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

Takashi Yamamoto, Padma Nair, Neil E. Jacobsen, Josef Vagner, Vinod Kulkarni, Peg Davis, Shou Wu Ma, Edita Navratilova, Henry I. Yamamura, Todd W. Vanderah, Frank Porreca, Josephine Lai, Victor J. Hruby

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5164-5175
Number of pages12
JournalJournal of Medicinal Chemistry
Volume52
Issue number16
DOIs
StatePublished - Aug 27 2009

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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