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The Effect of Cyanopyrrolidine Derivatives on the Activity of Prolyl Endopeptidase, Acute Exudative Inflammation and Visceral Pain in Mice

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Abstract—

Cyanopyrrolidine derivatives benzyloxycarbonyl-methionyl-cyanopyrrolidine (ZMetPrdN), benzyloxycarbonyl-phenylalanyl-cyanopyrrolidine (ZPhePrdN), tert-butyl-hydroxycarbonyl-glycyl-cyanopyrrolidine (BocGlyPrdN), tert-butyl-hydroxycarbonyl-methionyl-cyanopyrrolidine (BocMetPrdN) are inhibitors of prolyl endopeptidase (PREP; ЕС 3.4.21.26) with the IC50 values ranged from 2 nM to 12 nM. Besides inhibition of PREP, ZMetPrdN, ZPhePrdN, and BocMetPrdN also inhibited activity of dipeptidyl peptidase IV (DPP-4; ЕС 3.4.14.5) with the IC50 values ranged from 1100 nM to 3200 nM. In the acetic acid writhing test in mice all the compounds demonstrated antinociceptive properties. However, only the cyanopyrrolidine derivatives with aromatic substituents (ZMetPrdN and ZPhePrdN) decreased acute exudative inflammation in animals. Three hours after induction of inflammation, the studied cyanopyrrolidine derivatives increased PREP activity and compensatory decreased DPP-4 activity in serum of mice. Thus, one of the components of the mechanism responsible for realization of the antinociceptive and antiexudative properties of the studied derivatives of cyanopyrrolidine is obviously associated with their ability to inhibit PREP activity.

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Authors and Affiliations

  1. Zakusov Institute of Pharmacology, ul. Baltiyskaya 8, 125315, Moscow, Russia

    E. A. Ivanova, N. N. Zolotov & T. A. Voronina

  2. Institute of Biomedical Chemistry, ul. Pogodinskaya 10, 119435, Moscow, Russia

    V. F. Pozdnev

Authors
  1. E. A. Ivanova
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  2. N. N. Zolotov
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  3. V. F. Pozdnev
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  4. T. A. Voronina
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Correspondence to E. A. Ivanova.

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COMPLIANCE WITH ETHICAL STANDARDS

All manipulations with experimental animals were carried out in accordance with international and Russian regulatory documents: Order of the Ministry of Health of the Russian Federation no. 199n of April 1, 2016 and Directive 2010/63/EU of the European Parliament and the Council of the European Union for the Protection of Animals Used in Scientific purposes. Animals were kept in accordance with the sanitary and epidemiological rules of SR 2.2.1.3218-14 “Sanitary and epidemiological requirements for the design, equipment and maintenance of experimental biological clinics (vivariums).” The experiments were approved by the Commission on Biomedical Ethics of Zakusov Institute of Pharmacology (Protocol no. 1 of January 20, 2017).

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Authors declare that they have no conflict of interest.

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Translated by A. Medvedev

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Ivanova, E.A., Zolotov, N.N., Pozdnev, V.F. et al. The Effect of Cyanopyrrolidine Derivatives on the Activity of Prolyl Endopeptidase, Acute Exudative Inflammation and Visceral Pain in Mice. Biochem. Moscow Suppl. Ser. B 14, 180–185 (2020). https://doi.org/10.1134/S1990750820020055

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  • DOI: https://doi.org/10.1134/S1990750820020055

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