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 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.

Evaluation of Receptor Affinity, Analgesic Activity and Cytotoxicity of a Hybrid Peptide, AWL3020

“…This is consistent with the receptor affinity profile of our derivative (very low μOR affinity and reasonable δOR binding). Notably, AWL3020 is weaker an analgesic than our previously reported hybrid JZ031, which additionally was characterized by a fast onset of analgesic activity (Dyniewicz et al 2017).…”

“…Regarding the second option, that the low NK1R affinity is due to the presence of the opioid part, previous reports on the opioid-(anti)tachykinin hybrids provide useful material for comparisons. In the past many papers dealing with such compounds were reported, including a few with our contributions (Matalinska et al 2013;Dyniewicz et al 2017). Yanamoto and co-workers (Yamamoto et al 2007) considered a series of compounds, where an enkephalin fragment was joined with mixed organic/peptide antitachikinin pharmacophore, H-Tyr-D-Ala-Gly-Phe-Xxx-Pro-Leu-Trp-O-3,5-Bzl(CF 3 ) 2 (Bzlbenzyl, Xxx-various amino acids).…”

Antinociceptive and Cytotoxic Activity of Opioid Peptides with Hydrazone and Hydrazide Moieties at the C-Terminus

“…Moreover, in the case of H-Tyr-D-Ala-Gly-Phe-sequence (1), two additional linkers were considered (c, -NH-NH-C(=O)-CH 2 ; and d, -NH-NH-C(=O)-NH-N=CH-). One of the compounds resulting from these efforts, JZ031 (1a), has been already described [33]. In the present contribution, we extend that report by discussing the synthesis, receptor binding, and molecular modelling of further 11 compounds.…”

The analgesic hybrid of dermorphin/substance P and analog of enkephalin improve wound healing in streptozotocin‐induced diabetic rats

“…The biphalin was obtained by classic solution phase synthesis using modified methods described previously by Lipkowski et al and Dyniewicz et al To the synthesis N‐t‐butyloxycarbonyl (Boc) protected amino acids were used. The synthesis were conducted in DMF, N,N′‐dicyclohexylcarbodiimide (DCC)/ N‐hydroxysuccinimide (HOSu)/ 1,1,3,3‐Tetramethylguanidine (TMG) were used as coupling reagents.…”

“…The method was described previously by Niescioruk et al 26 The completion of Fmoc cleavage and coupling reaction was monitored by the Kaiser test. The completed peptide was cleaved from resin by trifluoroacetic acid (TFA) and purified by preparative RP-HPLC using C12 col The biphalin was obtained by classic solution phase synthesis using modified methods described previously by Lipkowski et al 22 and Dyniewicz et al 27 To the synthesis N-t-butyloxycarbonyl (Boc) protected amino acids were used. The synthesis were conducted in DMF, N,N 0dicyclohexylcarbodiimide (DCC)/ N-hydroxysuccinimide (HOSu)/ 1,1,3,3-Tetramethylguanidine (TMG) were used as coupling reagents.…”