μ-オピオイド受容体アゴニストとORL-1受容体アンタゴニストから成るキメラペプチドの受容体親和性と鎮痛活性

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-D-Arg-Phe-βAla-NH_2) linked to the ORL-1 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 ORL-1 receptors in mouse brain membranes. In particular, chimeric peptide 2, which consists of dermorphin and Ac-RYYRIK-NH_2 connected by a long spacer, had high binding affinities toward both receptors. In the tail-flick test following intracerebroventricular (i.c.v.) administration of chimeric peptides containing the YRFB sequence (3 and 4) unexpectedly showed much less potent antinociceptive activity (ED_<5O>>100 pmole/mouse). These results suggest the involvement of nociceptin-like effects of the Ac-RYYRIK pharmacophore in the peptides, and the regulation of μ-opioid receptor-mediated antinociception in brain. The present chimeric peptides (2, 3 and 4) may be useful as pharmacological tools for studies on μ-opioid receptor/ORL-1 receptor heterodimers.