A new selective antagonist of the nociceptin receptor

Abstract

[Phe 1 C(CH 2 -NH)Gly 2 ]NC(1-13)NH 2 has been tested in the electrically stimulated guinea pig ileum and mouse vas deferens, two nociceptin sensitive preparations. The new compound showed per se little or no eect in the two tissues, but it displaced to the right the concentration-response curves of nociceptin in a concentration-dependent manner. Reinscheid et al., 1995) to be the endogenous ligand of the opioid-like orphan receptor (ORL-1). Despite the structural homology of NC and its receptor with the peptides and receptors of the opioid family this peptide/receptor system appears to be pharmacologically distinct from the opioids. During the last two years several papers have described new biological eects mediated by NC both in the periphery and in the central nervous system. Such eects were not modi®ed by naloxone or other more selective opioid receptor antagonists and were considered to be mediated by the activation of a speci®c NC receptor (the ORL-1). Lack of selective NC receptor antagonists prevented a de®nitive pharmacological characterization of ORL-1. In 1997, Kobayashi et al. showed that carbetapentane and rimcazole act as antagonists at the NC receptor. However these compounds showed little anity (IC 50 about 10 mM) and, more importantly, they were found to interact also with other functional sites such as s-, m-, and k-opioid receptors and M 1 -muscarinic receptors. Being non selective, they were therefore considered of little utility for receptor characterization.In the present study, we describe the chemical structure and the in vitro pharmacological eects of [Phe

Further characterization of the ORL1 receptor‐mediated inhibition of noradrenaline release in the mouse brain in vitro

“…Our previous superfusion study on mouse cortex slices had shown that the inhibitory e ect of nociceptin on noradrenaline release was antagonized by the unselective ORL 1 receptor antagonist naloxone benzoylhydrazone (described by Dunnill et al, 1996;Nicholson et al, 1998) and the selective partial ORL 1 agonist [Phe 1 c(CH 2 -NH)Gly 2 ]-nociceptin(1 ± 13)NH 2 (described by Guerrini et al, 1998), suggesting that nociceptin acts via ORL 1 receptors. This view is further supported by our present ®nding that [Tyr 14 ]-nociceptin (identi®ed as a potent ORL 1 receptor ligand by Reinscheid et al, 1995;Berzetei-Gurske et al, 1996;Shimohigashi et al, 1996;Mathis et al, 1997) mimicked the e ect of nociceptin, in a manner sensitive to naloxone benzoylhydrazone.…”

Comparison of the effects of [Phe1Ψ(CH2‐NH)Gly2]Nociceptin (1–13)NH2 in rat brain, rat vas deferens and CHO cells expressing recombinant human nociceptin receptors

“…However, it had been di cult to demonstrate the direct activation of the NC-receptor by NC due to the absence of a selective antagonist for this receptor. Recently, a selective competitive antagonist for the NC-receptor, [Phe 1 C(CH 2 -NH)Gly 2 ]nociceptin(1-13)NH 2 ([F/G]NC(1-13)NH 2 ) has been reported by three of us (GC, RG, RB, Guerrini et al, 1998;Calo' et al, 1998a).…”

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

“…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].…”

“…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]. Studies showed that this pseudopeptide maintains good affinity and shows a variety of activities including antagonist [2,6], partial agonist [10] and agonist [8,11] activities at OP 4 receptor, depending on the tissue preparation. As to the mechanism of the change in chemical terms, the replacement of CO with CH 2 in this pseudopepetide eliminates the possibility of forming hydrogen bonds; at the same time it increases the flexibility of the N-terminal part of the molecule by transforming the amide into an amine function.…”