Discriminatory synergistic effect of Trp-substitutions in superagonist [(Arg/Lys)14, (Arg/Lys)15]nociceptin on ORL1 receptor binding and activation

Hirokazu Nishimura, Jinglan Li, Kaname Isozaki, Kazushi Okada, Ayami Matsushima, Takeru Nose, Tommaso Costa, Yasuyuki Shimohigashi

研究成果: ジャーナルへの寄稿学術誌査読

5 被引用数 (Scopus)


ORL1 is an endogenous G protein-coupled receptor for neuropeptide nociceptin. [(R/K)14, (R/K)15]nociceptin is a superagonist that strongly activates the ORL1 receptor. We have previously found that substituting with Trp can reproduce the potentiation induced by Arg or Lys at position 14. In the present study, in order to ensure the effect of Trp-substitution on the activities of [(R/K)14, (R/K)15]nociceptin, we synthesized [W14, (R/K)15]nociceptin and [(R/K)14, W15]nociceptin. [W14, (R/K)15]nociceptin was found to exhibit threefold higher binding activity and 10-fold greater potency in a functional [35S]GTPγS functional assay as compared to wild-type nociceptin. However, when only Trp was placed in position 15, the resulting analogues, [(R/K)14, W15]nociceptin, showed only a moderate enhancement of binding and biological activity (2-3 fold in both). These results indicate that the placement of Trp at position 14, unlike at position 15, enhances in a synergistic fashion the interaction of nociceptin with the ORL1 receptor. The results indicate that specific interactions feasible for Arg/Lys and Trp in common must be there for aromatic residues in ORL1, thus forming a cation/π interaction or π/π hydrophobic interaction. The necessity for a favorable electrostatic interaction appears strict in position 15.

ジャーナルBioorganic and Medicinal Chemistry
出版ステータス出版済み - 8月 1 2009

!!!All Science Journal Classification (ASJC) codes

  • 生化学
  • 分子医療
  • 分子生物学
  • 薬科学
  • 創薬
  • 臨床生化学
  • 有機化学


「Discriminatory synergistic effect of Trp-substitutions in superagonist [(Arg/Lys)14, (Arg/Lys)15]nociceptin on ORL1 receptor binding and activation」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。