ANTINOCICEPTIVE ANALOGS OF ORPHANIN FQ NOCICEPTIN(1-11)/

The presence of pairs of basic amino acids within the sequence of orph anin FQ/nociceptin (OFQ/N) peptide, the endogenous ligand for the ORL1 /KOR-3 receptor, has raised the possibility that processing might gene rate pharmacologically important truncated peptides, including OFQ/N(1 -11). OFQ/N(1-11) is pharmacologically active in vivo with a potency c omparable 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(1 0)]OFQ/N(1-11) given supraspinally in mice were antinociceptive in the tailflick assay in mice. The tyrosine analogs showed similar potencie s as OFQ/N( 1-11) but longer durations of action. This response was re adily reversed by the opioid antagonist naloxone despite poor affiniti es for these analogs at opioid receptors. Another compound, [Tyr(11)]O FQ/N(1-11) was highly epileptogenic, inducing naloxone-sensitive seizu res in greater than 50% of the mice tested at doses comparable to thos e examined with the other analogs. These results indicate that it is p ossible to make analgesic OFQ/N(1-11) analogs. The activity of [lodoTy r(10)]OFQ/N(1-11) suggests that it may prove useful as a radioligand i n exploring potential OFQ/N(1-11) binding sites. (C) 1998 Elsevier Sci ence Inc.