[Nphe(1),Arg(14),Lys(15)]nociceptin-NH2, a novel potent and selective antagonist of the nociceptin/orphanin FQ receptor

1 Nociceptin/orphanin FQ (N/OFQ) modulates several biological functions by activating a speci®c G-protein coupled receptor (NOP). Few molecules are available that selectively activate or block the NOP receptor. Here we describe the in vitro and in vivo pharmacological pro®le of a novel NOP receptor ligand, [Nphe1,Arg14,Lys15]N/OFQ-NH2 (UFP-101). 2 UFP-101 binds to the human recombinant NOP receptor expressed in Chinese hamster ovary (CHO) cells with high a nity (pKi 10.2) and shows more than 3000 fold selectivity over classical opioid receptors. UFP-101 competitively antagonizes the e ects of N/OFQ on GTPg35S binding in CHOhNOP cell membranes (pA2 9.1) and on cyclic AMP accumulation in CHOhNOP cells (pA2 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 [3H]-5-HT, UFP-101 competitively antagonized the e ects of N/OFQ with pA2 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.