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. Author manuscript; available in PMC: 2022 Oct 24.
Published in final edited form as: J Med Chem. 2020 Jul 31;63(21):12387–12402. doi: 10.1021/acs.jmedchem.0c00643

Table 2.

Biological activities of representative NPFF-derived peptidic probes.

Ligand Sequence Usage In vitro activities In vivo activities
NPFF (a.k.a. F8Fa, 1) FLFQPQRF-NH2 Agonist hNPFFR1 COS-7 or HEK cells Kd = 1.13 nM4
hNPFFR2 COS-7 or HEK cells Kd = 0.21 – 0.37 nM4, 81
Rat spinal cord Ki = 0.21 – 0.34 nM19, 77, 78, 81
hNPFFR2 EC50 = 3.16 nM81
Analgesia1, 10, 11, 3638, 77, 78
Opioid abuse45, 49, 53
Amphetamine abuse5557
Cocaine abuse58
Cardiovascular activities32, 59, 60, 62
Gastrointestinal mobility74
[Tyr1]NPFF (a.k.a. Y8Fa, 2) YLFQPQRF-NH2 Agonist Rat spinal cord Ki = 0.20 nM77 Pain77
Anorectic effect in fasted mice.82
1DMe (3) [D-Tyr1,(NMe)Phe3] YLFQPQRF-NH2 Metabolically stable agonist hNPFFR1 Ki = 2.0 – 7.9 nM4, 80
hNPFFR2 Ki = 3.2 nM4
rNPFFR1 Ki = 1.6 nM4
rNPFFR2 Ki = 2.0 nM4
Rat spinal cord Ki = 0.07 – 034 nM77, 78, 80, 81
hNPFFR2 EC50 = 2.69 nM81
Analgesia77 38, 40, 78, 80
Opioid abuse52
Gastrointestinal mobility75
Nic-1DMe (4) [D-Tyr1,(NMe)Phe3,Nic-Pro5] YLFQPQRF-NH2 Metabolically stable agonist Rat spinal cord Ki = 0.07 nM80
hNPFFR1 Ki = 1.30 nM80
Pain80
NPVF (5) VPNLPQRF-NH2 NPFFR1 agonist hNPFFR1 Ki = 0.59 nM23
hNPFFR2 Ki = 23 nM23
Cardiovascular activities62
dNPA (6) [D-Asn1,(NMe)Ala3] NPAFLFQPQRF-NH2 NPFFR2 agonist hNPFFR1 Ki = 2.9 nM23
hNPFFR2 Ki = 0.027 nM23
Cardiovascular activities62
FMRFamide (7) FMRF-NH2 Agonist Rat spinal cord Ki = 1.8 nM19
hNPFFR2 Ki = 6.6 nM81
hNPFFR2 EC50 = 517 nM81
Pain36
Feeding65
Gastrointestinal mobility74
PQRFamide (8) PQRF-NH2 Agonist hNPFFR1 Ki = 40 nM4
Rat spinal cord Ki = 15.5 nM81
hNPFFR2 Ki = 25 nM4
rNPFFR1 Ki = 25 nM4
rNPFFR2 Ki = 25 nM4
hNPFFR2 EC50 = 309 nM81
Cardiovascular activities61
PFR(Tic)amide (9) [Tic-Arg3]PFR(Tic)-NH2 (Fig. 1) NPFFR1 antagonist, NPFFR2 agonist Rat NPFFR1 Ki = 101 nM56
Rat NPFFR1 IC50 = 0.1 nM56
hNPFFR2 EC50 = 2400 ± 400 nM83
Opioid abuse47
Cardiovascular activities61
daY8Ra (10) [desamino-Tyr1]YFLFQPQR-NH2 Metabolically stable antagonist Rat spinal cord Ki = 0.20 ± 0.04 nM50 Opioid addiction50
Dansyl-PQRNH2 (11) [dns-Pro1]PQR-NH2 (Fig. 1) CNS permeable antagonist Rat spinal cord Ki = 13 μM84 Opioid addiction47, 84
RF9 (12) See Fig. 1 Agonist/ Antagonist hNPFFR1 Ki = 58 nM32
hNPFFR2 Ki = 75 nM32
Pain32
Opioid addiction32
Cardiovascular activities32
GJ14 (13) See Fig. 1 Antagonist hNPFFR1 EC50 = 21 nM72
hNPFFR1 EC50 = 387 nM72
Anxiety72