A high affinity, mu-opioid receptor-selective enkephalin analogue lacking an N-terminal tyrosine

We report a high affinity, μ opioid receptor selective enkephalin analogue in which the N-terminal tyrosine residue thought to be required for such high affinity is replaced by phenylalanine. The high affinity can be traced to a shift of the ligand's N-terminal residue within the μ receptor binding pocket, which diminishes the importance of the usual hydrogen bond between the tyrosine phenolic moiety and the receptor. The synthesis of the potent μ opioid receptor agonist JH-54 is described.