title: Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist - neurokinin-1 antagonist peptidomimetics.
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.
authors.affiliation: 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.
authors.forename: Karel
authors.initials: K
authors.lastname: Guillemyn
authors.affiliation: 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.
authors.forename: Patrycia
authors.initials: P
authors.lastname: Kleczkowska
authors.affiliation: Neuropeptide Laboratory, Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, PL 02-106, Warsaw, Poland. Electronic address: alesniak@imdik.pan.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Lesniak
authors.affiliation: Neuropeptide Laboratory, Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, PL 02-106, Warsaw, Poland. Electronic address: jolantadyniewicz@gmail.com.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Dyniewicz
authors.affiliation: 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Van der Poorten
authors.affiliation: 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.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Van den Eynde
authors.affiliation: Department of Pharmacology, University of Arizona, 1501 N. Campbell Ave, Tucson AZ, 85724-5050, USA. Electronic address: keratti@freemail.hu.
authors.forename: Attila
authors.initials: A
authors.lastname: Keresztes
authors.affiliation: Department of Pharmacology, University of Arizona, 1501 N. Campbell Ave, Tucson AZ, 85724-5050, USA. Electronic address: evarga@email.arizona.edu.
authors.forename: Eva
authors.initials: E
authors.lastname: Varga
authors.affiliation: Department of Pharmacology, University of Arizona, 1501 N. Campbell Ave, Tucson AZ, 85724-5050, USA. Electronic address: lai@email.arizona.edu.
authors.forename: Josephine
authors.initials: J
authors.lastname: Lai
authors.affiliation: Department of Pharmacology, University of Arizona, 1501 N. Campbell Ave, Tucson AZ, 85724-5050, USA. Electronic address: frankp@email.arizona.edu.
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.affiliation: 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.
authors.forename: Nga N
authors.initials: NN
authors.lastname: Chung
authors.affiliation: 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.
authors.forename: Carole
authors.initials: C
authors.lastname: Lemieux
authors.affiliation: 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.
authors.forename: Joanna
authors.initials: J
authors.lastname: Mika
authors.affiliation: 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.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Rojewska
authors.affiliation: 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.
authors.forename: Wioletta
authors.initials: W
authors.lastname: Makuch
authors.affiliation: Animal Physiology and Neurobiology Department, University of Leuven (KU Leuven), Naamsestraat 59, 3000 Leuven, Belgium. Electronic address: Joost.VanDuppen@bio.kuleuven.be.
authors.forename: Joost
authors.initials: J
authors.lastname: Van Duppen
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343, Kraków, Poland. Electronic address: barbara.przewlocka@gmail.com.
authors.forename: Barbara
authors.initials: B
authors.lastname: Przewlocka
authors.affiliation: Animal Physiology and Neurobiology Department, University of Leuven (KU Leuven), Naamsestraat 59, 3000 Leuven, Belgium. Electronic address: Jozef.VandenBroeck@bio.kuleuven.be.
authors.forename: Jozef
authors.initials: J
authors.lastname: Vanden Broeck
authors.affiliation: Neuropeptide Laboratory, Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, PL 02-106, Warsaw, Poland. Electronic address: andrzej@lipkowski.org.
authors.forename: Andrzej W
authors.initials: AW
authors.lastname: Lipkowski
authors.affiliation: 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.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Schiller
authors.affiliation: 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.
authors.forename: Dirk
authors.initials: D
authors.lastname: Tourwé
authors.affiliation: 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.
authors.forename: Steven
authors.initials: S
authors.lastname: Ballet
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008968:Molecular Conformation; D064729:Neurokinin-1 Receptor Antagonists / Q000494:pharmacology*; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D011957:Receptors, Opioid / Q000819:agonists*
chemical_list: D064729:Neurokinin-1 Receptor Antagonists; D057786:Peptidomimetics; D018040:Receptors, Neurokinin-1; D011957:Receptors, Opioid
keywords: Acute pain; Hybrid peptides; NK1R antagonism; Neuropathic pain; Opioid agonism; Tolerance