title: Receptor binding properties and antinociceptive effects of chimeric peptides consisting of a micro-opioid receptor agonist and an ORL1 receptor antagonist.
abstract: Receptor binding properties and antinociceptive activities of chimeric peptides linked by spacers were investigated. The peptides consisted of the micro-opioid receptor ligand dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH(2)) or its analog YRFB (Tyr-D-Arg-Phe-betaAla-NH(2)) linked to the ORL1 receptor ligand Ac-Arg-Tyr-Tyr-Arg-Ile-Lys-NH(2) (Ac-RYYRIK-NH(2)). All chimeric peptides were found to possess high receptor binding affinities for both micro-opioid and ORL1 receptors in mouse brain membranes although their binding affinities for both receptors in spinal membranes were significantly lower. Among them, chimeric peptide 2, which consists of dermorphin and Ac-RYYRIK-NH(2) connected by a long spacer, had the highest binding affinity towards both receptors. In the tail-flick test following intrathecal (i.t.) administration to mice, all chimeric peptides showed potent and dose-dependent antinociceptive activities with an ED(50) of 1.34-4.51 (pmol/mouse), nearly comparable to dermorphin alone (ED(50); 1.08 pmol/mouse). In contrast to their micro-opioid receptor binding profiles, intracerebroventricular (i.c.v.) administration of the chimeric peptides resulted in much less potent antinociceptive activity (ED(50) 5.55-100< pmol/mouse) than when administered i.t. (ED(50): 1.34-4.51 pmol/mouse). These results suggest the involvement of nociceptin-like agonistic effects of the Ac-RYYRIK pharmacophore in the peptides, and the regulation of mu-opioid receptor-mediated antinociception in brain. The present chimeric peptides may be useful as pharmacological tools for studies on micro-opioid receptor/ORL1 receptor heterodimers.
authors.affiliation: Tohoku Pharmaceutical University, Komatsushima, Sendai, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Kawano
authors.forename: Risa
authors.initials: R
authors.lastname: Ito
authors.forename: Miharu
authors.initials: M
authors.lastname: Nishiyama
authors.forename: Mai
authors.initials: M
authors.lastname: Kubo
authors.forename: Tomoko
authors.initials: T
authors.lastname: Matsushima
authors.forename: Motoko
authors.initials: M
authors.lastname: Minamisawa
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ambo
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
mesh_terms: D000700:Analgesics / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009292:Narcotic Antagonists; D018847:Opioid Peptides / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D000094942:Nociceptin Receptor
chemical_list: D000700:Analgesics; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010455:Peptides; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; C030058:dermorphin; D000094942:Nociceptin Receptor; C000722287:Oprl1 protein, mouse