Structure and biological activity of endogenous and synthetic agonists of GPR119

Tyurenkov, I. N.; Озеров, А. А.; Куркин, Д. В.; Logvinova, E O; Бакулин, Д. А.; Волотова, Е. В.; Borodin, D. D.

doi:10.1070/rcr4737

Cited by 9 publications

(7 citation statements)

References 72 publications

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“…(D) Linear connection core agonists. The dotted boxes are the different motifs of the synthesis agonists, the EC 50 are derived from other literature reports ( Jones et al, 2009 ; Shah and Kowalski, 2010 ; Buzard et al, 2012 ; Tyurenkov et al, 2018 ; Li et al, 2021 ; Qian et al, 2022 ). The chemical structure formula of GPR119 synthesis agonists are shown in Supplementary Figure S6 ; Supplementary Table S3 .…”

Section: Resultsmentioning

confidence: 99%

Structure of human GPR119-Gs complex binding APD597 and characterization of GPR119 binding agonists

Li,

Qian,

Wang

et al. 2024

Front. Pharmacol.

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The rhodopsin-like receptor GPR119 plays a crucial role in glucose homeostasis and is an emerging target for the treatment of type 2 diabetes mellitus. In this study, we analyzed the structure of GPR119 with the agonist APD597 bound and in complex with the downstream G protein trimer by single particle cryo-electron microscopy (cryo-EM). Structural comparison in combination with function assay revealed the conservative and specific effects of different kinds of GPR119 agonists. The activation mechanism of GPR119 was analyzed by comparing the conformational changes between the inactive and active states. The interaction between APD597 derivatives and synthetic agonists with GPR119 was analyzed by molecular docking technique, and the necessary structural framework was obtained. The above conclusions can provide structural and theoretical basis for the development of therapeutic drugs for type 2 diabetes mellitus.

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Section: Resultsmentioning

confidence: 99%

Structure of human GPR119-Gs complex binding APD597 and characterization of GPR119 binding agonists

Li,

Qian,

Wang

et al. 2024

Front. Pharmacol.

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“…Индукция секреции ГПП-1 свободными жирными кислотами (СЖК или Free Fatty Acids -FFA) сильно зависит от концентрации Ca 2+ в цитозоле. СЖК увеличивают секрецию ГПП-1, стимулируя приток внеклеточного Ca 2+ через каналы Ca 2+ на поверхности клетки [26,35,36].…”

Section: влияние липидов на секрецию гпп-1unclassified

Physiology and pharmacology of glucagon-like peptide-1 receptor

Kurkin,

Bakulin,

Morkovin

et al. 2024

Farm. farmakol. (Pâtigorsk)

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Modern approaches to the treatment of type 2 diabetes mellitus (T2DM) are aimed not only at glycemic control, but also at reducing cardiovascular risks. The increasing prevalence of the disease and the need for effective treatment options highlight the importance of glucagon-like peptide-1 (GLP-1) receptor agonists in the pharmacotherapy structure.The aim of the work was to review the literature regarding the physiology of GLP-1 and the therapeutic potential and development trends of its agonists.Materials and methods. The search for the review materials was carried out using the abstract databases of PubMed, Google Scholar and e-Library. The search was carried out for publications from 2000 to 2023, using the following keywords: “GLP-1”; “GLP-1R agonists”; “GIP”; “exenatide”; “liraglutide”; “dulaglutide”; “semaglutide”; “lixisenatide”; “albiglutide”; “taspoglutide” taking into account various spellings.Results. The interaction of almost all food components with enteroendocrine cells of the intestine leads to the secretion of incretins (primarily GLP-1) into the blood, triggering a complex of physiological reactions aimed primarily at the rapid utilization of incoming glucose (regulation of insulin and glucagon secretion), as well as the central regulation of dietary behavior (slowing gastric emptying and the formation of a feeling of satiety). A wide distribution of the GLP-1 receptor in various tissues and organs, its connection with intracellular signaling cascades aimed at launching energy-consuming remodeling (recovery) processes in endothelial cells, heart, neurons, beta cells, etc., is the basis for a wide range of pleiotropic effects of GLP-1 unrelated to its hypoglycemic effect. The discovery of synthetic GLP-1 receptor agonists with a long period of action has made it possible not only to therapeutically influence various parts of carbohydrate metabolism disorders, but also to increase the functional reserves of the target diabetes organs, reducing the risk of developing complications of the disease. Incretin-like drugs are well tolerated, with nausea being the most common side effect. The factors limiting a wider use of the drugs include their high cost and the preferred form of a subcutaneous solution. The current research is focused on the development of long-acting, oral, dual and triple agonists, fixed-dose combinations, and small molecule drugs.Conclusion. GLP-1 receptor agonists are a class of effective and safe drugs for the treatment of diabetes and obesity, which is rapidly developing in the most advanced areas of pharmacy. A further development of this group and the solution of the identified problems will open up new opportunities for the treatment of diabetes and its complications.

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“…Óêàçàííûå ëåêàðñòâåííûå ñðåäñòâà îáëàäàþò âûñîêîé ýôôåêòèâíîñòüþ è áåçîïàñíîñòüþ, èõ ìîaeíî ïðèìåíÿòü â êîìáèíàöèè ñ ãèïîãëèêåìè÷åñêèìè ïðåïàðàòàìè äðóãèõ ãðóïï. Îäíàêî âûñîêàÿ ñòîèìîñòü è íåîáõîäèìîñòü ïðèìåíåíèÿ â ëåêàðñòâåííîé ôîðìå äëÿ èíúåêöèé àãîíèñòîâ ðåöåïòîðîâ GLP-1 äåëàåò èõ íåäîñòóïíûìè äëÿ áîëüøèíñòâà áîëüíûõ, à èíãèáèòîðû DPP-4 îáëàäàþò ìåíüøåé ýôôåêòèâíîñòüþ [1,14].…”

Section: ââåäåíèåunclassified

“…Ïîäîáíîå äåéñòâèå àãîíèñòîâ GPR119 áûëî îòìå÷åíî â ðÿäó íåäàâíèõ èññëåäîâàíèé [9]. Â ëèòåðàòóðå òàêaeå øèðîêî ïðåäñòàâëåíû ãëþêîçîíåçàâèñèìûå ýôôåêòû GLP-1, íàïðàâëåííûå íà ïîääåðaeàíèå aeèçíåñïîñîáíîñòè b-êëåòîê, ñíèaeåíèå àïïåòèòà, êîððåêöèþ íåêîòîðûõ íàðóøåíèé ñåðäå÷íî-ñîñóäèñòîé ñèñòåìû (ýíäîòåëèî-è êàðäèîïîçèòèâíîå äåéñòâèå) [6,8,14].…”

Section: ðåçóëüòàòû è èõ îáñóAeäåíèåunclassified

Гипогликемическая Активность Новых Агонистов Рецепторов Глюкагоноподобного Пептида-1

Тюренков¹,

Куркин²,

Бакулин³

et al. 2020

Эксп. и клин. фармакол.

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На крысах линии Вистар с экспериментальным сахарным диабетом изучена гипогликемическая активность новых агонистов рецепторов глюкагоноподобного пептида-1 (GPR119). После определения уровня гликемии и формирования групп (в исследование включали животных с уровнем гликемии в пределах 10 – 18 ммоль/л) исследуемые агонисты GPR119 (ZB-16, ZB-17, ZB-18 и ZB-20) вводили в течение 4 недель в 3 дозах (0,1; 1 и 10 мг/кг внутрижелудочно с помощью зонда). Гипогликемическую активность соединений оценивали через 7, 14 и 28 дней применения по уровню глюкозы в плазме крови натощак (после 6 ч голодания), а также скорости ее утилизации при проведении перорального теста на толерантность к глюкозе (ПТТГ). В качестве препаратов сравнения применяли метформин (400 мг/кг) и ситаглиптин (10 мг/кг). Курсовое введение исследуемых агонистов GPR119 сопровождалось снижением уровня гликемии натощак и увеличением скорости утилизации глюкозы по данным ПТТГ. Наиболее выраженным гипогликемическим действием обладало соединение ZB-16 в дозе 1 мг/кг, при этом значимый эффект наблюдали уже через 7 дней введения. Выраженность гипогликемического действия ZB-16 через 28 дней применения была сопоставима с таковой в группах крыс, получавших метформин и ситаглиптин. Таким образом, агонист рецепторов GPR119 — соединение ZB-16 — в дозе 1 мг/кг при 4-недельном введении животным с экспериментальным сахарным диабетом оказывает выраженное гипогликемическое действие, значительно снижая уровень гликемии натощак и повышая скорость утилизации глюкозы при проведении ПТТГ.

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Structure and biological activity of endogenous and synthetic agonists of GPR119

Cited by 9 publications

References 72 publications

Structure of human GPR119-Gs complex binding APD597 and characterization of GPR119 binding agonists

Structure of human GPR119-Gs complex binding APD597 and characterization of GPR119 binding agonists

Physiology and pharmacology of glucagon-like peptide-1 receptor

Гипогликемическая Активность Новых Агонистов Рецепторов Глюкагоноподобного Пептида-1

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