Spontaneous degradation via diketopiperazine formation of peptides containing a tetrahydroisoquinoline-3-carboxylic acid residue in the 2-position of the peptide sequence

The δ-opioid antagonists H-Tyr-Tic-Phe-OH (Tic = tetrahydroisoquinoline-3-carboxylic acid) and H-Tyr-Tic-Phe-Phe-NH₂ were shown to undergo spontaneous Tyr-Tic diketopiperazine formation with concomitant cleavage of the Tic-Phe peptide bond in DMSO but not in aqueous solution at pH 7.7.