Antinociceptive analogs of orphanin FQ/nociceptin(1–11)

Abstract

The presence of pairs of basic amino acids within the sequence of orphanin FQ/nociceptin (OFQ/N) peptide, the endogenous ligand for the ORL 1KOR-3 receptor, has raised the possibility that processing might generate pharmacologically important truncated peptides, including OFQ/N(1–11). OFQ/N(1–11) is pharmacologically active in vivo with a potency comparable to OFQ/N. Several tyrosine-containing analogs of OFQ/N(1–11) have been synthesized and examined for antinociceptive activity. Like OFQ/N(1–11), [Tyr 1]OFQ/N(1–11), [Tyr 10]OFQ/N(1–11) and [IodoTyr 10]OFQ/N(1–11) given supraspinally in mice were antinociceptive in the tailflick assay in mice. The tyrosine analogs showed similar potencies as OFQ/N(1–11) but longer durations of action. This response was readily reversed by the opioid antagonist naloxone despite poor affinities for these analogs at opioid receptors. Another compound, [Tyr 11]OFQ/N(1–11) was highly epileptogenic, inducing naloxone-sensitive seizures in greater than 50% of the mice tested at doses comparable to those examined with the other analogs. These results indicate that it is possible to make analgesic OFQ/N(1–11) analogs. The activity of [IodoTyr 10]OFQ/N(l–l 1) suggests that it may prove useful as a radioligand in exploring potential OFQ/N(1–11) binding sites.