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Amino Acids

, Volume 51, Issue 10–12, pp 1527–1545 | Cite as

Synthesis, characterization and anticonvulsant activity of new series of N-modified analogues of VV-hemorphin-5 with aminophosphonate moiety

  • Petar TodorovEmail author
  • Petia Peneva
  • Jana Tchekalarova
  • Miroslav Rangelov
  • Stela Georgieva
  • Nadezhda Todorova
Original Article
  • 75 Downloads

Abstract

A new series of N-modified analogues of the VV-hemorphin-5 with aminophosphonate moiety have been synthesized, characterized and investigated for anticonvulsant activity. The novel peptide analogues were prepared by solid-phase peptide synthesis–Fmoc-strategy and were evaluated in the timed intravenous pentylenetetrazole infusion test (ivPTZ) and 6-Hz psychomotor seizure test in mice. The acute neurological toxicity was determined using the rotarod test. The redox potentials at glass carbonic electrode (GC) and the acid/base properties as pKa values of these peptide analogues were compared with the electrochemical behaviour of tyrosine- and tryptophan-containing peptides using different voltamperometric modes. Among the five tested peptide analogues, V3p was the most active against the ivPTZ test with effect comparable to that of the VV-hemorphin-5 (V1) used as a positive control. Dose-dependent elevation of the seizure threshold for myoclonic twitch and generalized clonic seizures was observed after i.c.v. administration of V2p, V4p and V5p as well as for forelimbs tonus in V4p peptides. The peptide analogues V2p–V5p were able to suppress dose-dependent psychomotor seizures in the 6-Hz test. In contrast, the V6p peptide showed either a pro-convulsant effect in the iv PTZ test or was inactive in the 6-Hz test. No changes in motor coordination were noted with the novel peptides. Docking study results suggest that kappa opioid receptor binding could be the mechanism of action of peptide derivatives with anticonvulsant activity. The results suggest that incorporation of aminophosphonate moiety at position 1 of the VV-hemorphin-5 scaffold deserve further evaluation in models of epilepsy and derivatization.

Keywords

Hemorphin analogues SPPS Aminophosphonates Anticonvulsant activity Molecular docking Electrochemistry 

Notes

Acknowledgements

This work was financially supported by the Bulgarian National Scientific Fund project КП-06-OПP 03/3 of the Ministry of Education and Science, Bulgaria.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures were performed in agreement with the European Communities Council Directive 2010/63/EU. The experimental design was approved by the Institutional Ethics Committee. There are no human participants.

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Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Organic ChemistryUniversity of Chemical Technology and MetallurgySofiaBulgaria
  2. 2.Institute of NeurobiologyBulgarian Academy of SciencesSofiaBulgaria
  3. 3.Institute of Organic Chemistry with Centre of PhytochemistryBulgarian Academy of SciencesSofiaBulgaria
  4. 4.Department of Analytical ChemistryUniversity of Chemical Technology and MetallurgySofiaBulgaria
  5. 5.Institute of Biodiversity and Ecosystem ResearchBulgarian Academy of SciencesSofiaBulgaria
  6. 6.Institute of Mineralogy and CrystallographyBulgarian Academy of SciencesSofiaBulgaria

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