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Opioid receptor‐like 1 (ORL1) receptor binding and the biological properties of Ac‐Arg‐Tyr‐Tyr‐Arg‐Ile‐Arg‐NH 2 and its analogs
Author(s) -
Ambo A.,
Kohara H.,
Kawano S.,
Sasaki Y.
Publication year - 2007
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.900
Subject(s) - nociceptin receptor , receptor , chemistry , opioid receptor , opioid , stereochemistry , pharmacology , opioid peptide , biochemistry , medicine
Hexapeptides such as Ac‐Arg‐Tyr‐Tyr‐Arg‐Ile‐Lys‐NH 2 and Ac‐Arg‐Tyr‐Tyr‐Arg‐Trp‐Arg‐NH 2 have been isolated from a combinatorial peptide library as small peptide ligands for the opioid peptide‐like 1 (ORL1) receptor. To investigate the detailed structural requirements of hexapeptides, 25 analogs of these hexapeptides, based on the novel analog Ac‐Arg‐Tyr‐Tyr‐Arg‐Ile‐Arg‐NH 2 (1), were synthesized and tested for their ORL1 receptor affinity and agonist/antagonist activity on mouse vas deferens (MVD) tissues. Analog 1 and its Cit 6 ‐analog (10) were found to possess high affinity to the ORL1 receptor, comparable to that of nociceptin/orphanin FQ, and exhibited potent antagonist activity (pA 2 values of 7.77 for 1 and 7.51 for 10, which are higher than that of [NPhe 1 ]nociceptin(1–13)‐NH 2 (6.90) on MVD assay. It was also found that the amino acid residue in position 5 plays a key role in agonist/antagonist activity, i.e. an L ‐configuration aliphatic amino acid is required for potent antagonist activity, while a nonchiral or D ‐configuration residue produces potent agonist activity. These lines of evidence may provide insight into the mechanisms controlling agonist/antagonist switching in the ORL1 receptor, and may also serve to help developing more potent ORL1 agonists and antagonists. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd.