Improving metabolic stability by glycosylation: Bifunctional peptide derivatives that are opioid receptor agonists and neurokinin 1 receptor antagonists

In order to obtain a metabolically more stable analgesic peptide derivative, O-β-glycosylated serine (Ser(Glc)) was introduced into TY027 (Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-3′,5′-Bzl(CF₃) ₂) which was a previously reported bifunctional compound with δ/μ opioid agonist and neurokinin-1 receptor antagonist activities and with a half-life of 4.8 h in rat plasma. Incorporation of Ser(Glc) into various positions of TY027 gave analogues with variable bioactivities. Analogue 6 (Tyr-D-Ala-Gly-Phe-Nle-Pro-Leu-Ser(Glc)-Trp-NH-3′,5′-Bzl(CF ₃)₂) was found to have effective bifunctional activities with a well-defined conformation with two β-turns based on the NMR conformational analysis in the presence of DPC micelles. In addition, 6 showed significant improvement in its metabolic stability (70 ± 9% of 6 was intact after 24 h incubation in rat plasma). This improved metabolic stability, along with its effective and δ selective bifunctional activities, suggests that 6 could be an interesting research tool and possibly a promising candidate as a novel analgesic drug.