Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist - neurokinin-1 antagonist peptidomimetics

Karel Guillemyn, Patrycia Kleczkowska, Anna Lesniak, Jolanta Dyniewicz, Olivier Van der Poorten, Isabelle Van den Eynde, Attila Keresztes, Eva Varga, Josephine Lai, Frank Porreca, Nga N. Chung, Carole Lemieux, Joanna Mika, Ewelina Rojewska, Wioletta Makuch, Joost Van Duppen, Barbara Przewlocka, Jozef Vanden Broeck, Andrzej W. Lipkowski, Peter W. SchillerDirk Tourwé, Steven Ballet

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

A reported mixed opioid agonist - neurokinin 1 receptor (NK1R) antagonist 4 (Dmt-D-Arg-Aba-Gly-(3',5'-(CF3)2)NMe-benzyl) was modified to identify important features in both pharmacophores. The new dual ligands were tested in vitro and subsequently two compounds (lead structure 4 and one of the new analogues 22, Dmt-D-Arg-Aba-β-Ala-NMe-Bn) were selected for in vivo behavioural assays, which were conducted in acute (tail-flick) and neuropathic pain models (cold plate and von Frey) in rats. Compared to the parent opioid compound 33 (without NK1R pharmacophore), hybrid 22 was more active in the neuropathic pain models. Attenuation of neuropathic pain emerged from NK1R antagonism as demonstrated by the pure NK1R antagonist 6. Surprisingly, despite a lower in vitro activity at NK1R in comparison with 4, compound 22 was more active in the neuropathic pain models. Although potent analgesic effects were observed for 4 and 22, upon chronic administration, both manifested a tolerance profile similar to that of morphine and cross tolerance with morphine in a neuropathic pain model in rat.

Original languageEnglish (US)
Pages (from-to)64-77
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume92
DOIs
StatePublished - Mar 6 2015

Keywords

  • Acute pain
  • Hybrid peptides
  • Neuropathic pain
  • NK1R antagonism
  • Opioid agonism
  • Tolerance

ASJC Scopus subject areas

  • Medicine(all)

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    Guillemyn, K., Kleczkowska, P., Lesniak, A., Dyniewicz, J., Van der Poorten, O., Van den Eynde, I., Keresztes, A., Varga, E., Lai, J., Porreca, F., Chung, N. N., Lemieux, C., Mika, J., Rojewska, E., Makuch, W., Van Duppen, J., Przewlocka, B., Vanden Broeck, J., Lipkowski, A. W., ... Ballet, S. (2015). Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist - neurokinin-1 antagonist peptidomimetics. European Journal of Medicinal Chemistry, 92, 64-77. https://doi.org/10.1016/j.ejmech.2014.12.033