Design of δ-opioid peptide antagonists for emerging drug applications

The need for delta-receptor-selective opioid antagonists has led to their development based on structure-activity relationships of delta- and mu-opioid agonists. The unusual amino acid 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), found in a series of H-Tyr-Tic-Phe-(Phe)-OH peptides, is an essential feature of derivatives discussed in this article. Elimination of Phe yields the H-Tyr-Tic-OH dipeptide antagonists, while substitution of Tyr by 2',6'-dimethyl-L-tyrosine (Dmt) gives H-Dmt-Tic-OH and numerous potent, high-affinity and ultraselective delta-opioid antagonists. This article reviews the emergence of derivatives based on the Tyr-Tic and Dmt-Tic pharmacophores as lead structures, and discusses potential clinical and therapeutic applications.