Replacement of the N-terminal Tyrosine Residue in Opioid Peptides with 3-(2,6-Dimethyl-4-carbamoylphenyl)propanoic Acid (Dcp) Results in Novel Opioid Antagonists

3-(2,6-Dimethyl-4-carbamoylphenyl)propanoic acid (Dcp), a 2‘,6‘-dimethyltyrosine analogue containing a carbamoyl group in place of the hydroxyl function and lacking the amino group, was synthesized. The replacement of Tyr in an enkephalin analogue and in dynorphin A(1-11)-NH₂ with Dcp resulted in the first opioid peptide-derived antagonists that do not contain a phenolic hydroxyl group at the 1-position residue. The cyclic peptide Dcp-c[d-Cys-Gly-Phe(pNO₂)-d-Cys]NH₂ represents a novel, potent μ opioid antagonist.