[Nphe¹,Arg¹⁴,Lys¹⁵]Nociceptin‐NH₂, a novel potent and selective antagonist of the nociceptin/orphanin FQ receptor

Abstract

2 UFP-101 binds to the human recombinant NOP receptor expressed in Chinese hamster ovary (CHO) cells with high a nity (pK i 10.2) and shows more than 3000 fold selectivity over classical opioid receptors. UFP-101 competitively antagonizes the e ects of N/OFQ on GTPg 35 S binding in CHO hNOP cell membranes (pA 2 9.1) and on cyclic AMP accumulation in CHO hNOP cells (pA 2 7.1), being per se inactive at concentrations up to 10 mM. 3 In isolated peripheral tissues of mice, rats and guinea-pigs, and in rat cerebral cortex synaptosomes preloaded with [ 3 H]-5-HT, UFP-101 competitively antagonized the e ects of N/OFQ with pA 2 values in the range of 7.3 ± 7.7. In the same preparations, the peptide was inactive alone and did not modify the e ects of classical opioid receptor agonists. 4 UFP-101 is also active in vivo where it prevented the depressant action on locomotor activity and the pronociceptive e ect induced by 1 nmol N/OFQ i.c.v. in the mouse. In the tail withdrawal assay, UFP-101 at 10 nmol produces per se a robust and long lasting antinociceptive e ect. 5 UFP-101 is a novel, potent and selective NOP receptor antagonist which appears to be a useful tool for future investigations of the N/OFQ-NOP receptor system.

Nociceptin/Orphanin FQ Modulates Motor Behavior and Primary Motor Cortex Output Through Receptors Located in Substantia Nigra Reticulata

“…It is noteworthy that motor activation was induced by doses of UFP-101 (1 nmol i.c.v.) that were found ineffective in modulating spontaneous locomotion (Kuzmin et al, 2004;Gavioli et al, 2003;Rizzi et al, 2007;Sakoori and Murphy, 2008), pain (Calò et al, 2002(Calò et al, , 2005Rizzi et al, 2006) or depression (Gavioli et al, 2003). This finding strengthens the view that exercise-induced movement is the most sensitive biological parameter influenced by endogenous N/OFQ, possibly due to phasic release of N/OFQ under motor activation (Marti et al, 2005).…”

In vitro and in vivo studies on UFP-112, a novel potent and long lasting agonist selective for the nociceptin/orphanin FQ receptor

“…The electrically evoked contractions (twitches) were measured isotonically with a strain gauge transducer (Basile 7006) and recorded with the PC based acquisition system PowerLab 4/25 (model ML845, ADInstruments, Australia). After an equilibration period of about 60 min, the contractions induced by electrical field stimulation were stable; at this time, cumulative concentration-response curves to N/OFQ or UFP-112 were performed (0.5 log-unit step) in the absence or in presence of antagonists (the selective NOP receptor antagonist UFP-101 [11], or the non selective classical opioid receptor antagonist naloxone, (15 min preincubation time).…”

Nociceptin/orphanin FQ receptor blockade attenuates MPTP-induced parkinsonism

“…N/OFQ inhibits the activity of DA neurons located in the SN compacta (SNc; Marti et al, 2004a) and impairs spontaneous (Reinscheid et al, 1995;Devine et al, 1996) and exercise-induced locomotion (Marti et al, 2004a) in rodents. Conversely, selective NOP receptor antagonists, such as [Nphe 1 , Arg 14 , Lys 15 ]N/OFQ-NH 2 (UFP-101; Calò et al, 2002) and 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H benzimidazol-2-one (J-113397 or compound B; Kawamoto et al, 1999) increase striatal DA release and rotarod performance (Marti et al, 2004a), indicating that endogenous N/OFQ exerts an inhibitory control on physiologically-stimulated locomotion. We have proposed that endogenous N/OFQ plays a pathogenic role in PD (Marti et al, 2005).…”