Synthesis and biological activities of flavonoid derivatives as A sub(3) adenosine receptor antagonists

A broad screening of phytochemicals has demonstrated that certain flavone and flavonol derivatives have a relatively high affinity at A sub(3) adenosine receptors, with K sub(i) values of greater than or equal to 1 mu M (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 A sub(3) receptors, determined in competitive binding assays versus [ super(125)I]AB-MECA [N super(6)-(4-amino-3-iodobenzyl) adenosine-5'-(N-methyluronamide)]. Affinity was determined in radioligand binding assays at rat brain A sub(1) and A sub(2A) receptors using [ super(3)H]-N super(6)-PIA ([ super(3)H]-(R)-N super(6)-phenylisopropyladenosine) and [ super(3)H]CGS21680 [[ super(3)H]-2-[[4-(2-carboxyethyl)phenyl]ethylamino] 5'-(N-ethylcarbamoyl)adenosine], respectively. The triethyl and tripropyl ether derivatives of the flavonol galangin, 4, had K sub(i) values of 0.3-0.4 mu M at human A sub(3) receptors. The presence of a 5-hydroxyl group increased selectivity of flavonols for human A sub(3) receptors. The 2',3,4',7-tetraethyl ether derivative of the flavonol morin, 7, displayed a K sub(i) value of 4.8 mu M at human A sub(3) receptors and was inactive at rat A sub(1)/A sub(2A) receptors. 3,6-Dichloro-2'-(isopropyloxy)-4'-methylflavone, 11e, was both potent and highly selective ( similar to 200-fold) for human A sub(3) receptors (K sub(i) = 0.56 mu M). Among dihydroflavonol analogues, the 2-styryl instead of the 2-aryl substituent, in 15, afforded selectivity for human A sub(3) vs rat A sub(1) or A sub(2A) receptors. The 2-styryl-6-propoxy derivative, 20, of the furanochromone visnagin was 30-fold selective for human A sub(3) receptors vs either rat A sub(1) or A sub(2A) receptors. Several of the more potent derivatives effectively antagonized the effects of an agonist in a functional A sub(3) receptor assay, i.e. inhibition of adenylyl cyclase in CHO cells expressing cloned rat A sub(3) receptors. In conclusion, these series of flavonoids provide leads for the development of novel potent and subtype selective A sub(3) antagonists.