title: 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 ORL1/KOR-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), [Tyr1]OFQ/N(1-11), [Tyr10]OFQ/N(1-11) and [IodoTyr10]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, [Tyr11]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 [IodoTyr10]OFQ/N(1-11) suggests that it may prove useful as a radioligand in exploring potential OFQ/N(1-11) binding sites.
authors.affiliation: The Cotzias Laboratory of Neuro-Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Mathis
authors.forename: I E
authors.initials: IE
authors.lastname: Goldberg
authors.forename: G C
authors.initials: GC
authors.lastname: Rossi
authors.forename: L
authors.initials: L
authors.lastname: Leventhal
authors.forename: G W
authors.initials: GW
authors.lastname: Pasternak
mesh_terms: D000818:Animals; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009619:Nociceptors / Q000187:drug effects*; D018847:Opioid Peptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D011957:Receptors, Opioid / Q000819:agonists; D000097629:Nociceptin
chemical_list: D018847:Opioid Peptides; D010446:Peptide Fragments; D011957:Receptors, Opioid; D000097629:Nociceptin