Australian Journal of Chemistry Australian Journal of Chemistry Society
An international journal for chemical science
RESEARCH ARTICLE

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

Jingjing Wan A , Mehdi Mobli B , Andreas Brust A , Markus Muttenthaler A , Åsa Andersson A , Lotten Ragnarsson A , Joel Castro C , Irina Vetter A , Johnny X. Huang A , Mathias Nilsson D , Stuart M. Brierley C , Matthew A. Cooper A , Richard J. Lewis A and Paul F. Alewood A E
+ Author Affiliations
- Author Affiliations

A Institute of Molecular Bioscience, The University of Queensland, St Lucia, Qld 4072, Australia.

B Centre for Advanced Imaging, The University of Queensland, St Lucia, Qld 4072, Australia.

C The University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, SA 5000, Australia.

D School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK.

E Corresponding author. Email: p.alewood@imb.uq.edu.au

Australian Journal of Chemistry 70(2) 162-171 https://doi.org/10.1071/CH16407
Submitted: 11 July 2016  Accepted: 15 September 2016   Published: 17 October 2016

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.


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