Format

Send to

Choose Destination
See comment in PubMed Commons below
Biopolymers. 2014 Jan;102(1):107-14. doi: 10.1002/bip.22437.

Translation of structure-activity relationships from cyclic mixed efficacy opioid peptides to linear analogues.

Author information

1
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109.

Erratum in

  • Biopolymers. 2014 Sep;102(5):426.

Abstract

Most opioid analgesics used in the treatment of pain are mu opioid receptor (MOR) agonists. While effective, there are significant drawbacks to opioid use, including the development of tolerance and dependence. However, the coadministration of a MOR agonist with a delta opioid receptor (DOR) antagonist slows the development of MOR-related side effects, while maintaining analgesia. We have previously reported a series of cyclic mixed efficacy MOR agonist/DOR antagonist ligands. Here we describe the transfer of key features from these cyclic analogs to linear sequences. Using the linear MOR/DOR agonist, Tyr-DThr-Gly-Phe-Leu-Ser-NH2 (DTLES), as a lead scaffold, we replaced Phe(4) with bulkier and/or constrained aromatic residues shown to confer DOR antagonism in our cyclic ligands. These replacements failed to confer DOR antagonism in the DTLES analogs, presumably because the more flexible linear ligands can adopt binding poses that will fit in the narrow binding pocket of the active conformations of both MOR and DOR. Nonetheless, the pharmacological profile observed in this series, high affinity and efficacy for MOR and DOR with selectivity relative to KOR, has also been shown to reduce the development of unwanted side effects. We further modified our lead MOR/DOR agonist with a C-terminal glucoserine to improve bioavailability. The resulting ligand displayed high efficacy and potency at both MOR and DOR and no efficacy at KOR.

KEYWORDS:

delta opioid receptor; homology modeling; mixed efficacy; mu opioid receptor

PMID:
24436042
PMCID:
PMC4132888
DOI:
10.1002/bip.22437
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Wiley Icon for PubMed Central
    Loading ...
    Support Center