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

Peptides. 2008 Aug;29(8):1413-23. doi: 10.1016/j.peptides.2008.03.022. Epub 2008 Apr 10.

Abstract

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-NH(2)) showed potent binding and agonist activities at delta and mu opioid receptors but weak binding to CCK receptors. The NMR structure of the lead compound displayed similar conformational features of opioid and CCK ligands.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Disulfides / chemical synthesis*
  • Disulfides / chemistry
  • Drug Design*
  • Models, Molecular
  • Molecular Sequence Data
  • Narcotic Antagonists
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / chemistry
  • Receptors, Cholecystokinin* / agonists
  • Receptors, Cholecystokinin* / antagonists & inhibitors
  • Receptors, Opioid* / agonists
  • Structure-Activity Relationship

Substances

  • Disulfides
  • Narcotic Antagonists
  • Peptides, Cyclic
  • Receptors, Cholecystokinin
  • Receptors, Opioid