JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on October 27, 2004; DOI: 10.1124/jpet.104.077339

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jpet.104.077339v1
312/3/1114    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Carra', G.
Right arrow Articles by Calo, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Carra', G.
Right arrow Articles by Calo, G.


Received for publication September 9, 2004.
Revised October 22, 2004.
Accepted for publication October 25, 2004.

[(pF)Phe4,Arg14,Lys15]N/OFQ-NH2 (UFP-102), a highly potent and selective agonist of the nociceptin/orphanin FQ receptor

Giacomo Carra' 1, Anna Rizzi 1, Remo Guerrini 1, Timothy A Barnes 2, John Mc Donald 2, Cristopher P Hebbes 2, Flora Mela 1, Velga A Kenigs 3, Giuliano Marzola 1, Daniela Rizzi 1, Elaine Gavioli 1, Silvia Zucchini 1, Domenico Regoli 1, Michele Morari 1, Severo Salvadori 1, David J Rowbotham 2, David G Lambert 2, Daniel R Kapusta 4, Girolamo Calo 5*

1 University of Ferrara 2 Leicester Royal Infirmary 3 Lousiana State University 4 Louisisa State University 5 Ferrara University

* Address correspondence to: E-mail: g.calo{at}unife.it

Abstract

A novel ligand for the nociceptin/orphanin FQ (N/OFQ) receptor (NOP), [(pF)Phe4,Arg14,Lys15]N/OFQ-NH2 (UFP-102) has been generated by combining in the N/OFQ-NH2 sequence two chemical modifications, [Arg14,Lys15] and [(pF)Phe4], that have been previously demonstrated to increase potency. In vitro, UFP-102 bound with high affinity to the human NOP receptor, showed at least 200-fold selectivity over classical opioid receptors and mimicked N/OFQ effects in CHOhNOP cells, isolated tissues from various species, and mouse cortical synaptosomes releasing 5-HT. UFP-102 showed similar maximal effects but higher potency (2 - 48 fold) relative to N/OFQ. The effects of UFP-102 were sensitive to NOP selective antagonists (J-113397, pA2 7.75 - 8.12 and UFP-101 pA2 6.91 - 7.33) but not to naloxone, and no longer observed in tissues taken from NOP receptor knockout mice (NOP-/-). In vivo, UFP-102 (0.01 - 0.3 nmol, i.c.v.) mimicked the pronociceptive action of N/OFQ (0.1 - 10 nmol, i.c.v.) in the mouse tail withdrawal assay, displaying higher potency and longer lasting effects. The action of UFP-102 was not apparent in NOP-/- mice. Similar results were obtained measuring locomotor activity in mice. In conscious rats, UFP-102 (0.05 nmol, i.c.v.) produced a marked and sustained decrease in heart rate, mean arterial pressure, and urinary sodium excretion and a profound increase in urine flow rate. These effects were comparable to those evoked by N/OFQ at 5 nmol. Collectively, these findings demonstrate that UFP-102 behaves as a highly potent and selective NOP receptor agonist which produces long lasting effects in vivo.


Key words: NOP receptor, cardiovascular and renal functions, isolated tissues, nociceptin/orphanin FQ, recombinant receptors, tail withdrawal assay


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
T. V. Khroyan, N. T. Zaveri, W. E. Polgar, J. Orduna, C. Olsen, F. Jiang, and L. Toll
SR 16435 [1-(1-(Bicyclo[3.3.1]nonan-9-yl)piperidin-4-yl)indolin-2-one], a Novel Mixed Nociceptin/Orphanin FQ/{micro}-Opioid Receptor Partial Agonist: Analgesic and Rewarding Properties in Mice
J. Pharmacol. Exp. Ther., February 1, 2007; 320(2): 934 - 943.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2004 by the American Society for Pharmacology and Experimental Therapeutics.