A series of 40 flavonoids were investigated as antagonists at P2Y 2 receptors expressed in NG108-15 cells (mouse neuroblastoma  rat glioma hybrid cell line) in a functional assay measuring the inhibition of UTP-stimulated intracellular calcium release. Several flavonoids were identified as potent antagonists at P2Y 2 receptors with IC 50 values in the low micromolar concentration range; they were similarly potent or more potent than the standard P2Y 2 antagonists Reactive Blue 2 and suramin. Flavone derivatives proved to be more potent than flavanones. The flavone derivatives catechin and epicatechin were inactive. However, a bicyclic benzopyranone ring system was found to be not an absolute prerequisite for P2Y 2 antagonism, since the chalcone derivative b-oxo-aurentiacin (14) was also relatively potent (IC 50 19 mM). Investigated flavone glycosides were completely inactive. The most potent P2Y 2 receptor antagonists of the present series were kaempferol (19), heptamethoxyflavon (29), and tangeretin (25), with IC 50 values between 6-19 mM. Increased lipophilicity by introducing (additional) methyl groups did not generally increase antagonistic potency. Structure-activity relationships proved to be complex. Concentration-response curves for the P2Y 2 agonist UTP were not shifted to the right in the presence of increasing concentrations of tangeretin (25), and EC 50 values for UTP were not affected by the antagonist, but the amplitude of the response was reduced, indicating allosteric antagonism. In conclusion, we have identified flavonoids as novel lead structures for the development of noncompetitive antagonists at P2Y 2