Characterization of [Nphe¹]nociceptin(1‐13)NH₂, a new selective nociceptin receptor antagonist

Abstract

1 Nociceptin (orphanin FQ) is a novel neuropeptide capable of inducing a variety of biological actions via activation of a speci®c G-protein coupled receptor. However, the lack of a selective nociceptin receptor antagonist has hampered our understanding of nociceptin actions and the role of this peptide in pathophysiological states. As part of a broader programme of research, geared to the identi®cation and characterization of nociceptin receptor ligands, we report that the novel peptide [Nphe 1 ]nociceptin(1-13)NH 2 acts as the ®rst truly selective and competitive nociceptin receptor antagonist and is devoid of any residual agonist activity. ]nociceptin(1-13)NH 2 is also active in vivo, where it prevents the pronociceptive and antimorphine actions of intracerebroventricularly applied nociceptin, measured in the mouse tail withdrawal assay. Moreover, [Nphe 1 ]nociceptin(1-13)NH 2 produces per se a dose dependent, naloxone resistant antinociceptive action and, at relatively low doses, potentiates morphine-induced analgesia. 4 Collectively our data indicate that [Nphe 1 ]nociceptin(1-13)NH 2 , acting as a nociceptin receptor antagonist, may be the prototype of a new class of analgesics.

[(pF)Phe4,Arg14,Lys15]N/OFQ-NH2 (UFP-102), a Highly Potent and Selective Agonist of the Nociceptin/Orphanin FQ Receptor

“…Currently available ligands for the NOP receptor and their therapeutic potential have been recently reviewed by Zaveri (2003). These are 1) nonpeptide ligands generally discovered via high-throughput screening in industrial laboratories (e.g., the NOPselective antagonists J-113397 (Ozaki et al, 2000) and SB-612111 (Zaratin et al, 2004); 2) small peptides identified by screening of synthetic peptide combinatorial libraries [e.g., the NOP-selective partial agonist Ac-RYYRWK-NH 2 (Dooley et al, 1997) or the nonselective NOP ligand peptide III-BTD (Becker et al, 1999)]; and 3) N/OFQrelated peptides identified by classical structure activity relationship studies (for review, see Guerrini et al, 2000), including the full agonists N/OFQ(1-13)-NH 2 and N/OFQ-NH 2 (Calo et al, 1996), the partial agonist [Phe 1 ⌿(CH 2 -NH)Gly 2 ]N/OFQ(1-13)-NH 2 , and the pure antagonist [Nphe 1 ]N/OFQ(1-13)-NH 2 (Calo et al, 2000a).…”

Study in vitro and in vivo of nociceptin/orphanin FQ(1–13)NH2 analogues substituting N-Me-Gly for Gly2 or Gly3

“…In the present study, we found i. 3 ]NC(1-13)NH 2 suggested that the hydrophobicity of the N-terminal tetrapeptide showed no significant effect on the binding and activating activities of NC to OP 4 receptor, but the flexibility of this region seems to play very important roles in the NC-OP 4 receptor interaction. The present work also helps to provide a novel and simplified method to perform structure-activity study, which could investigate the roles of the hydrophobicity and flexibility of defined fragment in the native peptide at the same time through a simple replacement.…”

“…Taking NC(1-13)NH 2 as a template, a series of analogues were designed and synthesized to study the structure-activity relationship of the N-terminal tetrapeptide of NC [2,3,6,14]. In an attempt to protect NC(1-13)NH 2 from degradation by aminopeptidases, the pseudopeptide [Phe 1 (CH 2 -NH)Gly 2 ]NC(1-13)NH 2 ([F/G]NC(1-13)NH 2 ) was designed [1,2].…”

Characterization of opiates, neuroleptics, and synthetic analogs at ORL1 and opioid receptors

“…It also acted similarly to nociceptin in a variety of in vivo assays, including its action with respect to analgesic activity (Grisel et al, 1998). However, Calo et al (2000) later described a new peptide analog, [NPhe 1 N/OFQ(1-13)NH 2 ], which was a selective and competitive nociceptin antagonist, devoid of any residual agonist activity.…”