M. Kawano, K. Okada, Takeshi Honda
Oct 1, 2002
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Journal
Journal of Peptide Science
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. Copyright © 2002 European Peptide Society and John Wiley & Sons, Ltd.