Novel Opioid Peptide Derived Antagonists Containing (2S)-2-Methyl-3-(2,6-dimethyl-4-carbamoylphenyl)propanoic Acid [(2S)-Mdcp]

A synthesis of the novel tyrosine analogue (2S)-2-methyl-3-(2,6-dimethyl-4-carbamoylphenyl)propanoic acid [(2S)-Mdcp] (15) was developed. In (2S)-Mdcp, the amino and hydroxyl groups of 2′,6′-dimethyltyrosine are replaced by a methyl and a carbamoyl group, respectively, and its substitution for Tyr¹ in opioid agonist peptides resulted in compounds showing antagonism at all three opioid receptors. The cyclic peptide (2S)-Mdcp-c[d-Cys-Gly-Phe(pNO₂)-d-Cys]NH₂ (1) was a potent and selective μ antagonist, whereas (2S)-Mdcp-c[d-Pen-Gly-Phe(pF)-Pen]-Phe-OH (3) showed subnanomolar δ antagonist activity and extraordinary δ selectivity.