In vitro and in vivo studies of dansylated compounds, the putative agonists and antagonists on neuropeptide FF receptors.
To further evaluate the importance of C-terminal modification of neuropeptide FF (NPFF), in the present work, four dansylated NPFF analogues, including two putative agonists (dansyl-PQRFamide and dansyl-GSRFamide) and two putative antagonists (dansyl-PQRamide and dansyl-GSRamide), were synthesized and investigated to address their potencies and efficacies in a series of in vitro and in vivo assays. (1) In the isolated mouse colon bioassay, the four dansylated compounds showed agonistic profiles: both dansyl-GSRFamide (1-10 microM) and dansyl-GSRamide (1-10 microM) dose-dependently caused colonic contractions, which were attenuated by pretreatment with BIBP3226; dansyl-PQRFamide and dansyl-PQRamide evoked modest colonic contractions at a high dose of 50 microM. (2) In urethane-anaesthetized rats, both dansyl-PQRFamide (50-300 nmol/kg, i.v.) and dansyl-GSRFamide (15-50 nmol/kg, i.v.) dose-dependently increased the mean arterial pressure and heart rate in a manner similar to NPFF (50-300 nmol/kg, i.v.); on the contrary, the two putative antagonists (100-800 nmol/kg, i.v.) decreased blood pressure in a dose-dependent manner. All the results suggest that dansyl-PQRFamide and dansyl-GSRFamide are NPFF full agonists; in contrast, dansyl-GSRamide and dansyl-PQRamide behave as agonists in vitro and antagonists in vivo on NPFF receptors. The findings reveal that the C-terminal Phe might be a crucial residue to determine the efficacy. In addition, the novel analogue dansyl-GSRFamide may be developed as a highly potent agonist to investigate the NPFF system.
Fang
Quan
Q
Department of Biochemistry and Molecular Biology, School of Life Science, Lanzhou University, 222 Tian Shui South Road, Lanzhou 730000, PR China.
Guo
Jia
J
Peng
Ya-li
YL
Chang
Min
M
He
Feng
F
Chen
Qiang
Q
Wang
Rui
R
D000818:Animals; D001681:Biological Assay; D002319:Cardiovascular System / Q000187:drug effects; D003106:Colon / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D011312:Pressure; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D018013:Receptors, Neuropeptide / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013116:Spinal Cord / Q000378:metabolism
D018013:Receptors, Neuropeptide; C083929:neuropeptide FF receptor