Dermorphin tetrapeptide analogues with 2', 6'-dimethylphenylalanine (Dmp) substituted for aromatic amino acids have high μ opioid receptor binding and biological activities

• Published in: Bioorganic & medicinal chemistry letters Vol. 13; no. 7; pp. 1269 - 1272
• Main Authors: AMBO, Akihiro, NIIZUMA, Hideko, SASAKI, Ai, KOHARA, Hirokazu, SASAKI, Yusuke
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 07.04.2003
• Subjects: Amino Acids, Aromatic - chemistry; Analgesics, Opioid - chemical synthesis; Analgesics, Opioid - metabolism; Analgesics, Opioid - pharmacology; Animals; Biological and medical sciences; Dose-Response Relationship, Drug; Enkephalin, Ala-MePhe-Gly- - metabolism; Guinea Pigs; Ileum - drug effects; In Vitro Techniques; Indicators and Reagents; Kinetics; Male; Medical sciences; Mice; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Oligopeptides - chemical synthesis; Oligopeptides - metabolism; Oligopeptides - pharmacology; Opioid Peptides; Pain Measurement - drug effects; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Phenylalanine - analogs & derivatives; Phenylalanine - chemistry; Receptors, Opioid, mu - antagonists & inhibitors; Receptors, Opioid, mu - metabolism; Vas Deferens - drug effects; Peptides; Rodentia; μ Opioid receptor; Smooth muscle; Selectivity; Ileum; In vitro; Vas deferens; Vertebrata; Biological fixation; Mammalia; Guinea pig; Structure activity relation; Mouse; Tetrapeptide; Animal; Peptide synthesis; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00110-0

To investigate the value of the 2',6'-dimethylphenylalanine (Dmp) residue as an aromatic amino acid substitution, we prepared analogues of the mu opioid receptor-selective dermorphin tetrapeptide Tyr-D-Arg-Phe-betaAla-NH(2) (YRFB) in which Dmp or its D-isomer replaced Tyr(1) or Phe(3). Replacing Phe(3) with Dmp essentially tripled mu receptor affinity and the receptor's in vitro biological activities as determined with the guinea pig ileum (GPI) assay but did not change delta receptor affinity. Despite an inversion of the D configuration at this position, mu receptor affinity and selectivity remained comparable with those of the L-isomer. Replacing the N-terminal Tyr residue with Dmp produced a slightly improved mu receptor affinity and a potent GPI activity, even though the substituted compound lacks the side chain phenolic hydroxyl group at the N-terminal residue. Dual substitution of Dmp for Tyr(1) and Phe(3) produced significantly improved mu receptor affinity and selectivity compared with the singly substituted analogues. Subcutaneous injection of the two analogues, [Dmp(3)]YRFB and [Dmp(1)]YRFB, in mice produced potent analgesic activities that were greater than morphine in the formalin test. These lines of evidence suggest that the Dmp residue would be an effective aromatic amino acid surrogate for both Tyr and Phe in the design and development of novel opioid mimetics.