Prospects for potentiation of hepatobiliary protector drugs using CGPR receptor antagonists

Currently, it is believed that the calcitonin gene-associated peptide (CGRP) plays one of the key roles not only in the pathophysiology of nocyperception-mediated pathologies, but also in the mechanisms of development of inflammatory-dystrophic phenomena in the sites of localization of the greatest number of CGRP receptors, one of the which is the hepatobiliary system. To target CGRP ligands and CGRP receptors, two types of drugs have been developed that block CGRP function: monoclonal antibodies (containing antibodies either against CGRP itself or against its receptor) and small molecules (hepants). The decisive advantage of the use of monoclonal antibody preparations is their non-liver-related metabolism, as well as the absence of an effect on the pharmacokinetics and pharmacodynamics of other low-molecular-weight drugs when used simultaneously.
The main goal of this study is to assess the potential for potentiation of hepatobiliary protector drugs using CGPR receptor antagonists. Analyzing the data obtained, it can be concluded that the hepatoprotective drug "Hepaton" in combination with monoclonal antibodies of class G2 (IgG2), which binds with high affinity to the receptor of calcitonin-gene-related peptide, significantly reduces the duration of hexenal sleep, which indicates the activation of the detoxifying function of the liver. when exposed to a combination of such drugs, which indicates the potentiation of drugs-protectors of the hepatobiliary system using antagonists of CGPR receptors.
Based on both experimental and scientific literature data, it can be concluded that drugs antagonists of CGPR receptors have an extremely wide range of applications in the future, including for potentiating other drugs used for pharmacological correction of various pathologies. Rational influence on CGPR receptors can reliably influence the maintenance of homeostasis and nociception of the hepatobiliary system.

1. Андреева, Н. Л. Влияние Гепатона на ректальную температуру и длительность гексеналового сна / Н.Л. Андреева, В. С. Понамарев, М. С. Голодяева // Международный вестник ветеринарии. – 2019. – № 3. – С. 44-47.

2. Венгеровский А.И., Маркова И.В., Саратиков А.С. Доклиническое изучение гепатозащитных средств//Ведомости Фармакологического комитета. -1999. -№ 2. - С. 9-12.

3. Патент № 2672056 C2 Российская Федерация, МПК C07D 471/20, C07D 213/61, C07D 213/62. Способ получения антагонистов рецепторов CGRP : № 2014141158 : заявл. 13.03.2013 : опубл. 09.11.2018 / К. М. Белык, Э. Клитор, Ш. Ч. Ко [и др.] ; заявитель МЕРК ШАРП И ДОУМ КОРП.

4. Патент № 2742414 C1 Российская Федерация, МПК A61K 31/198, A61K 31/355, A61K 31/575. Препарат комплексный с гепатопротекторной активностью для крупного рогатого скота : № 2020120624 : заявл. 16.06.2020 : опубл. 05.02.2021 / В. С. Понамарев, Н. Л. Андреева, О. С. Попова, В. А. Барышев.

5. Патент № 2742826 C2 Российская Федерация, МПК C07K 14/585, A61K 38/22, A61P 25/06. Пептидные антагонисты пептидных гормонов из семейства кальцитонина (CGRP) и их применение : № 2017119773 : заявл. 06.06.2017 : опубл. 11.02.2021 / К. Д. Соарес ; заявитель СОАРЕС Кристофер Дж.

6. Толочко, З. С. Влияние холецистокинина-8 (CCK-8) на артериальное давление и содержание кальцитонин-ген-связанного пептида (CGRP) в крови крыс при гипертензии, вызванной фруктозой или блокадой синтеза оксида азота / З. С. Толочко, В. К. Спиридонов // Бюллетень экспериментальной биологии и медицины. – 2021. – Т. 171. – № 5. – С. 608-612. – DOI 10.47056/0365-9615-2021-171-5-608-612.

7. CGRP signalling inhibits NO production through pannexin-1 channel activation in endothelial cells / P. S. Gaete, M. A. Lillo, M. Puebla [et al.] // Scientific Reports. – 2019. – Vol. 9. – No 1. – P. 7932. – DOI 10.1038/s41598-019-44333-w.

8. Dietary capsaicin normalizes CGRP peptidergic DRG neurons in experimental diabetic peripheral neuropathy / X. Y. Zhang, Z. Guo, T. P. Li, T. Sun // Scientific Reports. – 2021. – Vol. 11. – No 1. – P. 1704. – DOI 10.1038/s41598-021-81427-w.

9. Structure and dynamics of the CGRP receptor in apo and peptide-bound forms / T. M. Josephs, M. J. Belousoff, Y. L. Liang [et al.] // Science. – 2021. – Vol. 372. – No 6538. – P. eabf7258. – DOI 10.1126/science.abf7258originally.

10. TLR4 signaling selectively and directly promotes CGRP release from Vagal afferents in the mouse / L. Jia, S. Lee, J. K. Elmquist [et al.] // eNeuro. – 2021. – Vol. 8. – No 1. – P. 1-16. – DOI 10.1523/ENEURO.0254-20.2020.