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 A(3) adenosine receptors, with K-i values of greater than or equal to 1 mu M (Ji et al. J. Meld. Chem. 1996, 39, 781-788). We have further modified the flavone structure to achieve a degree of selectivity for cloned human brain A(3) receptors, determined in competitive binding assays versus [I-125]AB-MECA [N-6-(4-amino-3-iodobenzyl)adenosine-5 amide)l. Affinity was determined in radioligand binding assays at rat brain A(1) and A(2A) receptors using [H-3]-N-6-PIA ([H-3]-(R)-N-6-phenylisopropyladenosine and [H-3]CGS21680 [[H-3]-2-[[4-(2-carboxyethyl)phenyl]ethylamino]-5'-(N-ethylcarbamoyl)adenosine], respectively. The triethyl and tripropyl ether derivatives of the flavonol galangin, 4, had K-i values of 0.3-0.4 mu M at human A(3) receptors. The presence of a 5-hydroxyl group increased selectivity of flavonols for human A(3) receptors. The 2',3,4',7-tetraethyl ether derivative of the flavonol morin, 7, displayed a K-i value of 8.8 mu M at human A(3) receptors and was inactive at rat A(1)/A(2A) receptors. 3,6-Dichloro-2'-(isopropyloxy)-4'-methylflavone, 11e, was both potent and highly selective (similar to 200 fold) for human A(3) receptors (K-i 0.56 mu M). Among dihydroflavonol analogues, the 2-styryl instead of the 2-aryl substituent, in 15, afforded selectivity for human A(3) VS rat A(1) or A(2A) receptors. The 2-styryl-6-propoxy derivative, 20, of the furanochromone visnagin was 30-fold selective for human A(3) receptors vs either rat A(1) or A(2A) receptors. Several of the more potent derivatives effectively antagonized the effects of an agonist in a functional A(3) receptor assay, i.e. inhibition of adenylyl cyclase in CHO cells expressing cloned rat A(3) receptors. In conclusion, these series of flavonoids provide leads for the development of novel potent and subtype selective A(3) antagonists.