Structure-activity relationships of bifunctional cyclic disulfide peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors

Richard S. Agnes, Jinfa Ying, Katalin E. Kövér, Yeon Sun Lee, Peg Davis, Shou wu Ma, Hamid Badghisi, Frank Porreca, Josephine Lai, Victor J. Hruby

Research output: Contribution to journalArticle

18 Scopus citations


Prolonged opioid exposure increases the expression of cholecystokinin (CCK) and its receptors in the central nervous system (CNS), where CCK may attenuate the antinociceptive effects of opioids. The complex interactions between opioid and CCK may play a role in the development of opioid tolerance. We designed and synthesized cyclic disulfide peptides and determined their agonist properties at opioid receptors and antagonist properties at CCK receptors. Compound 1 (Tyr-c[d-Cys-Gly-Trp-Cys]-Asp-Phe-NH2) showed potent binding and agonist activities at δ and μ opioid receptors but weak binding to CCK receptors. The NMR structure of the lead compound displayed similar conformational features of opioid and CCK ligands.

Original languageEnglish (US)
Pages (from-to)1413-1423
Number of pages11
Issue number8
StatePublished - Aug 1 2008



  • Bifunctional peptides
  • G-Protein coupled receptors
  • Multivalent ligands
  • NMR conformation
  • Overlapping pharmacophores
  • Pain
  • Tolerance

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Endocrinology
  • Cellular and Molecular Neuroscience

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