Pharmacological characterization of the novel nociceptin/orphanin FQ receptor ligand, ZP120: in vitro and in vivo studies in mice

Abstract

1 This study reports on the pharmacological characterization of ZP120, a novel ligand of the nociceptin/orphanin FQ (N/OFQ) peptide receptor, NOP. ZP120 is a structure inducing probes modi®ed NOP ligand: Zealand Pharma proprietary SIP technology was used to increase the enzymatic stability and half-life of peptide. 2 In vitro, ZP120 mimicked the inhibitory e ects of N/OFQ in the electrically stimulated mouse vas deferens, showing however higher potency (pEC 50 8.88 vs 7.74), lower maximal e ects (E max 69+5% vs 91+2%), and slower onset of action. Like N/OFQ, the e ects of ZP120 were not modi®ed by 1 mM naloxone, but they were antagonized by the NOP receptor selective antagonist J-113397 (pA 2 7.80 vs ZP120, 7.81 vs N/OFQ). 3 In vivo, ZP120 mimicked the e ects of N/OFQ, producing pronociceptive e ects in the tail withdrawal assay and decreased locomotor activity after i.c.v., but not after i.v. administration in mice. ZP120 elicited similar maximal e ects as N/OFQ, but it was about 10 fold more potent and its e ects lasted longer. 4 In conclusion, the novel NOP receptor ligand ZP120 is a highly potent and selective partial agonist of the NOP receptor with prolonged e ects in vivo.

Pharmacodynamic Characterization of ZP120 (Ac-RYYRWKKKKKKK-NH2), a Novel, Functionally Selective Nociceptin/Orphanin FQ Peptide Receptor Partial Agonist with Sodium-Potassium-Sparing Aquaretic Activity

“…As demonstrated by others, we found that N/OFQ is a potent inhibitor of electrically induced contractions in the MVD preparation (Berzetei-Gurske et al, 1996;Caló et al, 1996;Rizzi et al, 2002) (Fig. 1).…”

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

“…Similar kinetics of action has been reported for other NOP ligands, such as the peptide ZP120 (Rizzi et al, 2002a) and the nonpeptide Ro 64-6198 (Rizzi et al, 2001b). The reason(s) for the differences in kinetic behav- Both pharmacological and knockout findings in vitro converge indicating that UFP-102 is a highly selective ligand whose effects are exclusively due to NOP receptor activation.…”

Nociceptin/orphanin FQ receptor blockade attenuates MPTP-induced parkinsonism

“…These effects, however, do not appear to be physiologically equivalent, motor inhibition being predominant (Marti et al, 2004a). Systemic injection of NOP receptor antagonists or deletion of the NOP receptor gene failed to affect spontaneous locomotion (Gavioli et al, 2003;Kuzmin et al, 2004;Marti et al, 2004a;Rizzi et al, 2007). In line with this view, we did not detect motor facilitation by J-113397 in the bar test (a static test), while there was a prominent effect in tests engaging the animals in repetitive and prolonged movements (i.e.…”