title: ORL1 and opioid receptor preferences of nociceptin and dynorphin A analogues with Dmp substituted for N-terminal aromatic residues.
abstract: Nociceptin (NOC) and dynorphin A (DYN) analogues containing 2',6'-dimethylphenylalanine (Dmp) in place of Phe or Tyr in position 1 and/or 4 were synthesized and their metabolic stability and receptor-binding properties were investigated. [Dmp1]NOC(1-13)-NH2 (1) possessed high ORL1 receptor affinity comparable to that of the parent peptide with substantially improved affinities for kappa-, mu-, and delta-opioid receptors. However, Dmp4 substitution of NOC peptide (2) reduced ORL1 receptor affinity. [Dmp1]DYN(1-13)-NH2 (4) and its Dmp4 analogue (5) possessed a 3-fold greater kappa-opioid receptor affinity and improved kappa-receptor selectivity compared to the parent peptide. Analogue 4 however exhibited an unexpectedly low in vitro bioactivity (GPI assay), suggesting, the phenolic hydroxyl group at the N-terminal residue in DYN peptide is extremely important for activation of the kappa-opioid receptor. Analogue 5 possessed an improved kappa-opioid receptor selectivity with an IC50 ratio of 1(kappa)/509(mu)/211598(delta); thus, this peptide may serve as a highly selective kappa-receptor agonist for pharmacological study. Dmp1 substitution in both the NOC and DYN peptides improved metabolic stability toward these peptides, while Dmp4 substitution provided no additional metabolic stability.
authors.affiliation: Tohoku Pharmaceutical University, 4-1 Komatsushima 4-chome, Aoba-ku, Sendai 981-8558, Japan. ysasaki@tohoku-pharm.ac.jp
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Susumu
authors.initials: S
authors.lastname: Kawano
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kohara
authors.forename: Hideko
authors.initials: H
authors.lastname: Watanabe
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ambo
mesh_terms: D000818:Animals; D002460:Cell Line; D004399:Dynorphins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000737:chemistry*; D009292:Narcotic Antagonists; D018847:Opioid Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry; D051381:Rats; D011957:Receptors, Opioid; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D004399:Dynorphins; D006841:Hydrocarbons, Aromatic; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010649:Phenylalanine; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C427023:2',6'-dimethylphenylalanine