Dermorphin tetrapeptide analogues with 2′,6′-dimethylphenylalanine (Dmp) substituted for aromatic amino acids have high μ opioid receptor binding and biological activities1

To investigate the value of the 2′,6′-dimethylphenylalanine (Dmp) residue as an aromatic amino acid substitution, we prepared analogues of the μ opioid receptor-selective dermorphin tetrapeptide Tyr- -Arg-Phe-βAla-NH2 (YRFB) in which Dmp or its -isomer replaced Tyr1 or Phe3. Replacing Phe3 with Dmp essentially tripled μ receptor affinity and the receptorʹs in vitro biological activities as determined with the guinea pig ileum (GPI) assay but did not change δ receptor affinity. Despite an inversion of the configuration at this position, μ receptor affinity and selectivity remained comparable with those of the -isomer. Replacing the N-terminal Tyr residue with Dmp produced a slightly improved μ 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 Tyr1 and Phe3 produced significantly improved μ receptor affinity and selectivity compared with the singly substituted analogues. Subcutaneous injection of the two analogues, [Dmp3]YRFB and [Dmp1]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.