ORL1 and opioid receptor preferences of nociceptin and dynorphin A analogues with Dmp substituted for N-terminal aromatic residues Original Research Article

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 κ-, μ-, and δ-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 κ-opioid receptor affinity and improved κ-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 κ-opioid receptor. Analogue 5 possessed an improved κ-opioid receptor selectivity with an IC50 ratio of 1(κ)/509(μ)/211598(δ); thus, this peptide may serve as a highly selective κ-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.