title: Opioid receptor-like 1 (ORL1) receptor binding and the biological properties of Ac-Arg-Tyr-Tyr-Arg-Ile-Arg-NH2 and its analogs.
abstract: 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.
authors: Department of Biochemistry, Tohoku Pharmaceutical University, Sendai 981-8558, Japan.
authors: A
authors: A
authors: Ambo
authors: H
authors: H
authors: Kohara
authors: S
authors: S
authors: Kawano
authors: Y
authors: Y
authors: Sasaki
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000378:metabolism* / Q000494:pharmacology; D011957:Receptors, Opioid / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects; D000094942:Nociceptin Receptor
chemical_list: D009842:Oligopeptides; D011957:Receptors, Opioid; C524810:acetyl-arginyl-tyrosyl-tyrosyl-arginyl-isoleucyl-argininamide; D000094942:Nociceptin Receptor