Effects of 4(1H)-quinolinone derivative, a novel non-nucleotide allosteric purinergic P2Y 2 agonist, on cardiomyocytes in neonatal rats

Abstract Purinergic P2Y 2 receptors, G-protein coupled receptors that primarily couple with Gαq/11-proteins, are activated equipotently by adenosine-5′-triphosphate (ATP) and uridine-5′-triphosphate. Evidence suggests that P2Y 2 agonists make potential drug candidates for the treatment of cardiovasc...

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Autores principales:	Kensuke Sakuma, Hideyuki Nakagawa, Tatsuo Oikawa, Masakuni Noda, Shota Ikeda
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7318d80836ef4964a22fb41a3fcb7561
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spelling	oai:doaj.org-article:7318d80836ef4964a22fb41a3fcb75612021-12-02T16:06:31ZEffects of 4(1H)-quinolinone derivative, a novel non-nucleotide allosteric purinergic P2Y 2 agonist, on cardiomyocytes in neonatal rats10.1038/s41598-017-06481-92045-2322https://doaj.org/article/7318d80836ef4964a22fb41a3fcb75612017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06481-9https://doaj.org/toc/2045-2322Abstract Purinergic P2Y 2 receptors, G-protein coupled receptors that primarily couple with Gαq/11-proteins, are activated equipotently by adenosine-5′-triphosphate (ATP) and uridine-5′-triphosphate. Evidence suggests that P2Y 2 agonists make potential drug candidates for the treatment of cardiovascular diseases. However, selective non-nucleotide, small-molecule P2Y 2 agonists have yet to be developed. In this report, we discuss Compound 89, a novel non-nucleotide allosteric P2Y 2 agonist that was active in signal transduction and gene induction, and in our in vitro cardiac hypertrophy model. Compound 89 exhibited selective P2Y 2 agonistic activity and potentiated responses to the endogenous agonist ATP, while exhibiting no agonistic activities for four other Gαq/11-coupled human P2Y (hP2Y) receptors and one representative Gαi/o-coupled hP2Y12 receptor. Its P2Y 2 agonistic effect on mouse P2Y 2 receptors suggested non-species-specific activity. Compound 89 acted as a pure positive allosteric modulator in a Ca2+ mobilization assay of neonatal rat cardiomyocytes; it potentiated ATP-induced expression of genes in the nuclear receptor 4A family (negative regulators of hypertrophic stimuli in cardiomyocytes). Additionally, Compound 89 attenuated isoproterenol-induced cardiac hypertrophy, presumably through dose-dependent interaction with pericellular ATP. These results indicate that Compound 89 is potentially efficacious against cardiomyocytes and therefore a good proof-of-concept tool for elucidating the therapeutic potential of P2Y2 activation in various cardiovascular diseases.Kensuke SakumaHideyuki NakagawaTatsuo OikawaMasakuni NodaShota IkedaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kensuke Sakuma Hideyuki Nakagawa Tatsuo Oikawa Masakuni Noda Shota Ikeda Effects of 4(1H)-quinolinone derivative, a novel non-nucleotide allosteric purinergic P2Y 2 agonist, on cardiomyocytes in neonatal rats
description	Abstract Purinergic P2Y 2 receptors, G-protein coupled receptors that primarily couple with Gαq/11-proteins, are activated equipotently by adenosine-5′-triphosphate (ATP) and uridine-5′-triphosphate. Evidence suggests that P2Y 2 agonists make potential drug candidates for the treatment of cardiovascular diseases. However, selective non-nucleotide, small-molecule P2Y 2 agonists have yet to be developed. In this report, we discuss Compound 89, a novel non-nucleotide allosteric P2Y 2 agonist that was active in signal transduction and gene induction, and in our in vitro cardiac hypertrophy model. Compound 89 exhibited selective P2Y 2 agonistic activity and potentiated responses to the endogenous agonist ATP, while exhibiting no agonistic activities for four other Gαq/11-coupled human P2Y (hP2Y) receptors and one representative Gαi/o-coupled hP2Y12 receptor. Its P2Y 2 agonistic effect on mouse P2Y 2 receptors suggested non-species-specific activity. Compound 89 acted as a pure positive allosteric modulator in a Ca2+ mobilization assay of neonatal rat cardiomyocytes; it potentiated ATP-induced expression of genes in the nuclear receptor 4A family (negative regulators of hypertrophic stimuli in cardiomyocytes). Additionally, Compound 89 attenuated isoproterenol-induced cardiac hypertrophy, presumably through dose-dependent interaction with pericellular ATP. These results indicate that Compound 89 is potentially efficacious against cardiomyocytes and therefore a good proof-of-concept tool for elucidating the therapeutic potential of P2Y2 activation in various cardiovascular diseases.
format	article
author	Kensuke Sakuma Hideyuki Nakagawa Tatsuo Oikawa Masakuni Noda Shota Ikeda
author_facet	Kensuke Sakuma Hideyuki Nakagawa Tatsuo Oikawa Masakuni Noda Shota Ikeda
author_sort	Kensuke Sakuma
title	Effects of 4(1H)-quinolinone derivative, a novel non-nucleotide allosteric purinergic P2Y 2 agonist, on cardiomyocytes in neonatal rats
title_short	Effects of 4(1H)-quinolinone derivative, a novel non-nucleotide allosteric purinergic P2Y 2 agonist, on cardiomyocytes in neonatal rats
title_full	Effects of 4(1H)-quinolinone derivative, a novel non-nucleotide allosteric purinergic P2Y 2 agonist, on cardiomyocytes in neonatal rats
title_fullStr	Effects of 4(1H)-quinolinone derivative, a novel non-nucleotide allosteric purinergic P2Y 2 agonist, on cardiomyocytes in neonatal rats
title_full_unstemmed	Effects of 4(1H)-quinolinone derivative, a novel non-nucleotide allosteric purinergic P2Y 2 agonist, on cardiomyocytes in neonatal rats
title_sort	effects of 4(1h)-quinolinone derivative, a novel non-nucleotide allosteric purinergic p2y 2 agonist, on cardiomyocytes in neonatal rats
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/7318d80836ef4964a22fb41a3fcb7561
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Effects of 4(1H)-quinolinone derivative, a novel non-nucleotide allosteric purinergic P2Y 2 agonist, on cardiomyocytes in neonatal rats

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