title: Hydrazone Linker as a Useful Tool for Preparing Chimeric Peptide/Nonpeptide Bifunctional Compounds.
abstract: The area of multitarget compounds, joining two pharmacophores within one molecule, is a vivid field of research in medicinal chemistry. Not only pharmacophoric elements are essential for the design and activity of such compounds, but the type and length of linkers used to connect them are also crucial. In the present contribution, we describe compound1in which a typical opioid peptide sequence is combined with a fragment characteristic for neurokinin-1 receptor (NK1R) antagonists through a hydrazone bridge. The compound has a high affinity for μ- and δ-opioid receptors (IC50= 12.7 and 74.0 nM, respectively) and a weak affinity for the NK1R. Molecular modeling and structural considerations explain the observed activities. In in vivo test, intrathecal and intravenous administrations of1exhibited a strong analgesic effect, which indicates potential BBB penetration. This letter brings an exemplary application of the hydrazone linker for fast, facile, and successful preparation of chimeric compounds.
authors.affiliation: Department of Neuropeptides, Mossakowski Medical Research Centre Polish Academy of Sciences , 5 Pawińskiego Str., 02-106 Warsaw, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Dyniewicz
authors.affiliation: Department of Neuropeptides, Mossakowski Medical Research Centre Polish Academy of Sciences , 5 Pawińskiego Str., 02-106 Warsaw, Poland.
authors.forename: Piotr F J
authors.initials: PF
authors.lastname: Lipiński
authors.affiliation: Department of Neuropeptides, Mossakowski Medical Research Centre Polish Academy of Sciences , 5 Pawińskiego Str., 02-106 Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Kosson
authors.affiliation: Department of Neuropeptides, Mossakowski Medical Research Centre Polish Academy of Sciences , 5 Pawińskiego Str., 02-106 Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Leśniak
authors.affiliation: Department of Neuropeptides, Mossakowski Medical Research Centre Polish Academy of Sciences , 5 Pawińskiego Str., 02-106 Warsaw, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Bochyńska-Czyż
authors.affiliation: Department of Neuropeptides, Mossakowski Medical Research Centre Polish Academy of Sciences , 5 Pawińskiego Str., 02-106 Warsaw, Poland.
authors.forename: Adriana
authors.initials: A
authors.lastname: Muchowska
authors.affiliation: Research Group of Organic Chemistry, Departments of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel , Pleinlaan 2, B-1050 Brussels, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Tourwé
authors.affiliation: Research Group of Organic Chemistry, Departments of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel , Pleinlaan 2, B-1050 Brussels, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Ballet
authors.affiliation: Department of Neuropeptides, Mossakowski Medical Research Centre Polish Academy of Sciences , 5 Pawińskiego Str., 02-106 Warsaw, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Misicka
authors.affiliation: Department of Neuropeptides, Mossakowski Medical Research Centre Polish Academy of Sciences , 5 Pawińskiego Str., 02-106 Warsaw, Poland.
authors.forename: Andrzej W
authors.initials: AW
authors.lastname: Lipkowski
keywords: Bifunctional ligands; NK1 antagonists; hydrazone linker; opioid agonists