Conopeptide-Derived κ-Opioid Agonists (Conorphins): Potent, Selective, and Metabolic Stable Dynorphin A Mimetics with Antinociceptive Properties

Andreas Brust, Daniel E. Croker, Barbara Colless, Lotten Ragnarsson, Åsa Andersson, Kapil Jain, Sonia Garcia-Caraballo, Joel Castro, Stuart M. Brierley, Paul F. Alewood, Richard J. Lewis

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16 Citations (Scopus)


Opioid receptor screening of a conopeptide library led to a novel selective κ-opioid agonist peptide (conorphin T). Intensive medicinal chemistry, guided by potency, selectivity, and stability assays generated a pharmacophore model supporting rational design of highly potent and selective κ-opioid receptor (KOR) agonists (conorphins) with exceptional plasma stability. Conorphins are defined by a hydrophobic benzoprolyl moiety, a double arginine sequence, a spacer amino acid followed by a hydrophobic residue and a C-terminal vicinal disulfide moiety. The pharmacophore model was supported by computational docking studies, revealing receptor-ligand interactions similar to KOR agonist dynorphin A (1-8). A conorphin agonist inhibited colonic nociceptors in a mouse tissue model of chronic visceral hypersensitivity, suggesting the potential of KOR agonists for the treatment of chronic abdominal pain. This new conorphine KOR agonist class and pharmacophore model provide opportunities for future rational drug development and probes for exploring the role of the κ-opioid receptor.

Original languageEnglish
Pages (from-to)2381-2395
Number of pages15
JournalJournal of medicinal chemistry
Issue number6
Publication statusPublished - 24 Mar 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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