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

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.

Nociceptin and dynorphin A analogues containing Dmp in position 1 and/or 4 were synthesized. Dmp is a useful surrogate in producing analogues with novel receptor-binding profiles.Figure optionsDownload as PowerPoint slide