title: Novel potent agonist [(pF)Phe4,Aib7,Aib11,Arg14,Lys15]N/OFQ-NH2 and antagonist [Nphe1,(pF)Phe4,Aib7,Aib11,Arg14,Lys15]N/OFQ-NH2 of nociceptin/orphanin FQ receptor.
abstract: Two novel ligands for the nociceptin/orphanin FQ (N/OFQ) receptor (NOP), [(pF)Phe4,Aib7, Aib11,Arg14,Lys15]N/OFQ-NH2 (peptide-1) and [Nphe1,(pF)Phe4,Aib7,Aib11,Arg14,Lys15]N/OFQ-NH2 (peptide-2), have been generated by combining different modifications of N/OFQ sequence. In the present study, we investigated the actions of two analogues and compared them with those of N/OFQ in four assays. Peptide-1 mimicked N/OFQ effects in mouse vas deferens and mouse colon and showed similar maximal effects but higher potency relative to N/OFQ. The effects of peptide-1 were sensitive to NOP receptor selective antagonist ([Nphe1]N/OFQ(1-13)-NH2) but not to naloxone in vitro. Peptide-1 (25 pmol, i.c.v.) mimicked the pronociceptive action of N/OFQ (2.5 nmol, i.c.v.) in mouse tail withdrawal assay, displaying higher potency and longer lasting effects. In anesthetized rats, peptide-1 (1 nmol/kg, i.v.) produced a marked decrease in mean arterial pressure, which was comparable to that evoked by i.v. N/OFQ (100 nmol/kg). Peptide-2 did not produce any effect per se but antagonized N/OFQ actions in mouse vas deferens and mouse colon assays. Peptide-2 is active in vivo where it prevented the pronociceptive effect induced by 2.5 nmol N/OFQ i.c.v. in the mouse tail withdrawal assay. Furthermore, peptide-2 at 5 nmol produced alone a robust and long lasting antinociceptive effect. Moreover, peptide-2 (10 and 40 nmol/kg i.v.) didn't produce any effect per se but antagonized hypotensive actions produced by i.v. administration of N/OFQ. Collectively, these findings demonstrate that [(pF)Phe4,Aib7,Aib11, Arg14,Lys15]N/OFQ-NH2 behaves as a highly potent NOP receptor agonist which produces long lasting effects in vivo and [Nphe1,(pF)Phe4,Aib7,Aib11,Arg14,Lys15]N/OFQ-NH2 acts as a pure and competitive antagonist of the NOP receptor.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Life Science, Lanzhou University, 222 Tian Shui South Road, Lanzhou 730000, PR China.
authors.forename: Ya-li
authors.initials: YL
authors.lastname: Peng
authors.forename: Min
authors.initials: M
authors.lastname: Chang
authors.forename: Shou-liang
authors.initials: SL
authors.lastname: Dong
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Ren-wen
authors.initials: RW
authors.lastname: Han
authors.forename: Guo-xing
authors.initials: GX
authors.lastname: Fu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003106:Colon / Q000187:drug effects / Q000502:physiology; D004594:Electrophysiology; D005260:Female; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists; D018847:Opioid Peptides / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000819:agonists / Q000187:drug effects*; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology; D000094942:Nociceptin Receptor
chemical_list: D009292:Narcotic Antagonists; D018847:Opioid Peptides; D011957:Receptors, Opioid; C512147:nociceptin-amide, (pF)Phe(4)-Aib(7,11)-Arg(14)-Lys(15)-; C512148:nociceptin-amide, Nphe(1)-(pF)Phe(4)-Aib(7,11)-Arg(14)-Lys(15)-; D009270:Naloxone; D000094942:Nociceptin Receptor