NPFFR2

Summary

NPFFR2 (neuropeptide FF receptor 2, HGNC:4525) is a protein-coding gene on chromosome 4q13.3, encoding Neuropeptide FF receptor 2 (Q9Y5X5). Receptor for NPAF (A-18-F-amide) and NPFF (F-8-F-amide) neuropeptides, also known as morphine-modulating peptides.

This gene encodes a member of a subfamily of G-protein-coupled neuropeptide receptors. This protein is activated by the neuropeptides A-18-amide (NPAF) and F-8-amide (NPFF) and may function in pain modulation and regulation of the opioid system. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 10886 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 61 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004885

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4525
Approved symbol	NPFFR2
Name	neuropeptide FF receptor 2
Location	4q13.3
Locus type	gene with protein product
Status	Approved
Aliases	NPFF2, NPGPR
Ensembl gene	ENSG00000056291
Ensembl biotype	protein_coding
OMIM	607449
Entrez	10886

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000308744, ENST00000344413, ENST00000358749, ENST00000395999, ENST00000506359, ENST00000940437

RefSeq mRNA: 3 — MANE Select: NM_004885 NM_001144756, NM_004885, NM_053036

CCDS: CCDS3552, CCDS47072

Canonical transcript exons

ENST00000308744 — 4 exons

Exon	Start	End
ENSE00001724493	72032000	72032200
ENSE00002045395	72146978	72148305
ENSE00003532862	72138040	72138139
ENSE00003652596	72128585	72128919

Expression profiles

Bgee: expression breadth ubiquitous, 105 present calls, max score 87.93.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4339 / max 72.5457, expressed in 176 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
48060	0.2101	111
48061	0.0673	29
48063	0.0629	28
48064	0.0530	24
48062	0.0178	4
48066	0.0144	4
48065	0.0085	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.93	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.93	gold quality
kidney epithelium	UBERON:0004819	76.93	gold quality
cardiac muscle of right atrium	UBERON:0003379	74.45	gold quality
left ventricle myocardium	UBERON:0006566	74.06	gold quality
placenta	UBERON:0001987	72.99	gold quality
epithelial cell of pancreas	CL:0000083	65.52	gold quality
myocardium	UBERON:0002349	60.93	gold quality
secondary oocyte	CL:0000655	58.44	gold quality
pancreatic ductal cell	CL:0002079	57.80	silver quality
islet of Langerhans	UBERON:0000006	57.20	gold quality
prefrontal cortex	UBERON:0000451	56.73	gold quality
amniotic fluid	UBERON:0000173	55.88	silver quality
endothelial cell	CL:0000115	55.75	gold quality
tibialis anterior	UBERON:0001385	55.60	silver quality
oocyte	CL:0000023	54.49	gold quality
deltoid	UBERON:0001476	54.44	gold quality
parietal pleura	UBERON:0002400	54.06	silver quality
upper arm skin	UBERON:0004263	53.52	gold quality
seminal vesicle	UBERON:0000998	52.57	silver quality
mucosa of stomach	UBERON:0001199	52.57	gold quality
quadriceps femoris	UBERON:0001377	51.14	gold quality
Brodmann (1909) area 9	UBERON:0013540	50.71	gold quality
vermiform appendix	UBERON:0001154	50.70	gold quality
calcaneal tendon	UBERON:0003701	50.42	gold quality
lower esophagus muscularis layer	UBERON:0035833	50.18	gold quality
lower esophagus	UBERON:0013473	50.17	gold quality
vastus lateralis	UBERON:0001379	49.91	gold quality
rectum	UBERON:0001052	49.78	gold quality
lymph node	UBERON:0000029	49.46	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-CURD-10	no	239.39
E-HCAD-30	no	121.41
E-ANND-3	no	3.40

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

32 targeting NPFFR2, 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-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-3616-5P	99.55	67.02	989
HSA-MIR-573	99.55	67.44	955
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-4721	99.26	66.05	818
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-449B-3P	99.20	67.24	1047
HSA-MIR-26B-3P	98.71	67.49	1102
HSA-MIR-1246	98.54	66.21	959
HSA-MIR-2117	98.48	67.97	1307
HSA-MIR-3158-3P	98.45	64.25	560
HSA-MIR-4684-5P	98.29	67.99	1650
HSA-MIR-3159	97.94	66.79	1098
HSA-MIR-450A-2-3P	97.91	67.56	1459
HSA-MIR-4445-5P	97.21	66.16	832
HSA-MIR-517-5P	97.13	68.43	781

Literature-anchored findings (GeneRIF, showing 15)

• Evidence does not support the hypothesis that NPGPR is involved in feeding regulation. (PMID:12609745)
• The BIBP3226 and PFR(Tic)amide, on Human neuropeptide FF receptor subtype 2 (hNPFF2) were investigated. (PMID:15127947)
• neuropeptide FF analogs show that NPFF2 receptors couple to the four subunits assayed. (PMID:15608144)
• expression of hNPFF2 receptor mRNA was up-regulated by neuropeptide FF (PMID:16336216)
• NPFF system may also have species-specific features since the NPFF2 receptor mRNA expression differs from that reported for rat (PMID:17157836)
• findings suggest that a common haplotype in the GPR74 gene protects against obesity, which, in part, is caused by a relief of inhibition of lipid mobilization from adipose tissue (PMID:17503329)
• we identified hFF2 positive neurons in the forebrain and medulla oblongata of individuals who died suddenly. (PMID:18565622)
• species-related differences in the binding properties of NPFF(2) receptors (PMID:19944730)
• Besides regulation of reproduction, kisspeptins have a potential to mediate physiological effects on autonomic regulation and nociception in humans via the NPFF2R pathways. (PMID:20600636)
• Four genetic loci were strongly and independently associated with obesity, NPY2R, NPFFR2, MC4R, and FTO. (PMID:21818152)
• These data show that NPFF-induced heterologous desensitization of MOP receptor signaling is mediated by GRK2 and could involve transphosphorylation within the heteromeric receptor complex. (PMID:22375000)
• The NPFF2 neuropeptide FF receptor phosphorylation sites have been mapped and their role identified in receptor regulation. (PMID:25326382)
• Effects of systematic N-terminus deletions and benzoylations of endogenous RF-amide peptides on NPFF1R, NPFF2R, GPR10, GPR54 and GPR103. (PMID:26211894)
• Genome-wide association analysis of psoriasis patients treated with anti-TNF drugs. (PMID:33058233)
• NPFFR2 gene compound heterozygous variants associated with preeclampsia identified by whole-exome sequencing. (PMID:36535464)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	NPFFR2	ENSDARG00000033635
danio_rerio	npffr2b	ENSDARG00000060702
mus_musculus	Npffr2	ENSMUSG00000035528
rattus_norvegicus	Npffr2	ENSRNOG00000003067
drosophila_melanogaster	SIFaR	FBGN0038880

Paralogs (16): GNRHR (ENSG00000109163), 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

Neuropeptide FF receptor 2 — Q9Y5X5 (reviewed: Q9Y5X5)

Alternative names: G-protein coupled receptor 74, G-protein coupled receptor HLWAR77, Neuropeptide G-protein coupled receptor

All UniProt accessions (3): A0A804CC06, A0PJM9, Q9Y5X5

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for NPAF (A-18-F-amide) and NPFF (F-8-F-amide) neuropeptides, also known as morphine-modulating peptides. Can also be activated by a variety of naturally occurring or synthetic FMRF-amide like ligands. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.

Subcellular location. Cell membrane.

Tissue specificity. Isoform 1 is abundant in placenta. Relatively highly expressed in thymus, testis, and small intestine. Expressed at low levels in several tissues including spleen, prostate, brain, heart, ovary, colon, kidney, lung, liver and pancreas and not expressed in skeletal muscle and leukocytes. Isoform 2 expression is highest in placenta (but at relatively low level compared to isoform 1). Very low level of expression in numerous tissues including adipose tissue and many brain regions. Isoform 3 is expressed in brain and heart and, at lower levels, in kidney, liver, lung and pancreas.

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

Isoforms (4)

UniProt ID	Names	Canonical?
Q9Y5X5-1	1, long form	yes
Q9Y5X5-2	2, short form
Q9Y5X5-3	3
Q9Y5X5-4	4

RefSeq proteins (3): NP_001138228, NP_004876, NP_444264 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR005395	NPFF_rcpt	Family
IPR005397	NPFF_rcpt_2	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (28 total): topological domain 8, transmembrane region 7, splice variant 5, glycosylation site 4, chain 1, region of interest 1, disulfide bond 1, sequence conflict 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9M1O	ELECTRON MICROSCOPY	2.49
9V1H	ELECTRON MICROSCOPY	2.85
9JG0	ELECTRON MICROSCOPY	2.91
9JFY	ELECTRON MICROSCOPY	3.21
9M54	ELECTRON MICROSCOPY	3.24

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5X5-F1	69.36	0.50

Antibody-complex structures (SAbDab): 4 — 9JFY, 9JG0, 9M1O, 9M54

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): 220–308

Glycosylation sites (4): 110, 122, 133, 300

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-389397	Orexin and neuropeptides FF and QRFP bind to their respective receptors
R-HSA-416476	G alpha (q) signalling events

MSigDB gene sets: 54 (showing top): chr4q13, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION, GOBP_RESPONSE_TO_HORMONE, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, GOMF_PEPTIDE_RECEPTOR_ACTIVITY, GOBP_DETECTION_OF_ABIOTIC_STIMULUS, GOBP_DETECTION_OF_STIMULUS, GOMF_G_PROTEIN_COUPLED_RECEPTOR_BINDING, BASAKI_YBX1_TARGETS_UP, GOMF_SIGNALING_RECEPTOR_BINDING, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, REACTOME_CLASS_A_1_RHODOPSIN_LIKE_RECEPTORS, REACTOME_G_ALPHA_Q_SIGNALLING_EVENTS

GO Biological Process (7): G protein-coupled receptor signaling pathway (GO:0007186), neuropeptide signaling pathway (GO:0007218), detection of abiotic stimulus (GO:0009582), cellular response to hormone stimulus (GO:0032870), regulation of MAPK cascade (GO:0043408), signal transduction (GO:0007165), regulation of adenylate cyclase activity (GO:0045761)

GO Molecular Function (4): G protein-coupled receptor activity (GO:0004930), neuropeptide receptor activity (GO:0008188), opioid receptor binding (GO:0031628), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), actin cytoskeleton (GO:0015629), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Peptide ligand-binding receptors	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor signaling pathway	2
G protein-coupled receptor activity	1
signal transduction	1
response to abiotic stimulus	1
detection of stimulus	1
response to hormone	1
cellular response to chemical stimulus	1
cellular response to endogenous stimulus	1
MAPK cascade	1
regulation of intracellular signal transduction	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
adenylate cyclase activity	1
regulation of catalytic activity	1
transmembrane signaling receptor activity	1
neuropeptide signaling pathway	1
G protein-coupled peptide receptor activity	1
neuropeptide binding	1
G protein-coupled receptor binding	1
binding	1
membrane	1
cell periphery	1
cytoskeleton	1
cellular anatomical structure	1

Protein interactions and networks

STRING

752 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NPFFR2	NPFF	O15130	998
NPFFR2	NPVF	Q9HCQ7	907
NPFFR2	QRFP	P83859	904
NPFFR2	GNA15	P30679	800
NPFFR2	PRLH	P81277	794
NPFFR2	GAL	P22466	694
NPFFR2	NPY	P01303	670
NPFFR2	KISS1	Q15726	592
NPFFR2	GNAO1	P09471	526
NPFFR2	GNRH1	P01148	445
NPFFR2	HCRT	O43612	434
NPFFR2	NPFFR1	Q9GZQ6	427
NPFFR2	SUCLG1	P53597	424
NPFFR2	SLC4A4	Q9Y6R1	390
NPFFR2	PRR32	B1ATL7	382

IntAct

11 interactions, top by confidence:

A	B	Type	Score
RAMP2	NPFFR2	psi-mi:“MI:0915”(physical association)	0.470
NPFFR2	RAMP2	psi-mi:“MI:0915”(physical association)	0.470
NPFFR2	RAMP2	psi-mi:“MI:2364”(proximity)	0.470
NPFFR2	RAMP1	psi-mi:“MI:0915”(physical association)	0.400
RAMP1	NPFFR2	psi-mi:“MI:0915”(physical association)	0.400
RAMP3	NPFFR2	psi-mi:“MI:0915”(physical association)	0.400
NPFFR2	RAMP3	psi-mi:“MI:0915”(physical association)	0.400
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350

BioGRID (5): FKBP7 (Two-hybrid), TMEM218 (Two-hybrid), TUSC5 (Two-hybrid), NPFFR2 (Affinity Capture-MS), NPFFR2 (Protein-RNA)

ESM2 similar proteins: A0A2R9YJI3, B2ZHY2, B3DM66, B4XF06, D4A3U0, O02777, O43194, O46635, P08909, P08911, P0C0W8, P14842, P18599, P20272, P21554, P28223, P28335, P32240, P34311, P34968, P35363, P47746, P50128, P50129, P56971, P70259, Q09502, Q333S9, Q5IS53, Q5IS66, Q5IS73, Q5IS98, Q5R4Q6, Q5U431, Q60F97, Q6DWJ6, Q71SP5, Q75Z89, Q801M1, Q80UC8

Diamond homologs: A5A4K9, A5A4L1, C3ZQF9, F1MV99, G4WMX4, O02835, O02836, O08725, O42179, O43614, O54799, O62729, O62809, O70342, O77408, P0DQD5, P11617, P20288, P22270, P24053, P24628, P25929, P25931, P28336, P29274, P30731, P30938, P30975, P32251, P35346, P35371, P41143, P47211, P47751, P49146, P49219, P49285, P49288, P49683, P50391

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
NPFFR2	“up-regulates activity”	GNAI1	binding
NPFFR2	“up-regulates activity”	GNAI3	binding
NPFFR2	“up-regulates activity”	GNAO1	binding
NPFFR2	“up-regulates activity”	GNAZ	binding
“neuropeptide FF receptor agonist”	“up-regulates activity”	NPFFR2	“chemical activation”
NPFFR2	up-regulates	Cell_migration
NPFFR2	up-regulates	Cell_invasion
NPFF	up-regulates	NPFFR2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	49
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

884 predictions. Top by Δscore:

Variant	Effect	Δscore
4:72128583:A:G	acceptor_gain	1.0000
4:72145686:GC:G	donor_gain	1.0000
4:72145708:A:G	donor_gain	1.0000
4:72061753:G:GT	donor_gain	0.9900
4:72096064:GA:G	donor_gain	0.9900
4:72126193:T:TA	donor_gain	0.9900
4:72126194:A:AA	donor_gain	0.9900
4:72128580:TTAA:T	acceptor_loss	0.9900
4:72128582:A:AG	acceptor_gain	0.9900
4:72128583:A:AC	acceptor_loss	0.9900
4:72128584:G:C	acceptor_loss	0.9900
4:72138038:AG:A	acceptor_gain	0.9900
4:72138039:GG:G	acceptor_gain	0.9900
4:72138135:GATAG:G	donor_gain	0.9900
4:72145717:A:G	donor_gain	0.9900
4:72146974:GCA:G	acceptor_loss	0.9900
4:72146976:A:AG	acceptor_gain	0.9900
4:72146977:G:GA	acceptor_gain	0.9900
4:72146977:G:GC	acceptor_loss	0.9900
4:72039413:GGTA:G	donor_loss	0.9800
4:72128579:A:AG	acceptor_gain	0.9800
4:72128582:AAG:A	acceptor_gain	0.9800
4:72128584:G:GG	acceptor_gain	0.9800
4:72138136:ATAGG:A	donor_loss	0.9800
4:72138139:GGT:G	donor_loss	0.9800
4:72138140:G:GA	donor_loss	0.9800
4:72138141:T:TC	donor_loss	0.9800
4:72146971:A:G	acceptor_gain	0.9800
4:72061754:A:T	donor_gain	0.9700
4:72069019:GCTAT:G	donor_gain	0.9700

AlphaMissense

3479 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:72147179:G:C	W312C	0.996
4:72147179:G:T	W312C	0.996
4:72147177:T:A	W312R	0.994
4:72147177:T:C	W312R	0.994
4:72138063:T:A	C220S	0.993
4:72138064:G:C	C220S	0.993
4:72147525:A:C	S428R	0.992
4:72147527:C:A	S428R	0.992
4:72147527:C:G	S428R	0.992
4:72128859:A:C	S192R	0.989
4:72128861:T:A	S192R	0.989
4:72128861:T:G	S192R	0.989
4:72147165:T:A	C308S	0.989
4:72147166:G:C	C308S	0.989
4:72128849:C:A	N188K	0.988
4:72128849:C:G	N188K	0.988
4:72138044:G:C	W213C	0.988
4:72138044:G:T	W213C	0.988
4:72147415:C:G	P391R	0.988
4:72138042:T:A	W213R	0.987
4:72138042:T:C	W213R	0.987
4:72138063:T:C	C220R	0.987
4:72138065:C:G	C220W	0.987
4:72147396:T:C	F385L	0.987
4:72147398:T:A	F385L	0.987
4:72147398:T:G	F385L	0.987
4:72147528:A:C	S429R	0.987
4:72147530:T:A	S429R	0.987
4:72147530:T:G	S429R	0.987
4:72138064:G:A	C220Y	0.986

dbSNP variants (sampled 300 via entrez): RS1000000234 (4:72047889 A>T), RS10000251 (4:72075851 T>A,G), RS1000029999 (4:72051179 A>T), RS1000037313 (4:72146851 T>C), RS10000437 (4:72075976 T>A,C,G), RS1000044497 (4:72124823 A>G), RS1000088346 (4:72050979 A>C), RS10000899 (4:72076683 A>C,G,T), RS1000091434 (4:72135976 T>C), RS1000105788 (4:72090303 C>T), RS1000115790 (4:72113115 G>A), RS1000118815 (4:72092930 G>A), RS1000129651 (4:72132583 C>A), RS1000135947 (4:72071864 A>C,G), RS1000148932 (4:72143095 G>A,T)

Disease associations

OMIM: gene MIM:607449 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5952 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 982 (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

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Neuropeptide FF/neuropeptide AF receptors

Most potent curated ligand interactions (16 total), top 16:

Ligand	Action	Affinity	Parameter
dNPA	Full agonist	10.57	pKi
[125I]EYF	Full agonist	10.2	pKd
1DMe	Full agonist	9.7	pKi
neuropeptide FF	Full agonist	9.7	pKi
EFWSLAAPQRF-NH2	Full agonist	9.6	pKi
[3H]EYF	Full agonist	9.3	pKd
pancreatic polypeptide	Full agonist	8.2	pKi
Y-RFRP-3	Full agonist	8.0	pKi
RFRP-3	Full agonist	7.8	pKi
compound 16a [PMID: 38522114]	Antagonist	7.57	pKi
MES304	Antagonist	7.52	pKi
BIBP3226	Antagonist	7.1	pKi
RF9	Antagonist	7.1	pKi
AC263093	Full agonist	5.9	pEC50
compound 46 [PMID: 25268943]	Antagonist	5.85	pKi
compound 8b [PMID: 38522114]	Antagonist	5.49	pKi

Binding affinities (BindingDB)

14 measured of 14 human assays (15 total across all organisms); most potent 14 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
NSC_123797	KI	5.2 nM
CAS_132709	KI	5.3 nM
CAS_68615	KI	13 nM
RFamide-related peptide 1	KI	15 nM
CAS_235433-36-0	KI	19 nM
NSC_0	KI	32 nM
RFamide-related peptide 3	KI	55 nM
CHEMBL2208305	KI	142 nM
CHEMBL2208307	KI	208 nM
CHEMBL2165922	EC50	298 nM
CHEMBL2208306	KI	424 nM
NSC_5311023	KI	640 nM
NPY 18-36	KI	1200 nM
NSC_0	KI	4200 nM

ChEMBL bioactivities

295 potent at pChembl≥5 of 295 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.70	Ki	0.02	nM	CHEMBL429731
10.57	Ki	0.027	nM	CHEMBL4460742
10.11	Ki	0.077	nM	CHEMBL4797394
9.68	Kd	0.21	nM	CHEMBL429731
9.43	Kd	0.37	nM	CHEMBL429731
9.33	Ki	0.47	nM	CHEMBL3360830
9.28	Ki	0.53	nM	CHEMBL3786309
9.27	Kd	0.54	nM	CHEMBL3786309
9.10	Ki	0.8	nM	CHEMBL3360830
9.10	IC50	0.79	nM	CHEMBL1672379
9.05	Ki	0.9	nM	CHEMBL2165920
8.92	Ki	1.2	nM	CHEMBL429731
8.85	Ki	1.42	nM	CHEMBL4779743
8.77	EC50	1.7	nM	CHEMBL2165920
8.66	Ki	2.17	nM	CHEMBL4800299
8.57	EC50	2.7	nM	CHEMBL429731
8.57	EC50	2.7	nM	CHEMBL3360830
8.50	EC50	3.16	nM	CHEMBL429731
8.49	Ki	3.2	nM	CHEMBL414263
8.49	Ki	3.2	nM	CHEMBL4790994
8.48	Ki	3.3	nM	CHEMBL5093771
8.41	Ki	3.9	nM	CHEMBL5567081
8.40	Ki	4	nM	CHEMBL2208319
8.40	Ki	4	nM	CHEMBL2208338
8.33	Ki	4.7	nM	CHEMBL5568142
8.25	EC50	5.6	nM	CHEMBL429731
8.18	Ki	6.6	nM	CHEMBL262202
8.08	Ki	8.4	nM	CHEMBL4790994
8.05	Ki	9	nM	CHEMBL2208322
7.96	EC50	11	nM	CHEMBL4797394
7.75	Ki	18	nM	CHEMBL1672380
7.72	EC50	19.2	nM	CHEMBL4800237
7.72	EC50	19.05	nM	CHEMBL4800237
7.66	Ki	22	nM	CHEMBL2208340
7.64	Ki	23	nM	CHEMBL2165920
7.60	Ki	25	nM	CHEMBL326770
7.60	EC50	25.3	nM	CHEMBL4783555
7.57	Ki	27	nM	CHEMBL3786583
7.57	Ki	27	nM	CHEMBL5557408
7.54	Ki	29	nM	CHEMBL5561599
7.52	Ki	30	nM	CHEMBL3361433
7.50	Ki	32	nM	CHEMBL5537038
7.48	EC50	33	nM	CHEMBL429731
7.48	EC50	33.1	nM	CHEMBL5435869
7.47	Ki	34	nM	CHEMBL5558362
7.43	Ki	37	nM	CHEMBL4793841
7.40	EC50	39.81	nM	CHEMBL429731
7.39	Ki	41	nM	CHEMBL3786376
7.38	EC50	41.3	nM	CHEMBL4759079
7.38	EC50	41.69	nM	CHEMBL4759079

PubChem BioAssay actives

295 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-[[(2S)-1-[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2R)-2,4-diamino-4-oxobutanoyl]pyrrolidine-2-carbonyl]-methylamino]propanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-3-phenylpropanoyl]amino]-5-oxopentanoyl]pyrrolidine-2-carbonyl]amino]-N-[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]pentanediamide	1740826: Displacement of [125I]EYF from human NPFFR2 expressed in CHO cells by gamma-counter method	ki	<0.0001	uM
(2S)-2-[[(2S)-1-[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-3-phenylpropanoyl]amino]-5-oxopentanoyl]pyrrolidine-2-carbonyl]amino]-N-[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]pentanediamide	1820161: Displacement of [125I]-1DMeNPFF from recombinant human NPFF2 receptor expressed in CHO cells by TopCount scintillation counting method	ki	<0.0001	uM
(2S)-2-[3-[(4S)-4-[[(2R)-2-[[(2S)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-oxo-4,5-dihydro-1H-2-benzazepin-2-yl]propanoylamino]-N-[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]-5-(diaminomethylideneamino)pentanamide	2075421: Displacement of [125I]-1-DMe-NPFF from human NPFF2 receptor	ki	0.0001	uM
(4S)-4-amino-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	1289947: Binding affinity to human NPFF2 receptor expressed in CHO cell membranes after 1 hr by liquid scintillation spectrophotometric counting	kd	0.0005	uM
(2S)-2-[[(2S)-1-[(2S)-5-amino-2-[[(2S)-2-[[(2R)-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]-methylamino]-4-methylpentanoyl]amino]-3-phenylpropanoyl]amino]-5-oxopentanoyl]pyrrolidine-2-carbonyl]amino]-N-[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]pentanediamide	1167041: Displacement of [3H]EYF from human NPFF2 receptor expressed in CHO cells after 1 hr by liquid scintillation counting analysis	ki	0.0005	uM
(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-phenylpropanoic acid	570384: Displacement of (D-[125I]Tyr1, MePhe3)-NPFF from NPFFR2 after 2 hrs	ic50	0.0008	uM
(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-4-amino-2-[[(2S)-1-[(2S)-2-amino-3-methylbutanoyl]pyrrolidine-2-carbonyl]amino]-4-oxobutanoyl]amino]-4-methylpentanoyl]pyrrolidine-2-carbonyl]amino]-N-[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]pentanediamide	1820161: Displacement of [125I]-1DMeNPFF from recombinant human NPFF2 receptor expressed in CHO cells by TopCount scintillation counting method	ki	0.0009	uM
phenyl (8R,9S,10S)-9-hydroxy-3,14,15,16-tetramethoxy-4,5,9,10-tetramethyltricyclo[10.4.0.02,7]hexadeca-1(16),2(7),3,5,12,14-hexaene-8-carboxylate	1740879: Displacement of TAMRA-NPFF from human NPFFR2 expressed in CHO-K1 cells preincubated for 15 mins followed by GTPgammaS addition and measured after 15 to 120 mins by competitive binding assay	ki	0.0014	uM
phenyl (9S,10S,11R)-10-hydroxy-3,4,5,18-tetramethoxy-9,10-dimethyltetracyclo[10.6.0.02,7.014,17]octadeca-1(12),2,4,6,13,17-hexaene-11-carboxylate	1740879: Displacement of TAMRA-NPFF from human NPFFR2 expressed in CHO-K1 cells preincubated for 15 mins followed by GTPgammaS addition and measured after 15 to 120 mins by competitive binding assay	ki	0.0022	uM
(2S)-2-[[(2S)-1-[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]-methylamino]-3-phenylpropanoyl]amino]-5-oxopentanoyl]pyrrolidine-2-carbonyl]amino]-N-[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]pentanediamide	1740816: Displacement of [125I]-1DMeNPFF from human NPFFR2 expressed in HEK293 cells incubated for 2 hrs by scintillation counting method	ki	0.0032	uM
(2R)-2-[[(2S)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]amino]-N-[(4S)-2-[3-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(4-benzylpiperidin-1-yl)-1-oxopentan-2-yl]amino]-3-oxopropyl]-3-oxo-4,5-dihydro-1H-2-benzazepin-4-yl]-5-(diaminomethylideneamino)pentanamide	2075421: Displacement of [125I]-1-DMe-NPFF from human NPFF2 receptor	ki	0.0032	uM
(2R)-N-[(2S)-1-amino-3-(2-bromophenyl)-1-oxopropan-2-yl]-5-(diaminomethylideneamino)-2-(3,3-diphenylprop-2-enoylamino)pentanamide	1820161: Displacement of [125I]-1DMeNPFF from recombinant human NPFF2 receptor expressed in CHO cells by TopCount scintillation counting method	ki	0.0033	uM
(2R)-2-[[(2S)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]amino]-N-[(4S)-2-[3-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-1-oxo-5-piperidin-1-ylpentan-2-yl]amino]-3-oxopropyl]-3-oxo-4,5-dihydro-1H-2-benzazepin-4-yl]-5-(diaminomethylideneamino)pentanamide	2075421: Displacement of [125I]-1-DMe-NPFF from human NPFF2 receptor	ki	0.0039	uM
(2R)-N-[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]-5-(diaminomethylideneamino)-2-[(2,2-diphenylacetyl)amino]pentanamide	718796: Displacement of [3H]FFRF-NH2 from human flag-tagged NPFF2 receptor expressed in CHO cells by scintillation counting	ki	0.0040	uM
N-[(2R)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-2-phenylbenzamide	718796: Displacement of [3H]FFRF-NH2 from human flag-tagged NPFF2 receptor expressed in CHO cells by scintillation counting	ki	0.0040	uM
(2R)-N-[(4S)-2-[3-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(4-benzylpiperidin-1-yl)-1-oxopentan-2-yl]amino]-3-oxopropyl]-3-oxo-4,5-dihydro-1H-2-benzazepin-4-yl]-5-(diaminomethylideneamino)-2-[[(2S)-2-(diaminomethylideneamino)-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]amino]pentanamide	2070836: Displacement of [125I]-1DMeNPFF from human NPFFR2 expressed in CHO cell membrane incubated for 1 hr by Topcount counting method	ki	0.0047	uM
(2S)-N-[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]-2-[[(2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-(diaminomethylideneamino)pentanamide	1740823: Displacement of [125I]EYF from human NPFFR2 expressed in CHO cell membranes	ki	0.0066	uM
N-[(2R)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-phenylbenzamide	718796: Displacement of [3H]FFRF-NH2 from human flag-tagged NPFF2 receptor expressed in CHO cells by scintillation counting	ki	0.0090	uM
N-[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]adamantane-1-carboxamide	1820161: Displacement of [125I]-1DMeNPFF from recombinant human NPFF2 receptor expressed in CHO cells by TopCount scintillation counting method	ki	0.0180	uM
(2S)-2-[[(2S)-1-[(4R,7S,13S)-13-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-7-benzyl-6,9,12-trioxo-1,2-dithia-5,8,11-triazacyclotetradecane-4-carbonyl]pyrrolidine-2-carbonyl]amino]-N-[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]pentanediamide	1701333: Agonist activity at NPFFR2 (unknown origin) expressed in HEK293-A cells assessed as inhibition of forskolin-stimulated cAMP accumulation incubated for 30 mins by competition PKA binding assay	ec50	0.0191	uM
N-[(2R)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]benzamide	718796: Displacement of [3H]FFRF-NH2 from human flag-tagged NPFF2 receptor expressed in CHO cells by scintillation counting	ki	0.0220	uM
(2S)-N-[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-2-[[(2S)-pyrrolidine-2-carbonyl]amino]pentanediamide	1740816: Displacement of [125I]-1DMeNPFF from human NPFFR2 expressed in HEK293 cells incubated for 2 hrs by scintillation counting method	ki	0.0250	uM
(2S)-2-[[(2S)-1-[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]pyrrolidine-2-carbonyl]amino]-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-5-oxopentanoyl]pyrrolidine-2-carbonyl]amino]-N-[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]pentanediamide	1740840: Agonist activity at NPFFR2 (unknown origin) expressed in HEK-293A cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins followed by [3H] cAMP addition measured after 2 hrs by scintillation counting method	ec50	0.0253	uM
(4S)-4-amino-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[[(2S)-5-amino-1-[[(2S)-5-[[amino-(4-aminobutylcarbamoylamino)methylidene]amino]-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid;tris(2,2,2-trifluoroacetic acid)	1289950: Displacement of [3H]EYE from human NPFF2 receptor expressed in CHO cell membranes after 1 hr by liquid scintillation spectrophotometric counting	ki	0.0270	uM
N-[[1-benzyl-4-(naphthalen-1-ylmethyl)piperidin-4-yl]methyl]-3-piperidin-1-ylpropanamide;hydrochloride	2075408: Displacement of [3H]-EYF from monoclonal human NPFF2 receptor expressed in CHO cells incubated for 1 hr by competitive radioligand binding assay	ki	0.0270	uM
(2R)-1-[(2S)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]-N-[(4S)-2-[3-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(4-benzylpiperidin-1-yl)-1-oxopentan-2-yl]amino]-3-oxopropyl]-3-oxo-4,5-dihydro-1H-2-benzazepin-4-yl]pyrrolidine-2-carboxamide	2070836: Displacement of [125I]-1DMeNPFF from human NPFFR2 expressed in CHO cell membrane incubated for 1 hr by Topcount counting method	ki	0.0290	uM
N-[[1-benzyl-4-(naphthalen-1-ylmethyl)piperidin-4-yl]methyl]-2-(diaminomethylideneamino)acetamide	1167041: Displacement of [3H]EYF from human NPFF2 receptor expressed in CHO cells after 1 hr by liquid scintillation counting analysis	ki	0.0300	uM
(2S)-2-[3-[(2S)-2-[[(2R)-2-[[(2S)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]-methylamino]propanoyl]amino]-3-oxo-2,5-dihydro-1H-benzo[g][2]benzazepin-4-yl]propanoylamino]-N-[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]-5-(4-benzylpiperidin-1-yl)pentanamide	2070836: Displacement of [125I]-1DMeNPFF from human NPFFR2 expressed in CHO cell membrane incubated for 1 hr by Topcount counting method	ki	0.0320	uM
(2S)-2-[[(3S,9R,14E,17S)-17-[(2S)-2-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]carbamoyl]pyrrolidine-1-carbonyl]-3-benzyl-4-methyl-2,5,8-trioxo-1,4,7-triazacycloheptadec-14-en-9-yl]amino]-3-(4-hydroxyphenyl)propanoic acid	2004925: Agonist activity at NPFF2R (unknown origin) transfected in HEK293 cells co-expressing Galphaq15 assessed as increase in calcium mobilization by Fluo-4AM dye based assay	ec50	0.0331	uM
N-[(2S)-5-(4-benzylpiperidin-1-yl)-1-oxo-1-(2-phenylethylamino)pentan-2-yl]-2-phenylbenzamide	2075419: Displacement of [3H]-FFRFamide from N-terminal Flag-fused human NPFF2 receptor expressed in CHO cell membranes incubated for 1 hr by Topcount scintillation counting analysis	ki	0.0340	uM
5-(3,4-dichlorophenyl)-1,4-dihydropyrimidin-2-amine	1740889: Displacement of [3H]-FFRF-NH2 from human NPFFR2 expressed in CHO cell membrane by Topcount scintillation counting method	ki	0.0370	uM
(4S)-4-amino-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-1-oxo-5-[[(Z)-N’-[4-(propanoylamino)butylcarbamoyl]carbamimidoyl]amino]pentan-2-yl]amino]-1,5-dioxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid;bis(2,2,2-trifluoroacetic acid)	1289950: Displacement of [3H]EYE from human NPFF2 receptor expressed in CHO cell membranes after 1 hr by liquid scintillation spectrophotometric counting	ki	0.0410	uM
(2S)-2-[[(2S)-1-[(2S)-5-amino-2-[[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylsulfanylbutanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-5-oxopentanoyl]pyrrolidine-2-carbonyl]amino]-N-[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]pentanediamide	1714359: Agonist activity at NPFFR2 (unknown origin) expressed in HEK293-A cells assessed as reduction in forskolin-induced cAMP accumulation incubated for 30 mins by competition PKA binding assay	ec50	0.0413	uM
N-[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]quinoline-2-carboxamide	718796: Displacement of [3H]FFRF-NH2 from human flag-tagged NPFF2 receptor expressed in CHO cells by scintillation counting	ki	0.0470	uM
(2S)-2-[[(2S)-1-[(5S,8S,16R)-16-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-5-benzyl-4-methyl-3,6,10,17-tetraoxo-1,4,7,11-tetrazacycloheptadecane-8-carbonyl]pyrrolidine-2-carbonyl]amino]-N-[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]pentanediamide	1812982: Agonist activity at NPFF2R (unknown origin) expressed in HEK293-A cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins in presence of 3-isobutyl-1-methylxanthine followed by forskolin and compound addition by competitive PKA binding assay	ec50	0.0498	uM
(2S)-2-[[(3S,9R,13E,16S)-16-[(2S)-2-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]carbamoyl]pyrrolidine-1-carbonyl]-3-benzyl-4-methyl-2,5,8-trioxo-1,4,7-triazacyclohexadec-13-en-9-yl]amino]-3-(4-hydroxyphenyl)propanoic acid	2004925: Agonist activity at NPFF2R (unknown origin) transfected in HEK293 cells co-expressing Galphaq15 assessed as increase in calcium mobilization by Fluo-4AM dye based assay	ec50	0.0523	uM
(2S)-2-[[2-[(2S)-2-[[(2R)-2-[[(2S)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]-methylamino]propanoyl]amino]-3-oxo-2,5-dihydro-1H-benzo[g][2]benzazepin-4-yl]acetyl]amino]-N-[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]-5-(4-benzylpiperidin-1-yl)pentanamide	2070836: Displacement of [125I]-1DMeNPFF from human NPFFR2 expressed in CHO cell membrane incubated for 1 hr by Topcount counting method	ki	0.0540	uM
N-[(2S)-5-(1-aminoethylideneamino)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]adamantane-1-carboxamide	1167036: Antagonist activity at human NPFF2 receptor expressed in African green monkey COS-1 cells	ki	0.0750	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	570384: Displacement of (D-[125I]Tyr1, MePhe3)-NPFF from NPFFR2 after 2 hrs	ic50	0.0760	uM
(2S)-2-[[(2S)-1-[(5S,8R,16S)-16-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-5-benzyl-4-methyl-3,6,10,17-tetraoxo-1,4,7,11-tetrazacycloheptadecane-8-carbonyl]pyrrolidine-2-carbonyl]amino]-N-[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]pentanediamide	1812982: Agonist activity at NPFF2R (unknown origin) expressed in HEK293-A cells assessed as inhibition of forskolin-induced cAMP accumulation preincubated for 30 mins in presence of 3-isobutyl-1-methylxanthine followed by forskolin and compound addition by competitive PKA binding assay	ec50	0.0813	uM
N-[[1-benzyl-4-[(3,4-dichlorophenyl)methyl]piperidin-4-yl]methyl]-2-(diaminomethylideneamino)acetamide	1167041: Displacement of [3H]EYF from human NPFF2 receptor expressed in CHO cells after 1 hr by liquid scintillation counting analysis	ki	0.0820	uM
2-(diaminomethylideneamino)-N-[(1,4-dibenzylpiperidin-4-yl)methyl]acetamide	1167041: Displacement of [3H]EYF from human NPFF2 receptor expressed in CHO cells after 1 hr by liquid scintillation counting analysis	ki	0.0840	uM
(2R)-N-[(2R)-1-amino-3-(2-bromophenyl)-1-oxopropan-2-yl]-5-(diaminomethylideneamino)-2-(3,3-diphenylprop-2-enoylamino)pentanamide	1820161: Displacement of [125I]-1DMeNPFF from recombinant human NPFF2 receptor expressed in CHO cells by TopCount scintillation counting method	ki	0.0840	uM
(2R)-5-(diaminomethylideneamino)-2-[(2,2-diphenylacetyl)amino]-N-[(4-hydroxyphenyl)methyl]pentanamide	1266468: Binding affinity to human NPFF2 receptor expressed in CHO cells	ki	0.0840	uM
(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]propanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylsulfanylbutanoyl]pyrrolidine-2-carbonyl]amino]-N-[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]pentanediamide	1714359: Agonist activity at NPFFR2 (unknown origin) expressed in HEK293-A cells assessed as reduction in forskolin-induced cAMP accumulation incubated for 30 mins by competition PKA binding assay	ec50	0.0870	uM
2-(4-methylquinolin-2-yl)guanidine	1740861: Binding affinity to human NPFFR2 by radioligand binding assay	ki	0.0910	uM
N-[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]benzamide	718796: Displacement of [3H]FFRF-NH2 from human flag-tagged NPFF2 receptor expressed in CHO cells by scintillation counting	ki	0.0920	uM
N-[(2R)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-4-phenylbenzamide	718796: Displacement of [3H]FFRF-NH2 from human flag-tagged NPFF2 receptor expressed in CHO cells by scintillation counting	ki	0.0940	uM
2-[(E)-[5-(2-methylphenyl)furan-2-yl]methylideneamino]guanidine	439331: Agonist activity at human NPFF2 receptor expressed in cells assessed as beta-galactosidase levels after 5 days	ec50	0.1000	uM
2-[(E)-[5-[2-(trifluoromethyl)phenyl]furan-2-yl]methylideneamino]guanidine;hydrochloride	1740872: Agonist activity at NPFFR2 (unknown origin) expressed in mouse NIH3T3 cells by receptor selection and amplification technology assay	ec50	0.1000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, increases expression	7
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
bisphenol A	decreases methylation	1
deoxynivalenol	increases expression	1
quercitrin	decreases expression	1
trichostatin A	increases expression	1
arsenite	increases methylation	1
sodium arsenite	affects splicing, decreases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases expression	1
Zoledronic Acid	increases expression	1
Carbamazepine	affects expression	1
Silicon Dioxide	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1
Aflatoxin B1	decreases methylation	1

ChEMBL screening assays

111 unique, capped per target: 62 functional, 47 binding, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1058555	Functional	Antagonist activity at human NPFF2 receptor expressed in HEK293T cells assessed as inhibition of PGE2-induced cAMP release	Discovery of selective nonpeptidergic neuropeptide FF2 receptor agonists. — J Med Chem
CHEMBL1681415	Binding	Displacement of (D-[125I]Tyr1, MePhe3)-NPFF from NPFFR2 at 10 uM after 2 hrs	Activation of Neuropeptide FF Receptors by Kisspeptin Receptor Ligands. — ACS Med Chem Lett
CHEMBL4700947	ADMET	Activation of human NPFF2R overexpressing CHO cells assessed as inhibition of forskolin-stimulated cAMP degradation incubated for 30 mins in presence of IBMX and 10% FBS by fluorescence based assay	Design of a Long-Acting and Selective MEG-Fatty Acid Stapled Prolactin-Releasing Peptide Analog. — ACS Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_H476	CHO-K1/NPFF2/Galpha15	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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