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Purinergic P2Y  2   receptors, G-protein coupled receptors that primarily couple with Gα q/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 Gα q/11 -coupled human P2Y (hP2Y) receptors and one representative Gα i/o -coupled hP2Y 12  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 Ca 2+  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 P2Y 2  activation in various cardiovascular diseases.

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