Synthesis of Multivalent [Lys8]-Oxytocin Dendrimers that Inhibit Visceral Nociceptive Responses

Jingjing Wan, Mehdi Mobli, Andreas Brust, Markus Muttenthaler, Asa Andersson, Lotten Ragnarsson, Joel Castro, Irina Vetter, Johnny Huang, Mathias Nilsson, Stuart Brierley, Matthew Cooper, Richard Lewis, Paul Alewood

    Research output: Contribution to journalArticlepeer-review

    8 Citations (Scopus)


    Peptide dendrimers are a novel class of precisely defined macromolecules of emerging interest. Here, we describe the synthesis, structure, binding affinity, receptor selectivity, functional activity, and antinociceptive properties of oxytocin-related dendrimers containing up to 16 copies of [Lys8]-oxytocin or LVT. These were generated using a copper(i)-catalyzed azide-alkyne cycloaddition (CuAAc) reaction with azido-pegylated LVT peptides on an alkyne-polylysine scaffold. 2D NMR analysis demonstrated that each attached LVT ligand was freely rotating and maintained identical 3D structures in each dendrimeric macromolecule. The binding affinity Ki at the oxytocin receptor increased approximately 17-, 12-, 3-, and 1.5-fold respectively for the 2-, 4-, 8-, and 16-mer dendrimeric LVT conjugates, compared with monomer azido-pegylated LVT (Ki = 9.5 nM), consistent with a multivalency effect. A similar trend in affinity was also observed at the related human V1a, V1B, and V2 receptors, with no significant selectivity change observed across this family of receptors. All LVT dendrimers were functionally active in vitro on human oxytocin receptors and inhibited colonic nociceptors potently in a mouse model of chronic abdominal pain.

    Original languageEnglish
    Pages (from-to)162-171
    Number of pages10
    JournalAustralian Journal of Chemistry
    Issue number2
    Publication statusPublished - 2017


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