Hydrazone Linker as a Useful Tool for Preparing Chimeric Peptide/Nonpeptide Bifunctional Compounds. IF 3.794

Jolanta Dyniewicz, Piotr F. J. Lipinski, Piotr Kosson, Anna Lesniak, Marta Bochynska-Czyz, Adriana Muchowska, Dirk Tourwe, Steven Ballet, Aleksandra Misicka, Andrzej W. Lipkowski

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 compound 1 in 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 (IC 50= 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 of 1 exhibited 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.

Original languageEnglish
Pages (from-to)73-77
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume8
Issue number1
DOIs
Publication statusPublished - 12 Jan 2017

Keywords

  • Bifunctional ligands
  • Hydrazone linker
  • NK1 antagonists
  • Opioid agonists

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