NPFF2 receptor | Neuropeptide FF/neuropeptide AF receptors | IUPHAR/BPS Guide to PHARMACOLOGY

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NPFF2 receptor

Target not currently curated in GtoImmuPdb

Target id: 301

Nomenclature: NPFF2 receptor

Family: Neuropeptide FF/neuropeptide AF receptors

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 420 4q21 NPFFR2 neuropeptide FF receptor 2 2,4
Mouse 7 417 5 E1 Npffr2 neuropeptide FF receptor 2
Rat 7 417 14p22 Npffr2 neuropeptide FF receptor 2 2
Previous and Unofficial Names
F8Famide receptor | GPR74 [2] | NPGPR | G protein-coupled receptor 74
Database Links
Specialist databases
GPCRDB npff2_human (Hs), npff2_mouse (Mm), npff2_rat (Rn)
Other databases
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
RefSeq Nucleotide
RefSeq Protein
Natural/Endogenous Ligands
neuropeptide AF {Sp: Human} , neuropeptide AF {Sp: Mouse} , neuropeptide AF {Sp: Rat}
neuropeptide FF {Sp: Human, Mouse, Rat}
neuropeptide SF {Sp: Human}
RFRP-1 {Sp: Human}
RFRP-3 {Sp: Human}
Comments: Neuropeptide AF is the most potent endogenous agonist
Potency order of endogenous ligands (Human)
neuropeptide AF (NPFF, O15130), neuropeptide FF (NPFF, O15130) > PrRP-31 (PRLH, P81277) > FMRF, QRFP43 (QRFP, P83859) > neuropeptide SF (NPFF, O15130)  [5]

Download all structure-activity data for this target as a CSV file

Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[125I]EYF Hs Full agonist 10.2 pKd 15
pKd 10.2 (Kd 6.3x10-11 M) [15]
[3H]EYF Hs Full agonist 9.3 pKd 25
pKd 9.3 (Kd 5.4x10-10 M) [25]
dNPA Hs Full agonist 10.6 pKi 22
pKi 10.6 (Ki 2.7x10-11 M) [22]
neuropeptide FF {Sp: Human, Mouse, Rat} Hs Full agonist 9.7 pKi 7,14
pKi 9.7 [7,14]
EFWSLAAPQRF-NH2 Hs Full agonist 9.6 pKi 15
pKi 9.6 [15]
1DMe Hs Full agonist 8.5 – 9.7 pKi 2,7,15
pKi 8.5 – 9.7 [2,7,15]
pancreatic polypeptide {Sp: European common frog} Hs Full agonist 8.1 – 8.2 pKi 2,14
pKi 8.1 – 8.2 [2,14]
Y-RFRP-3 Hs Full agonist 8.0 pKi 7,15
pKi 8.0 [7,15]
RFRP-3 {Sp: Human} Hs Full agonist 7.8 pKi 7,15
pKi 7.8 [7,15]
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
RF9 Hs Antagonist 7.1 pKi 23
pKi 7.1 [23]
BIBP3226 Hs Antagonist 5.9 – 7.1 pKi 2,14
pKi 5.9 – 7.1 [2,14]
compound 46 [PMID: 25268943] Hs Antagonist 5.8 pKi 9
pKi 5.8 (Ki 1.426x10-6 M) [9]
Description: Binding affinity.
Antagonist Comments
BIBP3226 is also a selective antagonist of NPY1 receptors.
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
Calcium channel
Other - See Comments
Comments:  Reactivation of phospholipase C stimulated by carbachol in SH-SY5Y cells.
References:  15-16
Tissue Distribution
Amygdala > caudate putamen > whole brain > hippocampus > pituitary > small intestine, spleen > fetal kidney > thalamus, hypothalamus > fetal brain, fetal liver, kidney, lung, pancreas, spinal cord, skeletal muscle, substantia nigra.
Species:  Human
Technique:  RT-PCR.
References:  2
Species:  Mouse
Technique:  Radioligand binding.
References:  6
Species:  Rat
Technique:  Radioligand binding.
References:  6
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Measurement of cAMP levels in CHO cells transfected with the human NPFF2 receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Inhibition of forskolin-induced cAMP formation.
References:  4
Measurement of cAMP levels in HEK 293 cells transfected with the human NPFF2 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Inhibition of forskolin-induced cAMP formation.
References:  4
Measurement of Ca2+ levels in SH-SY5Y cells transfected with the human NPFF2 receptor.
Species:  Human
Tissue:  SH-SY5Y cells.
Response measured:  Ani-opioid effects on Ca2+ mobilisation.
References:  16
Measurement of [35S]GTPγS binding in CHO cells transfected with the human NPFF2 receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  [35S]GTPγS binding.
References:  5
Measurement of [35S]GTPγS binding stimulated by NPFF2 receptors in rat spinal cord.
Species:  Rat
Tissue:  Spinal cord.
Response measured:  [35S]GTPγS binding.
References:  8
Measurement of intracellular Ca2+ levels in rat dorsal root ganglion neurons endogenously expressing the NPFF2 receptor.
Species:  Rat
Tissue:  Dorsal root ganglion neurons.
Response measured:  Modulation of intracellular Ca2+ levels.
References:  19
Measurement of intracellular Ca2+ levels in rat dorsal raphe neurons endogenously expressing the NPFF2 receptor.
Species:  Rat
Tissue:  Dorsal raphe neurons.
Response measured:  Anti-opioid effects on Ca2+ levels.
References:  21
Physiological Functions
Modulation of opioid nociception.
Species:  Mouse
Tissue:  Brain and spinal cord.
References:  18
Species:  Mouse
Tissue:  Brain.
References:  3
Modulation of arterial blood pressure.
Species:  Rat
Tissue:  Heart.
References:  1,20
Modulation of food intake.
Species:  Rat
Tissue:  In vivo.
References:  10,17,24
Modulation of adipocyte metabolism.
Species:  Human
Tissue:  Adipose tissue.
References:  11
Modulation of locomotion induced by morphine.
Species:  Rat
Tissue:  Ventral tegmental area.
References:  13
Modulation of conditioned place preference to morphine.
Species:  Mouse
Tissue:  Brain.
References:  12


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1. Allard M, Labrouche S, Nosjean A, Laguzzi R. (1995) Mechanisms underlying the cardiovascular responses to peripheral administration of NPFF in the rat. J. Pharmacol. Exp. Ther., 274 (1): 577-83. [PMID:7616447]

2. Bonini JA, Jones KA, Adham N, Forray C, Artymyshyn R, Durkin MM, Smith KE, Tamm JA, Boteju LW, Lakhlani PP et al.. (2000) Identification and characterization of two G protein-coupled receptors for neuropeptide FF. J. Biol. Chem., 275 (50): 39324-31. [PMID:11024015]

3. Desprat C, Zajac JM. (1997) Hypothermic effects of neuropeptide FF analogues in mice. Pharmacol. Biochem. Behav., 58 (2): 559-63. [PMID:9300619]

4. Elshourbagy NA, Ames RS, Fitzgerald LR, Foley JJ, Chambers JK, Szekeres PG, Evans NA, Schmidt DB, Buckley PT, Dytko GM et al.. (2000) Receptor for the pain modulatory neuropeptides FF and AF is an orphan G protein-coupled receptor. J. Biol. Chem., 275 (34): 25965-71. [PMID:10851242]

5. Gouardères C, Mazarguil H, Mollereau C, Chartrel N, Leprince J, Vaudry H, Zajac JM. (2007) Functional differences between NPFF1 and NPFF2 receptor coupling: high intrinsic activities of RFamide-related peptides on stimulation of [35S]GTPgammaS binding. Neuropharmacology, 52 (2): 376-86. [PMID:17011599]

6. Gouardères C, Puget A, Zajac JM. (2004) Detailed distribution of neuropeptide FF receptors (NPFF1 and NPFF2) in the rat, mouse, octodon, rabbit, guinea pig, and marmoset monkey brains: a comparative autoradiographic study. Synapse, 51 (4): 249-69. [PMID:14696013]

7. Gouardères C, Quelven I, Mollereau C, Mazarguil H, Rice SQ, Zajac JM. (2002) Quantitative autoradiographic distribution of NPFF1 neuropeptide FF receptor in the rat brain and comparison with NPFF2 receptor by using [125I]YVP and [(125I]EYF as selective radioligands. Neuroscience, 115 (2): 349-61. [PMID:12421602]

8. Gouardères C, Zajac JM. (2007) Biochemical anti-opioid action of NPFF2 receptors in rat spinal cord. Neurosci. Res., 58 (1): 91-4. [PMID:17337079]

9. Journigan VB, Mésangeau C, Vyas N, Eans SO, Cutler SJ, McLaughlin JP, Mollereau C, McCurdy CR. (2014) Nonpeptide small molecule agonist and antagonist original leads for neuropeptide FF1 and FF2 receptors. J. Med. Chem., 57 (21): 8903-27. [PMID:25268943]

10. Kotani M, Mollereau C, Detheux M, Le Poul E, Brézillon S, Vakili J, Mazarguil H, Vassart G, Zajac JM, Parmentier M. (2001) Functional characterization of a human receptor for neuropeptide FF and related peptides. Br. J. Pharmacol., 133 (1): 138-44. [PMID:11325803]

11. Lefrere I, De Coppet P, Camelin JC, Le Lay S, Mercier N, Elshourbagy N, Bril A, Berrebi-Bertrand I, Feve B, Krief S. (2002) Neuropeptide AF and FF modulation of adipocyte metabolism. Primary insights from functional genomics and effects on beta-adrenergic responsiveness. J. Biol. Chem., 277 (42): 39169-78. [PMID:12149260]

12. Marchand S, Betourne A, Marty V, Daumas S, Halley H, Lassalle JM, Zajac JM, Frances B. (2006) A neuropeptide FF agonist blocks the acquisition of conditioned place preference to morphine in C57Bl/6J mice. Peptides, 27 (5): 964-72. [PMID:16494968]

13. Marco N, Stinus L, Allard M, Le Moal M, Simonnet G. (1995) Neuropeptide FLFQRFamide receptors within the ventral mesenchephalon and dopaminergic terminal areas: localization and functional antiopioid involvement. Neuroscience, 64 (4): 1035-44. [PMID:7753374]

14. Mollereau C, Gouardères C, Dumont Y, Kotani M, Detheux M, Doods H, Parmentier M, Quirion R, Zajac JM. (2001) Agonist and antagonist activities on human NPFF(2) receptors of the NPY ligands GR231118 and BIBP3226. Br. J. Pharmacol., 133 (1): 1-4. [PMID:11325787]

15. Mollereau C, Mazarguil H, Marcus D, Quelven I, Kotani M, Lannoy V, Dumont Y, Quirion R, Detheux M, Parmentier M et al.. (2002) Pharmacological characterization of human NPFF(1) and NPFF(2) receptors expressed in CHO cells by using NPY Y(1) receptor antagonists. Eur. J. Pharmacol., 451 (3): 245-56. [PMID:12242085]

16. Mollereau C, Mazarguil H, Zajac JM, Roumy M. (2005) Neuropeptide FF (NPFF) analogs functionally antagonize opioid activities in NPFF2 receptor-transfected SH-SY5Y neuroblastoma cells. Mol. Pharmacol., 67 (3): 965-75. [PMID:15608144]

17. Murase T, Arima H, Kondo K, Oiso Y. (1996) Neuropeptide FF reduces food intake in rats. Peptides, 17 (2): 353-4. [PMID:8801545]

18. Quelven I, Roussin A, Zajac JM. (2005) Comparison of pharmacological activities of Neuropeptide FF1 and Neuropeptide FF2 receptor agonists. Eur. J. Pharmacol., 508 (1-3): 107-14. [PMID:15680260]

19. Rebeyrolles S, Zajac JM, Roumy M. (1996) Neuropeptide FF reverses the effect of mu-opioid on Ca2+ channels in rat spinal ganglion neurones. Neuroreport, 7 (18): 2979-81. [PMID:9116223]

20. Roth BL, Disimone J, Majane EA, Yang HY. (1987) Elevation of arterial pressure in rats by two new vertebrate peptides FLFQPQRF-NH2 and AGEGLSSPFWSLAAPQRF-NH2 which are immunoreactive to FMRF-NH2 antiserum. Neuropeptides, 10 (1): 37-42. [PMID:3670567]

21. Roumy M, Zajac J. (1999) Neuropeptide FF selectively attenuates the effects of nociceptin on acutely dissociated neurons of the rat dorsal raphe nucleus. Brain Res., 845 (2): 208-14. [PMID:10536200]

22. Roussin A, Serre F, Gouardères C, Mazarguil H, Roumy M, Mollereau C, Zajac JM. (2005) Anti-analgesia of a selective NPFF2 agonist depends on opioid activity. Biochem. Biophys. Res. Commun., 336 (1): 197-203. [PMID:16129413]

23. Simonin F, Schmitt M, Laulin JP, Laboureyras E, Jhamandas JH, MacTavish D, Matifas A, Mollereau C, Laurent P, Parmentier M et al.. (2006) RF9, a potent and selective neuropeptide FF receptor antagonist, prevents opioid-induced tolerance associated with hyperalgesia. Proc. Natl. Acad. Sci. U.S.A., 103 (2): 466-71. [PMID:16407169]

24. Sunter D, Hewson AK, Lynam S, Dickson SL. (2001) Intracerebroventricular injection of neuropeptide FF, an opioid modulating neuropeptide, acutely reduces food intake and stimulates water intake in the rat. Neurosci. Lett., 313 (3): 145-8. [PMID:11682148]

25. Talmont F, Garcia LP, Mazarguil H, Zajac JM, Mollereau C. (2009) Characterization of two novel tritiated radioligands for labelling Neuropeptide FF (NPFF(1) and NPFF(2)) receptors. Neurochem. Int., 55 (8): 815-9. [PMID:19682524]


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