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

• Published in: Russian journal of bioorganic chemistry 2022-10, Vol.48 (5), p.1020-1026
• Main Authors: Sidorova, M. V., Palkeeva, M. E., Avdeev, D. V., Studneva, I. M., Serebryakova, L. I., Veselova, O. M., Dobrokhotov, I. V., Molokoedov, A. S., Pisarenko, O. I.
• Format: Article
• Language: English
• Subjects: Biochemistry; Biological activity; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Blood plasma; Chemical compounds; Creatine; Heart; Hemodynamics; Homogeneity; Ischemia; Kinases; Life Sciences; Organic Chemistry; Peptides; Pharmacology; Receptors; Solid phase synthesis
• ISSN: 1068-1620; 1608-330X
• DOI: 10.1134/S1068162022050223

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-NH 2 ) 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.