Novel opioid peptide derived antagonists containing (2S)-2-methyl-3-(2,6-dimethyl-4-carbamoylphenyl)propanoic acid [(2S)-Mdcp]

摘要

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 Tyr(1) in opioid agonist peptides resulted in compounds showing antagonism at all three opioid receptors. The cyclic peptide (2S)Mdcp-c[D-Cys-Gly-Phe(pNO(2))-D-Cys]NH2 (1) Was a potent and selective mu antagonist, whereas (2S)-Mdcp-C[D-Pen-GIy-Phe(pF)-Pen]-Phe-OH (3) showed subnanomolar delta antagonist activity and extraordinary delta selectivity.