Receptor Binding Properties and Antinociceptive Effects of Chimeric Peptides Consisting of a μ-Opioid Receptor Agonist and an ORL1 Receptor Antagonist(Medicinal Chemistry)

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概要

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• Receptor binding properties and antinociceptive activities of chimeric peptides linked by spacers were investigated. The peptides consisted of the μ-opioid receptor ligand dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH_2) or its analog YRFB (Tyr-o-Arg-Phe-βAla-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 μ-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 μ-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 μ-opioid receptor-mediated antinociception in brain. The present chimeric peptides may be useful as pharmacological tools for studies on μ-opioid receptor/ORLl receptor heterodimers.

• 2007-07-01

著者

• AMBO Akihiro

  Tohoku Pharmaceutical University

• SASAKI Yusuke

  Tohoku Pharmaceutical University

• Ambo A

  Tohoku Pharmaceutical University

• Sasaki Y

  Tohoku Pharmaceutical University

• Sasaki Y

  Institute Of Natural Medicine University Of Toyama

• Matsushima Tomoko

  Tohoku Pharmaceutical University

• KAWANO Susumu

  Tohoku Pharmaceutical University

• ITO Risa

  Tohoku Pharmaceutical University

• NISHIYAMA Miharu

  Tohoku Pharmaceutical University

• KUBO Mai

  Tohoku Pharmaceutical University

• MINAMISAWA Motoko

  Tohoku Pharmaceutical University

• Sasaki Youhei

  Faculty Of Pharmaceutical Sciences Hoshi University

• Sasaki Yusuke

  Tohoku College Of Pharmacy

• Sasaki Yohei

  Department Of Medicinal Plant Science Hoshi University

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