant	Effect	Δscore
19:917747:G:GG	donor_gain	1.0000
19:917747:GT:G	donor_loss	1.0000
19:917748:T:A	donor_loss	1.0000
19:918665:GCAG:G	donor_gain	1.0000
19:918666:CAG:C	donor_loss	1.0000
19:918667:AGGTG:A	donor_loss	1.0000
19:918668:GG:G	donor_loss	1.0000
19:918669:G:GA	donor_loss	1.0000
19:920104:CAGGT:C	donor_loss	1.0000
19:917742:CATCG:C	donor_gain	0.9900
19:917743:ATCG:A	donor_gain	0.9900
19:917744:TCG:T	donor_gain	0.9900
19:917749:GAGT:G	donor_loss	0.9900
19:918542:A:AG	acceptor_gain	0.9900
19:918543:G:GG	acceptor_gain	0.9900
19:918543:GCC:G	acceptor_gain	0.9900
19:918543:GCCA:G	acceptor_gain	0.9900
19:918595:C:CA	acceptor_gain	0.9900
19:919622:GTAG:G	donor_gain	0.9900
19:919625:GGT:G	donor_loss	0.9900
19:919626:G:A	donor_loss	0.9900
19:919868:GCACA:G	acceptor_loss	0.9900
19:919869:CACAG:C	acceptor_loss	0.9900
19:919870:ACAGG:A	acceptor_loss	0.9900
19:919871:CAGG:C	acceptor_loss	0.9900
19:919872:AGGCT:A	acceptor_loss	0.9900
19:920103:GCAG:G	donor_gain	0.9900
19:920107:G:GG	donor_gain	0.9900
19:920288:AGG:A	acceptor_gain	0.9900
19:920289:GGG:G	acceptor_gain	0.9900

AlphaMissense

2495 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:918548:C:A	N83K	0.997
19:918548:C:G	N83K	0.997
19:919529:A:C	S137R	0.997
19:919531:T:A	S137R	0.997
19:919531:T:G	S137R	0.997
19:919607:A:C	S163R	0.997
19:919609:C:A	S163R	0.997
19:919609:C:G	S163R	0.997
19:920365:T:C	F272L	0.996
19:920367:C:A	F272L	0.996
19:920367:C:G	F272L	0.996
19:917682:C:A	N60K	0.995
19:917682:C:G	N60K	0.995
19:918562:A:T	D88V	0.995
19:918561:G:T	D88Y	0.994
19:918642:T:A	C115S	0.994
19:918643:G:C	C115S	0.994
19:917744:T:A	I81N	0.993
19:918561:G:C	D88H	0.993
19:920380:G:C	G277R	0.993
19:918562:A:C	D88A	0.992
19:918563:C:A	D88E	0.992
19:918563:C:G	D88E	0.992
19:920015:C:G	P216R	0.992
19:917668:G:C	G56R	0.991
19:919524:C:A	A135D	0.991
19:919619:T:A	W167R	0.991
19:919619:T:C	W167R	0.991
19:920365:T:A	F272I	0.991
19:920510:C:A	P320Q	0.991

dbSNP variants (sampled 300 via entrez): RS1000594603 (19:921162 T>C), RS1000689257 (19:921379 T>C), RS1000868767 (19:917396 C>A,T), RS1001156812 (19:916209 C>T), RS1001581233 (19:917463 A>C), RS1001731058 (19:918334 T>A), RS1001971250 (19:916704 A>C,G), RS1002117177 (19:917384 G>C), RS1002320233 (19:916483 G>A), RS1002586037 (19:918468 G>A,T), RS1002693684 (19:918673 G>A,T), RS1003035519 (19:921433 T>C), RS1004120511 (19:915448 C>A), RS1004303223 (19:920159 T>C), RS1004622780 (19:918497 C>A,T)

Disease associations

OMIM: gene MIM:604161 | disease phenotypes: MIM:614837, MIM:176400, MIM:147950

GenCC curated gene-disease

Disease	Classification	Inheritance
hypogonadotropic hypogonadism 8 with or without anosmia	Definitive	Autosomal recessive
hypogonadotropic hypogonadism	Supportive	Autosomal dominant
central precocious puberty 1	Limited	Autosomal dominant

Mondo (5): hypogonadotropic hypogonadism 8 with or without anosmia (MONDO:0013910), urogenital tract malformation (MONDO:0019356), central precocious puberty 1 (MONDO:0008302), hypogonadotropic hypogonadism (MONDO:0018555), pituitary stalk interruption syndrome (MONDO:0019828)

Orphanet (5): Kallmann syndrome (Orphanet:478), Urogenital tract malformation (Orphanet:83001), NON RARE IN EUROPE: Central precocious puberty (Orphanet:759), Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432), Pituitary stalk interruption syndrome (Orphanet:95496)

HPO phenotypes

53 total (30 of 53 shown, HPO-id order):

HPO	Term
HP:0000002	Abnormality of body height
HP:0000006	Autosomal dominant inheritance
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:0000458	Anosmia
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000771	Gynecomastia
HP:0000786	Primary amenorrhea
HP:0000789	Infertility
HP:0000802	Impotence
HP:0000821	Hypothyroidism
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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005312_41	Menopause (age at onset)	2.000000e-10
GCST010572_12	Sweet taste preference	8.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0010156	sweet liking measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5413 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 105,477 (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
CHEMBL376756	KISSPEPTIN-10	3	982
CHEMBL221753	BENZETHONIUM CHLORIDE	2	104,434
CHEMBL3924151	TAK-448	2	61

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Kisspeptin receptor

Most potent curated ligand interactions (14 total), top 14:

Ligand	Action	Affinity	Parameter
kisspeptin-10	Full agonist	10.4	pKi
[125I]Tyr45-kisspeptin-15	Full agonist	10.0	pKd
[125I]kisspeptin-54 (human)	Full agonist	10.0	pKd
kisspeptin-15	Full agonist	10.0	pKi
[125I]kisspeptin-13 (human)	Full agonist	9.7	pKd
kisspeptin-54	Full agonist	9.5	pKi
4-fluorobenzoyl-FGLRW-NH2	Full agonist	9.2	pEC50
kisspeptin-14	Full agonist	8.8	pKi
kisspeptin-28	Full agonist	8.8	pEC50
[125I]kisspeptin-10 (human)	Full agonist	8.7	pKd
kisspeptin-13	Full agonist	8.4	pKi
[dY]1KP-10	Full agonist	8.4	pIC50
TAK-448	Agonist	8.28	pEC50
kisspeptin-9	Full agonist	7.0	pKi

Binding affinities (BindingDB)

22 measured of 22 human assays (22 total across all organisms); most potent 22 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(E,3R)-6-(methylamino)-3-(2-methylpropyl)hex-4-en-2-one	IC50	0.12 nM	US-8592379: Metastin derivative and use thereof
(2R,3E)-N-[(1S)-4-carbamimidamido-1-{[(1S)-1-carbamoyl-2-(1H-indol-3-yl)ethyl]carbamoyl}butyl]-5-[(2S)-2-[(4-fluorophenyl)formamido]-3-phenylpropanamido]-2-(2-methylpropyl)pent-3-enamide	IC50	0.12 nM
(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-amino-3-(4-hydroxyphenyl)propanamido]butanediamido]-3-(1H-indol-3-yl)propanamido]-N-[(1S)-1-{[(1S)-1-[({[(1S)-1-{[(1S)-4-carbamimidamido-1-{[(1S)-1-carbamoyl-2-phenylethyl]carbamoyl}butyl]carbamoyl}-3-methylbutyl]carbamoyl}methyl)carbamoyl]-2-phenylethyl]carbamoyl}-2-hydroxyethyl]butanediamide	IC50	0.12 nM
(5S)-5-hydroxy-6-(methylamino)-3-(2-methylpropyl)hexan-2-one	IC50	0.24 nM	US-8592379: Metastin derivative and use thereof
(2R,4S)-N-[(1S)-4-carbamimidamido-1-{[(1S)-1-carbamoyl-2-(1H-indol-3-yl)ethyl]carbamoyl}butyl]-5-[(2S)-2-[(4-fluorophenyl)formamido]-3-phenylpropanamido]-4-hydroxy-2-(2-methylpropyl)pentanamide	IC50	0.24 nM
2-(methylamino)-N-[(3S)-5-methyl-2-oxohexan-3-yl]acetamide	IC50	0.71 nM	US-8592379: Metastin derivative and use thereof
N-[(4-fluorophenyl)carbonyl]-L-phenylalanylglycyl-L-leucyl-L-arginyl-L-tryptophanamide	IC50	0.71 nM
(3S)-5-methyl-3-[3-(methylamino)propyl]hexan-2-one	IC50	1.2 nM	US-8592379: Metastin derivative and use thereof
(2S)-N-[(1S)-4-carbamimidamido-1-{[(1S)-1-carbamoyl-2-(1H-indol-3-yl)ethyl]carbamoyl}butyl]-2-{3-[(2S)-2-[(4-fluorophenyl)formamido]-3-phenylpropanamido]propyl}-4-methylpentanamide	IC50	1.2 nM
(E)-6-(methylamino)-3-(2-methylpropyl)hex-3-en-2-one	IC50	4.6 nM	US-8592379: Metastin derivative and use thereof
(2E)-N-[(1S)-4-carbamimidamido-1-{[(1S)-1-carbamoyl-2-(1H-indol-3-yl)ethyl]carbamoyl}butyl]-5-[(2S)-2-[(4-fluorophenyl)formamido]-3-phenylpropanamido]-2-(2-methylpropyl)pent-2-enamide	IC50	4.6 nM
(2R,4R)-N-[(1S)-4-carbamimidamido-1-{[(1S)-1-carbamoyl-2-(1H-indol-3-yl)ethyl]carbamoyl}butyl]-5-[(2S)-2-[(4-fluorophenyl)formamido]-3-phenylpropanamido]-4-hydroxy-2-(2-methylpropyl)pentanamide	IC50	5.7 nM
(E,5R)-5-hydroxy-6-(methylamino)-3-(2-methylpropyl)hex-3-en-2-one	IC50	32 nM	US-8592379: Metastin derivative and use thereof
(2E,4R)-N-[(1S)-4-carbamimidamido-1-{[(1S)-1-carbamoyl-2-(1H-indol-3-yl)ethyl]carbamoyl}butyl]-5-[(2S)-2-[(4-fluorophenyl)formamido]-3-phenylpropanamido]-4-hydroxy-2-(2-methylpropyl)pent-2-enamide	IC50	32 nM
(2S,4S)-N-[(1S)-4-carbamimidamido-1-{[(1S)-1-carbamoyl-2-(1H-indol-3-yl)ethyl]carbamoyl}butyl]-5-[(2S)-2-[(4-fluorophenyl)formamido]-3-phenylpropanamido]-4-hydroxy-2-(2-methylpropyl)pentanamide	IC50	32 nM
(2R)-N-[(1S)-4-carbamimidamido-1-{[(1S)-1-carbamoyl-2-(1H-indol-3-yl)ethyl]carbamoyl}butyl]-2-{2-[(2S)-2-[(4-fluorophenyl)formamido]-3-phenylpropanamido]acetamido}-4-methylpentanamide	IC50	240 nM
(5R)-5-hydroxy-6-(methylamino)-3-(2-methylpropyl)hexan-2-one	IC50	380 nM	US-8592379: Metastin derivative and use thereof
(2S,4R)-N-[(1S)-4-carbamimidamido-1-{[(1S)-1-carbamoyl-2-(1H-indol-3-yl)ethyl]carbamoyl}butyl]-5-[(2S)-2-[(4-fluorophenyl)formamido]-3-phenylpropanamido]-4-hydroxy-2-(2-methylpropyl)pentanamide	IC50	380 nM
(2E,4S)-N-[(1S)-4-carbamimidamido-1-{[(1S)-1-carbamoyl-2-(1H-indol-3-yl)ethyl]carbamoyl}butyl]-5-[(2S)-2-[(4-fluorophenyl)formamido]-3-phenylpropanamido]-4-hydroxy-2-(2-methylpropyl)pent-2-enamide	IC50	460 nM
(E,5S)-5-hydroxy-6-(methylamino)-3-(2-methylpropyl)hex-3-en-2-one	IC50	460 nM	US-8592379: Metastin derivative and use thereof
Adamantane-1-carboxylic acid [(S)-1-((S)-1-carbamoyl-2-phenyl-ethylcarbamoyl)-4-guanidino-butyl]-amide	IC50	830 nM
2-(methylamino)-N-[(3R)-5-methyl-2-oxohexan-3-yl]acetamide	IC50	3500 nM	US-8592379: Metastin derivative and use thereof

ChEMBL bioactivities

431 potent at pChembl≥5 of 434 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.66	EC50	0.022	nM	CHEMBL4539775
10.64	EC50	0.023	nM	CHEMBL2152055
10.62	EC50	0.024	nM	CHEMBL4533110
10.59	Ki	0.026	nM	CHEMBL3315315
10.57	Ki	0.027	nM	CHEMBL3314227
10.55	Ki	0.028	nM	CHEMBL3314217
10.55	EC50	0.028	nM	CHEMBL4462883
10.54	EC50	0.029	nM	CHEMBL2152060
10.49	Ki	0.032	nM	CHEMBL3086282
10.48	Ki	0.033	nM	CHEMBL3087927
10.47	Ki	0.034	nM	CHEMBL3314226
10.46	Ki	0.035	nM	KISSPEPTIN-10
10.44	Ki	0.036	nM	CHEMBL3314216
10.44	Ki	0.036	nM	CHEMBL3314224
10.43	Ki	0.037	nM	CHEMBL3314215
10.43	EC50	0.037	nM	CHEMBL4528114
10.42	Ki	0.038	nM	CHEMBL3314229
10.41	EC50	0.039	nM	CHEMBL2152056
10.41	Ki	0.039	nM	KISSPEPTIN-10
10.41	Ki	0.039	nM	CHEMBL3314223
10.39	EC50	0.041	nM	CHEMBL2151643
10.36	Ki	0.044	nM	CHEMBL3085809
10.35	Ki	0.045	nM	CHEMBL3087793
10.34	Ki	0.046	nM	CHEMBL2151642
10.31	EC50	0.049	nM	KISSPEPTIN-10
10.30	EC50	0.05	nM	CHEMBL2151646
10.29	Ki	0.051	nM	CHEMBL2151646
10.28	Ki	0.052	nM	CHEMBL3085804
10.28	Ki	0.052	nM	CHEMBL3314209
10.26	Ki	0.055	nM	CHEMBL3087929
10.24	EC50	0.058	nM	CHEMBL4451244
10.24	EC50	0.057	nM	CHEMBL3085809
10.21	Ki	0.062	nM	CHEMBL3087925
10.21	Ki	0.062	nM	KISSPEPTIN-10
10.19	EC50	0.065	nM	CHEMBL2151642
10.19	EC50	0.065	nM	KISSPEPTIN-10
10.19	EC50	0.065	nM	CHEMBL2152058
10.19	Ki	0.065	nM	CHEMBL3086283
10.17	EC50	0.068	nM	CHEMBL4541289
10.15	EC50	0.07	nM	CHEMBL3422407
10.15	EC50	0.07	nM	CHEMBL3422408
10.15	IC50	0.07	nM	KISSPEPTIN-10
10.14	EC50	0.072	nM	CHEMBL2151654
10.14	EC50	0.073	nM	CHEMBL3949159
10.13	Ki	0.074	nM	CHEMBL3314207
10.11	Ki	0.078	nM	CHEMBL2151654
10.10	EC50	0.08	nM	CHEMBL3422414
10.09	IC50	0.082	nM	KISSPEPTIN-10
10.07	Ki	0.086	nM	CHEMBL3086281
10.07	Ki	0.086	nM	CHEMBL3087926

PubChem BioAssay actives

429 with measured affinity, of 625 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
(2S)-2-[[(2R)-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2S)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]butanediamide	1179681: Displacement of radioligand from human KISS1R transfected in CHO cells	ki	<0.0001	uM
(2S)-2-[[(2R)-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2S,3R)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]butanediamide	1179681: Displacement of radioligand from human KISS1R transfected in CHO cells	ki	<0.0001	uM
(2S)-2-[[(2R)-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2S)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]butanediamide	1179681: Displacement of radioligand from human KISS1R transfected in CHO cells	ki	<0.0001	uM
(2S)-N-[(2S,3R)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]-2-[[(2R)-2-[3-(4-hydroxyphenyl)propanoylamino]-3-(1H-indol-3-yl)propanoyl]amino]butanediamide	1179681: Displacement of radioligand from human KISS1R transfected in CHO cells	ki	<0.0001	uM
(2S)-N-[(2S,3R)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]-2-[[(2R)-2-[[(2R)-2-(cyclopropanecarbonylamino)-3-(4-hydroxyphenyl)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]butanediamide	1179681: Displacement of radioligand from human KISS1R transfected in CHO cells	ki	<0.0001	uM
(2S)-N-[(2S,3R)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]-2-[[(2R)-2-[[(2R)-2-benzamido-3-(4-hydroxyphenyl)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]butanediamide	1179681: Displacement of radioligand from human KISS1R transfected in CHO cells	ki	<0.0001	uM
(2S)-2-[[(2R)-2-[[(2R)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2S,3R)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]butanediamide	1179681: Displacement of radioligand from human KISS1R transfected in CHO cells	ki	<0.0001	uM
(2S)-N-[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]butanediamide	1179681: Displacement of radioligand from human KISS1R transfected in CHO cells	ki	<0.0001	uM
(2S)-2-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-N-[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]butanediamide	1203589: Agonist activity at human wild-type KISS1R expressed in HEK293 cells assessed as induction of intracellular Ca2+ mobilization after 30 mins by Fluo4 NW Ca2+ assay	ec50	<0.0001	uM
N-[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]cyclopropanecarboxamide	1535393: Agonist activity at human KISS1R expressed in CHO cells assessed as increase in calcium mobilization measured at 2 secs interval for 2 mins by fluo-4 NW dye based FLIPR assay	ec50	<0.0001	uM
N-[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]pyridine-2-carboxamide	1535393: Agonist activity at human KISS1R expressed in CHO cells assessed as increase in calcium mobilization measured at 2 secs interval for 2 mins by fluo-4 NW dye based FLIPR assay	ec50	<0.0001	uM
N-[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]benzamide	1535393: Agonist activity at human KISS1R expressed in CHO cells assessed as increase in calcium mobilization measured at 2 secs interval for 2 mins by fluo-4 NW dye based FLIPR assay	ec50	<0.0001	uM
(2S)-N-[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]-2-[[[(2S)-2-[3-(1H-indol-3-yl)propanoylamino]-3-phenylpropanoyl]amino]carbamoylamino]-4-methylpentanamide	1535393: Agonist activity at human KISS1R expressed in CHO cells assessed as increase in calcium mobilization measured at 2 secs interval for 2 mins by fluo-4 NW dye based FLIPR assay	ec50	<0.0001	uM
(2S)-N-[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]butanediamide	1053424: Binding affinity to human KISS1R expressed in CHO cell membranes	ki	<0.0001	uM
(2S)-2-[[(2R)-2-[[(2R)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2S,3R)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]butanediamide	1179681: Displacement of radioligand from human KISS1R transfected in CHO cells	ki	<0.0001	uM
(2S)-N-[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]butanediamide	691440: Agonist activity at human OT7T175 assessed as increase in intracellular calcium level by FLIPR assay	ec50	<0.0001	uM
(2S)-N-[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-3-phenyl-1-sulfanylidenepropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]butanediamide	690936: Agonist activity at human KISS1R assessed as induction of intracellular calcium mobilization by fluorometric analysis	ec50	<0.0001	uM
(2S)-N-[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-6-(diaminomethylideneamino)-1-oxohexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]butanediamide	691440: Agonist activity at human OT7T175 assessed as increase in intracellular calcium level by FLIPR assay	ec50	<0.0001	uM
(2S)-N-[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]butanediamide	1053424: Binding affinity to human KISS1R expressed in CHO cell membranes	ki	<0.0001	uM
(2S)-N-[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-5-[[amino(dimethylamino)methylidene]amino]-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]butanediamide	691440: Agonist activity at human OT7T175 assessed as increase in intracellular calcium level by FLIPR assay	ec50	<0.0001	uM
(2S)-N-[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]butanediamide	1053424: Binding affinity to human KISS1R expressed in CHO cell membranes	ki	<0.0001	uM
(2S)-2-[[(2S)-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2S)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]butanediamide	1053424: Binding affinity to human KISS1R expressed in CHO cell membranes	ki	<0.0001	uM
(2S)-2-[[(2S)-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-naphthalen-2-ylpropanoyl]amino]-N-[(2S)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]butanediamide	1053424: Binding affinity to human KISS1R expressed in CHO cell membranes	ki	<0.0001	uM
(2S)-2-[[(2S)-2-[[(2R)-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2S)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-[(N-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]butanediamide	1053424: Binding affinity to human KISS1R expressed in CHO cell membranes	ki	<0.0001	uM
(2S)-2-[[(2R)-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-pyridin-4-ylpropanoyl]amino]-N-[(2S)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]butanediamide	1053424: Binding affinity to human KISS1R expressed in CHO cell membranes	ki	0.0001	uM
(2S)-2-[[(2R)-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-pyridin-4-ylpropanoyl]amino]-N-[(2S)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]butanediamide	1179681: Displacement of radioligand from human KISS1R transfected in CHO cells	ki	0.0001	uM
(2S)-2-[[(2R)-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-pyridin-4-ylpropanoyl]amino]-N-[(2S,3R)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]butanediamide	1179681: Displacement of radioligand from human KISS1R transfected in CHO cells	ki	0.0001	uM
(2S)-2-[[(2R)-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-pyridin-4-ylpropanoyl]amino]-N-[(2S)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]butanediamide	1179681: Displacement of radioligand from human KISS1R transfected in CHO cells	ki	0.0001	uM
(2S)-1-[(2S)-4-amino-2-[[(2R)-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-pyridin-4-ylpropanoyl]amino]-4-oxobutanoyl]-N-[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]pyrrolidine-2-carboxamide	1179681: Displacement of radioligand from human KISS1R transfected in CHO cells	ki	0.0001	uM
(2S)-2-[[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]butanoyl]amino]-3-hydroxypropanoyl]amino]-3-phenylpropanoyl]amino]carbamoylamino]-N-[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]-4-methylpentanamide	1179681: Displacement of radioligand from human KISS1R transfected in CHO cells	ki	0.0001	uM
(2S)-2-[[(2R)-2-[[(2R)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-3-pyridin-4-ylpropanoyl]amino]-N-[(2S,3R)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]butanediamide	1179681: Displacement of radioligand from human KISS1R transfected in CHO cells	ki	0.0001	uM
(2S)-2-[[(2S)-2-[[(2S)-6-acetamido-2-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]hexanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]butanediamide	1203589: Agonist activity at human wild-type KISS1R expressed in HEK293 cells assessed as induction of intracellular Ca2+ mobilization after 30 mins by Fluo4 NW Ca2+ assay	ec50	0.0001	uM
(2S)-2-[[(2S)-6-acetamido-2-[[(2S)-2-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-4-amino-4-oxobutanoyl]amino]hexanoyl]amino]-N-[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]butanediamide	1203589: Agonist activity at human wild-type KISS1R expressed in HEK293 cells assessed as induction of intracellular Ca2+ mobilization after 30 mins by Fluo4 NW Ca2+ assay	ec50	0.0001	uM
(2S)-N-[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]-4-methyl-2-[[[(2S)-2-(2-methylpropanoylamino)-3-phenylpropanoyl]amino]carbamoylamino]pentanamide	1535393: Agonist activity at human KISS1R expressed in CHO cells assessed as increase in calcium mobilization measured at 2 secs interval for 2 mins by fluo-4 NW dye based FLIPR assay	ec50	0.0001	uM
(2S)-N-[(2S)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]-2-[3-(1H-indol-3-yl)propanoylamino]butanediamide	1535393: Agonist activity at human KISS1R expressed in CHO cells assessed as increase in calcium mobilization measured at 2 secs interval for 2 mins by fluo-4 NW dye based FLIPR assay	ec50	0.0001	uM
N-[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]furan-3-carboxamide	1535393: Agonist activity at human KISS1R expressed in CHO cells assessed as increase in calcium mobilization measured at 2 secs interval for 2 mins by fluo-4 NW dye based FLIPR assay	ec50	0.0001	uM
N-[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]pyridine-4-carboxamide	1535393: Agonist activity at human KISS1R expressed in CHO cells assessed as increase in calcium mobilization measured at 2 secs interval for 2 mins by fluo-4 NW dye based FLIPR assay	ec50	0.0001	uM
(2S)-N-[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]-4-methyl-2-[[[(2S)-3-phenyl-2-(propanoylamino)propanoyl]amino]carbamoylamino]pentanamide	1535393: Agonist activity at human KISS1R expressed in CHO cells assessed as increase in calcium mobilization measured at 2 secs interval for 2 mins by fluo-4 NW dye based FLIPR assay	ec50	0.0001	uM
N-[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]cyclohexanecarboxamide	1535393: Agonist activity at human KISS1R expressed in CHO cells assessed as increase in calcium mobilization measured at 2 secs interval for 2 mins by fluo-4 NW dye based FLIPR assay	ec50	0.0001	uM
(2S)-2-[[(2S)-2-[[(2R)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2S,3R)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-3-(3-fluorophenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]butanediamide	1321525: Agonist activity at human KISS1R expressed in CHO/dhfr cells assessed as increase in intracellular Ca2+ levels measured for 180 secs by Fluo 3-AM dye based FLIPR assay	ec50	0.0001	uM
N-[(2S)-1-[[(E,4R)-4-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]carbamoyl]-6-methylhept-2-enyl]amino]-1-oxo-3-phenylpropan-2-yl]-4-fluorobenzamide	1798671: Receptor Binding Assay from Article 10.1021/jm800930w: “Development of Novel G-Protein-Coupled Receptor 54 Agonists with Resistance to Degradation by Matrix Metalloproteinase.”	ic50	0.0001	uM
(2S)-N-[(2R)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-1-oxo-3-pyridin-4-ylpropan-2-yl]-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]butanediamide	1053424: Binding affinity to human KISS1R expressed in CHO cell membranes	ki	0.0001	uM
(2S)-N-[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-4-(diaminomethylideneamino)-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]butanediamide	691440: Agonist activity at human OT7T175 assessed as increase in intracellular calcium level by FLIPR assay	ec50	0.0001	uM
(2S)-N-[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-1-oxo-3-pyridin-4-ylpropan-2-yl]-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]butanediamide	1053424: Binding affinity to human KISS1R expressed in CHO cell membranes	ki	0.0001	uM
(2S)-N-[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-6-[(N’-methylcarbamimidoyl)amino]-1-oxohexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]butanediamide	691440: Agonist activity at human OT7T175 assessed as increase in intracellular calcium level by FLIPR assay	ec50	0.0001	uM
(2S)-N-[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-5-[[amino(ethylamino)methylidene]amino]-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]butanediamide	691440: Agonist activity at human OT7T175 assessed as increase in intracellular calcium level by FLIPR assay	ec50	0.0001	uM
(2S)-N-[(2S,3S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]butanediamide	690936: Agonist activity at human KISS1R assessed as induction of intracellular calcium mobilization by fluorometric analysis	ec50	0.0001	uM
(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-4-oxobutanoyl]amino]-3-cyclohexylpropanoyl]amino]-N-[(2S)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]butanediamide	690936: Agonist activity at human KISS1R assessed as induction of intracellular calcium mobilization by fluorometric analysis	ec50	0.0001	uM
(2S)-N-[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]butanediamide	690936: Agonist activity at human KISS1R assessed as induction of intracellular calcium mobilization by fluorometric analysis	ec50	0.0001	uM
(2S)-N-[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-1-[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-[(N’-methylcarbamimidoyl)amino]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]hydrazinyl]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]butanediamide	1053424: Binding affinity to human KISS1R expressed in CHO cell membranes	ki	0.0001	uM

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	9
entinostat	increases expression, affects cotreatment	2
Tetrachlorodibenzodioxin	decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
sodium arsenate	increases abundance, increases expression	1
trichostatin A	increases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
cobaltous chloride	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
NSC 689534	increases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	decreases expression	1
Sevoflurane	increases expression, increases reaction, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	increases expression	1
Panobinostat	affects cotreatment, increases expression	1
Arsenic	increases abundance, increases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases expression	1
Hydrogen Peroxide	affects expression	1
Lipopolysaccharides	increases expression, increases reaction	1
Plant Extracts	affects cotreatment, decreases expression	1
Thimerosal	decreases expression	1
Tretinoin	increases expression	1
Triclosan	increases expression	1
Okadaic Acid	increases expression	1
Acrylamide	decreases expression	1

ChEMBL screening assays

48 unique, capped per target: 24 binding, 24 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1008755	Binding	Displacement of [125I]kisspeptin-15 from human GPR54 expressed in CHO cell membrane	Development of novel G-protein-coupled receptor 54 agonists with resistance to degradation by matrix metalloproteinase. — J Med Chem
CHEMBL1008757	Functional	Agonist activity at human GPR54 expressed in CHO cells assessed as effect on kisspeptin-10-induced response by FLIPR assay	Development of novel G-protein-coupled receptor 54 agonists with resistance to degradation by matrix metalloproteinase. — J Med Chem

Cellosaurus cell lines

4 cell lines: 3 spontaneously immortalized cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_H452	CHO-K1/KiSS1	Spontaneously immortalized cell line	Female
CVCL_KB37	GeneBLAzer GPR54-NFAT-bla CHO-K1	Spontaneously immortalized cell line	Female
CVCL_KW20	PathHunter C2C12 KISS1R beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_LA65	PathHunter U2OS KISS1R beta-arrestin	Cancer cell line	Female

Clinical trials (associated diseases)

80 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
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
NCT06760546	PHASE3	RECRUITING	A Trial of Setmelanotide in Patients With Congenital Hypothalamic Obesity (Sub-study of NCT05774756)
NCT00193661	PHASE2	COMPLETED	Observation Study of T-Gel (1%) in Treatment of Adolescent Boys With Hypogonadism
NCT00383656	PHASE2	UNKNOWN	Pulsatile GnRH in Anovulatory Infertility
NCT00697814	PHASE2	COMPLETED	Clomiphene in Males With Prolactinomas and Persistent Hypogonadism
NCT00706719	PHASE2	COMPLETED	To Evaluate Sperm Parameters in Men With Secondary Hypogonadism Previously Treated With Topical Testosterone
NCT00911586	PHASE2	COMPLETED	Pharmacokinetic Study to Determine Time to Steady-state
NCT01155518	PHASE2	TERMINATED	Hypogonadism in Young Men With Type 2 Diabetes
NCT01191320	PHASE2	COMPLETED	Study to Evaluate the Efficacy of Androxal in Controlling Blood Glucose in Men With Type-2 Diabetes Mellitus
NCT01270841	PHASE2	COMPLETED	Normalization of Morning Testosterone Levels in Men With Secondary Hypogonadism
NCT01386606	PHASE2	COMPLETED	The Effect on Androxal Versus Androgel on Morning Testosterone in Men With Secondary Hypogonadism (Low Testosterone)
NCT01894308	PHASE2	NOT_YET_RECRUITING	A Dose Ranging Study to Examine TDS-Testosterone 5%
NCT02369796	PHASE2	TERMINATED	A Phase 2a Pharmacodynamic Study of TAK-448 in Participants With Hypogonadotropic Hypogonadism
NCT02443090	PHASE2	UNKNOWN	Safety and Efficacy Study of Oral Fispemifene for the Treatment of Sexual Dysfunction in Hypogonadal Men
NCT02651688	PHASE2	COMPLETED	A Multi-Center Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Body Composition and Metabolic Parameters With Diet and Exercise in Conjunction With Treatment With 12.5 mg or 25 mg Enclomiphene
NCT02730169	PHASE2	COMPLETED	Safety and Efficacy of BGS649 in Male Obese Subjects With Hypogonadotropic Hypogonadism
NCT02733133	PHASE2	NOT_YET_RECRUITING	Product Transference Study of Testagen™ TDS®-Testosterone
NCT02908074	PHASE2	COMPLETED	A 6 Month Safety Extension Study of MBGS205
NCT03245827	PHASE2	TERMINATED	Hypogonadotropic Hypogonadism in Obese Young Males