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Synthesis of the Antagonist of the GalR2 Galanin Receptor and Studies of Its Biological Activity in Ischemia and Reperfusion of the Rat Heart In Vivo

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Abstract

The dose-dependent action of the M871 synthetic peptide antagonist of the GalR2 galanin receptor (H-Trp-Thr-Leu-Asn-Ser-Ala-Gly-Tyr-Leu-Leu-Gly-Pro-Glu-His-Pro-Pro-Pro-Ala-Leu-Ala-Leu-Ala-NH2) and the pharmacological agonist G (H-Trp-Thr-Leu-Asn-Ser-Ala-Gly-Tyr-Leu-Leu-Gly-Pro-βAla-His-OH) on sizes of the myocardial infarction (MI) and an activity of creatine kinase (CK-MB) in the blood plasma was studied on the in vivo model of regional ischemia and reperfusion of the rat heart. The peptides were prepared by the automatic solid phase synthesis using the Fmoc-strategy and purified by HPLC. The peptides had the appropriate molecular mass and the homogeneity of 97–98%. A blockage of the GalR2 receptors by the intravenous injection of M871 in doses of 3, 6, and 8 mg/kg before the beginning of the reperfusion had no influence on the MI sizes and the CK-MB activity in comparison with the control. The intravenous injection of the agonist G in a dose of 1 mg/kg at the beginning of the reperfusion significantly decreased the MI sizes and the CK-MB activity in the blood plasma in comparison with the control by 38 and 40%, respectively. Peptides M871 and G did not significantly affect the hemodynamic parameters of the heart. The preliminary intravenous injection of increasing doses of peptide M871 before an administration of agonist G resulted in a gradual increase in the MI sizes and the CK-MB activity. An application of compound M871 in doses of 6 or 8 mg/kg completely abrogated the cardioprotective effects of agonist G. These results suggested the participation of the GalR2 receptor in the protective action of the chimeric agonist G on the heart that was subjected to ischemia and reperfusion and pointed to the considerable promise of the molecular engineering of the peptide agonists of the GalR2 receptor for a design of therapeutic agents for a treatment of cardiovascular diseases.

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Funding

This study was supported by the Russian Foundation for Basic Research, projects nos. 18-015-0008-а and 18-015-00009a and the Ministry of the Health Care of the Russian Federation, project no. NIOKR 121031700143-1.

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Authors and Affiliations

  1. Chasov National Medical Research Center of Cardiology, Ministry of Health Care, 121552, Moscow, Russia

    M. V. Sidorova, M. E. Palkeeva, D. V. Avdeev, I. M. Studneva, L. I. Serebryakova, O. M. Veselova, I. V. Dobrokhotov, A. S. Molokoedov & O. I. Pisarenko

Authors
  1. M. V. Sidorova
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  2. M. E. Palkeeva
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  3. D. V. Avdeev
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  4. I. M. Studneva
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  5. L. I. Serebryakova
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  6. O. M. Veselova
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  7. I. V. Dobrokhotov
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  8. A. S. Molokoedov
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  9. O. I. Pisarenko
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Corresponding author

Correspondence to M. V. Sidorova.

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COMPLIANCE WITH ETHICAL STANDARDS

The studies on the animals were held in accordance with the international ethical guidelines for biomedical research involving animals which were approved by the Council for International Organizations of Medical Sciences in Geneva in 1985.

Conflict of Interests

The authors declare that they have no conflicts of interest.

Additional information

Abbreviations: Boc, tert-butyloxycarbonyl; But, tert-butyl; DCM, dichloromethane; DMF, N,N-dimethylformamide; DMSO, dimethyl sulfoxide; Fmoc, 9-fluorenymethoxycarbonyl; GalR, the galanin receptor; MALDI-TOF, matrix-assisted laser desorption/ionization time-off-flight mass spectrometry; 4-MePip, 4-methylpiperidine; NMM, N-methyl morpholine; TIS, triisopropylsilane; TBTU, N,N,N',N'-tetramethyl-О-(benzotriazol-1-yl)uronium tetrafluoroborate; TFA, trifluoroacetic acid; Trt, trityl; ROS, reactive oxygen species; AAR, area at risk; MI, myocardial infarction; I/R, ischemia/reperfusion; CK-МВ, the МВ creatine kinase; LV, left ventricle of a heart; SAP, systolic arterial pressure; HR, heart rate.

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Sidorova, M.V., Palkeeva, M.E., Avdeev, D.V. et al. Synthesis of the Antagonist of the GalR2 Galanin Receptor and Studies of Its Biological Activity in Ischemia and Reperfusion of the Rat Heart In Vivo. Russ J Bioorg Chem 48, 1020–1026 (2022). https://doi.org/10.1134/S1068162022050223

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