Design and synthesis of novel hydrazide-linked bifunctional peptides as δ/μ opioid receptor agonists and CCK-1/CCK-2 receptor antagonists

Yeon Sun Lee, Richard S. Agnes, Hamid Badghisi, Peg Davis, Shou Wu Ma, Josephine Lai, Frank Porreca, Victor J. Hruby

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

A series of hydrazide-linked bifunctional peptides designed to act as agonists for δ/μ opioid receptors and antagonists for CCK-1/CCK-2 receptors was prepared and tested for binding to both opioid and CCK receptors and in functional assays. SAR studies in the CCK region examined the structural requirements for the side chain groups at positions 1′, 2′, and 4′ and for the N-terminal protecting group, which are related to interactions not only with CCK, but also with opioid receptors. Most peptide ligands that showed high binding affinities (0.1 - 10 nM) for both δ and μ opioid receptors generally showed lower binding affinities (micromolar range) at CCK-1 and CCK-2 receptors, but were potent CCK receptor antagonists in the GPI/LMMP assay (up to Ke = 6.5 nM). The results indicate that it is reasonable to design chimeric bifunctional peptide ligands for different G-protein coupled receptors in a single molecule.

Original languageEnglish (US)
Pages (from-to)1773-1780
Number of pages8
JournalJournal of Medicinal Chemistry
Volume49
Issue number5
DOIs
StatePublished - Mar 5 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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