2. Academic Validation
  3. Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist - neurokinin-1 antagonist peptidomimetics

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

  • Eur J Med Chem. 2015 Mar 6:92:64-77. doi: 10.1016/j.ejmech.2014.12.033.
Karel Guillemyn 1,  Patrycia Kleczkowska 2,  Anna Lesniak 3,  Jolanta Dyniewicz 4,  Olivier Van der Poorten 5,  Isabelle Van den Eynde 6,  Attila Keresztes 7,  Eva Varga 8,  Josephine Lai 9,  Frank Porreca 10,  Nga N Chung 11,  Carole Lemieux 12,  Joanna Mika 13,  Ewelina Rojewska 14,  Wioletta Makuch 15,  Joost Van Duppen 16,  Barbara Przewlocka 17,  Jozef Vanden Broeck 18,  Andrzej W Lipkowski 19,  Peter W Schiller 20,  Dirk Tourwé 21,  Steven Ballet 22
Affiliations

Affiliations

  • 1 Laboratory of Organic Chemistry, Departments of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium. Electronic address: kguillem@vub.ac.be.
  • 2 Neuropeptide Laboratory, Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, PL 02-106, Warsaw, Poland; Department of Pharmacodynamics, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, Warsaw, Poland. Electronic address: hazufiel@wp.pl.
  • 3 Neuropeptide Laboratory, Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, PL 02-106, Warsaw, Poland. Electronic address: alesniak@imdik.pan.pl.
  • 4 Neuropeptide Laboratory, Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, PL 02-106, Warsaw, Poland. Electronic address: jolantadyniewicz@gmail.com.
  • 5 Laboratory of Organic Chemistry, Departments of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium. Electronic address: Olivier.Van.Der.Poorten@vub.ac.be.
  • 6 Laboratory of Organic Chemistry, Departments of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium. Electronic address: vandeneynde.isabelle@gmail.com.
  • 7 Department of Pharmacology, University of Arizona, 1501 N. Campbell Ave, Tucson AZ, 85724-5050, USA. Electronic address: keratti@freemail.hu.
  • 8 Department of Pharmacology, University of Arizona, 1501 N. Campbell Ave, Tucson AZ, 85724-5050, USA. Electronic address: evarga@email.arizona.edu.
  • 9 Department of Pharmacology, University of Arizona, 1501 N. Campbell Ave, Tucson AZ, 85724-5050, USA. Electronic address: lai@email.arizona.edu.
  • 10 Department of Pharmacology, University of Arizona, 1501 N. Campbell Ave, Tucson AZ, 85724-5050, USA. Electronic address: frankp@email.arizona.edu.
  • 11 Department of Chemical Biology and Peptide Research, Clinical Research Institute, 110 Avenue Des Pins Ouest, Montreal, QC, H2W1R7, Canada. Electronic address: NgocNga.chung@ircm.qc.ca.
  • 12 Department of Chemical Biology and Peptide Research, Clinical Research Institute, 110 Avenue Des Pins Ouest, Montreal, QC, H2W1R7, Canada. Electronic address: carole-lemieux@hotmail.com.
  • 13 Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343, Kraków, Poland. Electronic address: joamika@if-pan.krakow.pl.
  • 14 Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343, Kraków, Poland. Electronic address: rojewska@if-pan.krakow.pl.
  • 15 Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343, Kraków, Poland. Electronic address: makuch@if-pan.krakow.pl.
  • 16 Animal Physiology and Neurobiology Department, University of Leuven (KU Leuven), Naamsestraat 59, 3000 Leuven, Belgium. Electronic address: Joost.VanDuppen@bio.kuleuven.be.
  • 17 Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343, Kraków, Poland. Electronic address: barbara.przewlocka@gmail.com.
  • 18 Animal Physiology and Neurobiology Department, University of Leuven (KU Leuven), Naamsestraat 59, 3000 Leuven, Belgium. Electronic address: Jozef.VandenBroeck@bio.kuleuven.be.
  • 19 Neuropeptide Laboratory, Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, PL 02-106, Warsaw, Poland. Electronic address: andrzej@lipkowski.org.
  • 20 Department of Chemical Biology and Peptide Research, Clinical Research Institute, 110 Avenue Des Pins Ouest, Montreal, QC, H2W1R7, Canada. Electronic address: Peter.Schiller@ircm.qc.ca.
  • 21 Laboratory of Organic Chemistry, Departments of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium. Electronic address: datourwe@vub.ac.be.
  • 22 Laboratory of Organic Chemistry, Departments of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium. Electronic address: sballet@vub.ac.be.
PMID: 25544687 DOI: 10.1016/j.ejmech.2014.12.033
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.

Keywords

Acute pain; Hybrid peptides; NK1R antagonism; Neuropathic pain; Opioid agonism; Tolerance.

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