title: Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics.
abstract: Herein, the synthesis and biological evaluation of dual opioid agonists-neurokinin 1 receptor (NK1R) antagonists is described. In these multitarget ligands, the two pharmacophores do not overlap, and this allowed maintaining high NK1R affinity and antagonist potency in compounds 12 and 13. Although the fusion of the two ligands resulted in slightly diminished opioid agonism at the μ- and δ-opioid receptors (MOR and DOR, respectively), as compared to the opioid parent peptide, balanced MOR/DOR activities were obtained. Compared to morphine, compounds 12 and 13 produced more potent antinociceptive effects in both acute (tail-flick) and neuropathic pain models (von Frey and cold plate). Similarly to morphine, analgesic tolerance developed after repetitive administration of these compounds. To our delight, compound 12 did not produce cross-tolerance with morphine and high antihyperalgesic and antiallodynic effects could be reinstated after chronic administration of each of the two compounds.
authors.affiliation: Department of Organic Chemistry, Vrije Universiteit Brussel , Brussels, Belgium.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Betti
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences , Kraków, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Starnowska
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences , Kraków, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Mika
authors.affiliation: Neuropeptide Laboratory, Medical Research Centre, Polish Academy of Sciences , Warsaw, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Dyniewicz
authors.affiliation: Department of Organic Chemistry, Vrije Universiteit Brussel , Brussels, Belgium.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Frankiewicz
authors.affiliation: Department of Organic Chemistry, Vrije Universiteit Brussel , Brussels, Belgium.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Novoa
authors.affiliation: Neuropeptide Laboratory, Medical Research Centre, Polish Academy of Sciences , Warsaw, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Bochynska
authors.affiliation: Department of Pharmacology, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Attila
authors.initials: A
authors.lastname: Keresztes
authors.affiliation: Neuropeptide Laboratory, Medical Research Centre, Polish Academy of Sciences , Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Kosson
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences , Kraków, Poland.
authors.forename: Wioletta
authors.initials: W
authors.lastname: Makuch
authors.affiliation: Animal Physiology and Neurobiology Department, Katholieke Universiteit Leuven (KU Leuven) , Leuven, Belgium.
authors.forename: Joost
authors.initials: J
authors.lastname: Van Duppen
authors.affiliation: Department of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal , Montreal, Canada.
authors.forename: Nga N
authors.initials: NN
authors.lastname: Chung
authors.affiliation: Animal Physiology and Neurobiology Department, Katholieke Universiteit Leuven (KU Leuven) , Leuven, Belgium.
authors.forename: Jozef
authors.initials: J
authors.lastname: Vanden Broeck
authors.affiliation: Neuropeptide Laboratory, Medical Research Centre, Polish Academy of Sciences , Warsaw, Poland.
authors.forename: Andrzej W
authors.initials: AW
authors.lastname: Lipkowski
authors.affiliation: Department of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal , Montreal, Canada.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Schiller
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica NV , Beerse, Belgium.
authors.forename: Frans
authors.initials: F
authors.lastname: Janssens
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica NV , Beerse, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Ceusters
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica NV , Beerse, Belgium.
authors.forename: François
authors.initials: F
authors.lastname: Sommen
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica NV , Beerse, Belgium.
authors.forename: Theo
authors.initials: T
authors.lastname: Meert
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences , Kraków, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Przewlocka
authors.affiliation: Department of Organic Chemistry, Vrije Universiteit Brussel , Brussels, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Tourwé
authors.affiliation: Department of Organic Chemistry, Vrije Universiteit Brussel , Brussels, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Ballet
keywords: Designed multiple ligands; NK1 antagonism; acute pain; neuropathic pain; opioid agonism