Synthesis of multivalent [Lys8]-oxytocin dendrimers that inhibit visceral nociceptive responses

Wan, Jingjing, Mobli, Mehdi, Brust, Andreas, Muttenthaler, Markus, Andersson, Asa, Ragnarsson, Lotten, Castro, Joel, Vetter, Irina, Huang, Johnny X., Nilsson, Mathias, Brierley, Stuart M., Cooper, Matthew A., Lewis, Richard J. and Alewood, Paul F. (2017) Synthesis of multivalent [Lys8]-oxytocin dendrimers that inhibit visceral nociceptive responses. Australian Journal of Chemistry, 70 2: 162-171. doi:10.1071/CH16407

Author Wan, Jingjing
Mobli, Mehdi
Brust, Andreas
Muttenthaler, Markus
Andersson, Asa
Ragnarsson, Lotten
Castro, Joel
Vetter, Irina
Huang, Johnny X.
Nilsson, Mathias
Brierley, Stuart M.
Cooper, Matthew A.
Lewis, Richard J.
Alewood, Paul F.
Title Synthesis of multivalent [Lys8]-oxytocin dendrimers that inhibit visceral nociceptive responses
Formatted title
Synthesis of multivalent [Lys8]-oxytocin dendrimers that inhibit visceral nociceptive responses
Journal name Australian Journal of Chemistry   Check publisher's open access policy
ISSN 1445-0038
Publication date 2017-02-01
Year available 2016
Sub-type Article (original research)
DOI 10.1071/CH16407
Open Access Status Not yet assessed
Volume 70
Issue 2
Start page 162
End page 171
Total pages 10
Place of publication Clayton, VIC, Australia
Publisher C S I R O Publishing
Language eng
Formatted abstract
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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

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