Selective human adenosine A3 antagonists based on pyrido[2,1-f]purine-2,4-diones: novel features of hA3 antagonist binding.

Based on our previous results on the potent antagonist effect of 1H,3H-pyrido[2,1-f]purine-2,4-diones at the human A(3) adenosine receptor, new series of this family of compounds have been synthesized and evaluated in radioligand binding studies against the human A(1), A(2A), A(2B), and A(3) receptors. A remarkable improvement in potency, and most noticeable, in selectivity has been achieved, as exemplified by the 3-cyclopropylmethyl-8-methoxy-1-(4-methylbenzyl)-1H,3H-pyrido[2,1-f]purine-2,4-dione (10) that combines a very high affinity at hA(3) (K(i)=2.24 nM), with lack of affinity for the A(1), A(2A), and A(2B) receptors.