Synthesis and Biological Activities of Flavonoid Derivatives as A3 Adenosine Receptor Antagonists.

A broad screening of phytochemicals has demonstrated that certain flavone and flavonol derivatives have a relatively high affinity at A3 adenosine receptors, with Ki values of ≥1 μM (Ji et al. J. Med. Chem. 1996, 39, 781−788). We have further modified the flavone structure to achieve a degree of selectivity for cloned human brain A3 receptors, determined in competitive binding assays versus [125I]AB-MECA [N6-(4-amino-3-iodobenzyl)adenosine-5‘-(N-methyluronamide)]. Affinity was determined in radioligand binding assays at rat brain A1 and A2A receptors using [3H]-N6-PIA ([3H]-(R)-N6-phenylisopropyladenosine) and [3H]CGS21680 [[3H]-2-[[4-(2-carboxyethyl)phenyl]ethylamino]-5‘-(N-ethylcarbamoyl)adenosine], respectively. The triethyl and tripropyl ether derivatives of the flavonol galangin, 4, had Ki values of 0.3−0.4 μM at human A3 receptors. The presence of a 5-hydroxyl group increased selectivity of flavonols for human A3 receptors. The 2‘,3,4‘,7-tetraethyl ether derivative of the flavonol morin, 7, displaye...