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

Andreas Brust, Daniel Croker, Barbara Colless, Lotten Ragnarsson, Asa Andersson, Kapil Jain, Sonia Garcia-Caraballo, Joel Castro, Stuart Brierley, Paul Alewood, Richard Lewis

    Research output: Contribution to journalArticle

    15 Citations (Scopus)

    Abstract

    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
    Volume59
    Issue number6
    DOIs
    Publication statusPublished - 24 Mar 2016

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