Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/105327
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Type: Journal article
Title: Synthesis of multivalent [Lys⁸]-oxytocin dendrimers that inhibit visceral nociceptive responses
Other Titles: Synthesis of multivalent [Lys(8)]-oxytocin dendrimers that inhibit visceral nociceptive responses
Author: Wan, J.
Mobli, M.
Brust, A.
Muttenthaler, M.
Andersson, Å.
Ragnarsson, L.
Castro, J.
Vetter, I.
Huang, J.
Nilsson, M.
Brierley, S.
Cooper, M.
Lewis, R.
Alewood, P.
Citation: Australian Journal of Chemistry: an international journal for chemical science, 2017; 70(2):162-171
Publisher: CSIRO Publishing
Issue Date: 2017
ISSN: 0004-9425
1445-0038
Statement of
Responsibility: 
Jingjing Wan, Mehdi Mobli, Andreas Brust, Markus Muttenthaler, Åsa Andersson, Lotten Ragnarsson, Joel Castro, Irina Vetter, Johnny X. Huang, Mathias Nilsson, Stuart M. Brierley C, Matthew A. Cooper, Richard J. Lewis and Paul F. Alewood
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.
Description: Asa Andersson
Rights: Journal compilation © CSIRO 2017
DOI: 10.1071/CH16407
Grant ID: http://purl.org/au-research/grants/nhmrc/1063803
http://purl.org/au-research/grants/arc/DE150100784
http://purl.org/au-research/grants/arc/FT110100925
http://purl.org/au-research/grants/arc/FT130101215
Published version: http://dx.doi.org/10.1071/ch16407
Appears in Collections:Aurora harvest 8
Chemistry publications

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