Structural requirements of nociceptin antagonist Ac-RYYRIK-NH2 for receptor binding

Michiaki Kawano, Kazushi Okada, Takeshi Honda, Takeru Nose, Kazuyasu Sakaguchi, Tommaso Costa, Yasuyuki Shimohigashi

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Ac-RYYRIK-NH2 is a peptide isolated from the peptide library as an antagonist that inhibits the biological activities of nociceptin, a hyperalgesic neuropeptide. In order to clarify the structural requirements of this peptide for binding to the nociceptin receptor ORL1, systematic structure-activity studies were carried out. The result of Ala-scanning indicated that the N-terminal tripeptide RYY(= Arg-Tyr-Tyr) is crucially important for binding to the ORL1 receptor. Residual truncations from the N- or C-terminus revealed the special importance of the N-terminal Arg residue. The removal of protecting groups indicated that the N-terminal acetyl group is essential, but the C-terminal amide group is insignificant. These results indicated the conspicuous importance of acetyl-Arg at position 1 of Ac-RYYRIK-NH2 as a key structure allowing binding to the receptor. To investigate the binding site of this peptide in the ORL1 receptor, we synthesized and assayed a series of analogues of the nociceptin dibasic repeat region, residues 8-13 of RKSARK. None of the derivatives were active. Ac-RYYRIK-NH2 was inactive for the μ opioid receptor to which nociceptin binds with considerable strength. All the results suggested that the mode of binding between Ac-RYYRIK-NH2 and the ORL1 receptor is different to that between the ORL1 receptor and nociceptin, and that it may consist of interaction with the receptor site to which nociceptin(1-7) or -(14-17) binds.

Original languageEnglish
Pages (from-to)561-569
Number of pages9
JournalJournal of Peptide Science
Volume8
Issue number10
DOIs
Publication statusPublished - Oct 1 2002

Fingerprint

Peptides
Peptide Library
Opioid Receptors
Bioactivity
Neuropeptides
Amides
Binding Sites
nociceptin
nociceptin receptor
Derivatives
Scanning

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Kawano, M., Okada, K., Honda, T., Nose, T., Sakaguchi, K., Costa, T., & Shimohigashi, Y. (2002). Structural requirements of nociceptin antagonist Ac-RYYRIK-NH2 for receptor binding. Journal of Peptide Science, 8(10), 561-569. https://doi.org/10.1002/psc.415

Structural requirements of nociceptin antagonist Ac-RYYRIK-NH2 for receptor binding. / Kawano, Michiaki; Okada, Kazushi; Honda, Takeshi; Nose, Takeru; Sakaguchi, Kazuyasu; Costa, Tommaso; Shimohigashi, Yasuyuki.

In: Journal of Peptide Science, Vol. 8, No. 10, 01.10.2002, p. 561-569.

Research output: Contribution to journalArticle

Kawano, M, Okada, K, Honda, T, Nose, T, Sakaguchi, K, Costa, T & Shimohigashi, Y 2002, 'Structural requirements of nociceptin antagonist Ac-RYYRIK-NH2 for receptor binding', Journal of Peptide Science, vol. 8, no. 10, pp. 561-569. https://doi.org/10.1002/psc.415
Kawano, Michiaki ; Okada, Kazushi ; Honda, Takeshi ; Nose, Takeru ; Sakaguchi, Kazuyasu ; Costa, Tommaso ; Shimohigashi, Yasuyuki. / Structural requirements of nociceptin antagonist Ac-RYYRIK-NH2 for receptor binding. In: Journal of Peptide Science. 2002 ; Vol. 8, No. 10. pp. 561-569.
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