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. 2016 Nov 1;8(1):73-77.
doi: 10.1021/acsmedchemlett.6b00381. eCollection 2017 Jan 12.

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

Jolanta Dyniewicz  1 , Piotr F J Lipiński  1 , Piotr Kosson  1 , Anna Leśniak  1 , Marta Bochyńska-Czyż  1 , Adriana Muchowska  1 , Dirk Tourwé  2 , Steven Ballet  2 , Aleksandra Misicka  1 , Andrzej W Lipkowski  1
Affiliations

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

Jolanta Dyniewicz et al. ACS Med Chem Lett. .

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 (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 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.

Keywords: Bifunctional ligands; NK1 antagonists; hydrazone linker; opioid agonists.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Synthesis of Compound 1 (JZ031: H-Tyr-d-Ala-Gly-Phe-NH-N=CH-[3′,5′-(CF3)2-Ph])
Figure 1
Figure 1
Contacts of compounds 1, 5, and 6 with the MOR binding site. On the left interactions of the Tyr-d-Ala-Gly-Phe- part common to 1, 5 and 6 are depicted; on the right, interactions of the C-terminal parts of these molecules. The black dot marks the joint between the common part and the rest of the molecule in each case.
Figure 2
Figure 2
Analgesic responses of 1 (JZ031) in four different doses compared to morphine (MF) expressed as % MPE (means ± SEM); n = 6–8. Significance: *p < 0.05; **p < 0.01; ***p < 0.001 as compared to morphine. (a) i.v. administration, plantar test; (b) i.v. administration, tail-flick test; (c) i.th. administration, tail-flick test.
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