2-Oxopiperazine-based γ-turn conformationally constrained peptides: Synthesis of CCK-4 analogues

2-Oxopiperazine derivatives 1 have been designed as mimetics of γ-turn conformationally constrained tripeptides. The synthetic pathway devised for the preparation of both epimers of 1 at C5 involves a reductive amination of cyanomethyleneamino pseudopeptides with amino acid derivatives, followed by regiospecific lactamization of the resulting C-backbone branched pseudopeptides. The versatility of this methodology is illustrated in the synthesis of analogues of the tetrapeptides Boc-[Nle31]-CCK-4 and Boc-[Lys(o-tolylaminocarbonyl)31]-CCK-4. The introduction of the new conformational restriction into these Boc-CCK-4 analogues led to a loss of 2 or 3 orders of magnitude in the affinity at CCK receptors. These results suggest the absence of a γ-turn in the bioactive conformation of the C-terminal tripeptide of CCK-4.