Journal
PEPTIDES
Volume 29, Issue 8, Pages 1413-1423Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.peptides.2008.03.022
Keywords
multivalent ligands; bifunctional peptides; overlapping pharmacophores; G-protein coupled receptors; pain; tolerance; NMR conformation
Funding
- NIDA NIH HHS [P01 DA006284, R37 DA012394, P01 DA006284-17, DA06284, DA12394, R37 DA012394-08] Funding Source: Medline
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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 8 and L opioid receptors but weak binding to CCK receptors. The NMR structure of the lead compound displayed similar conformational features of opioid and CCK ligands. (c) 2008 Elsevier Inc. All rights reserved.
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