New 2-heterocyclyl-imidazo[2,1- i ]purin-5-one derivatives as potent and selective human A 3 adenosine receptor antagonists

A series of 4-allyl/benzyl-7,8-dihydro-8-methyl/ethyl-2-[(substituted) isoxazol/pyrazol-3/5-yl]-1H-imidazo[2,1-i]purin-5(4H)-ones has been synthesized and evaluated in radioligand binding assays to determine their affinities at the human A 1, A 2A, and A 3 adenosine receptors. Efficacy at the hA 2B AR and antagonism of selected ligands at the hA 3 AR were also assessed through cAMP experiments. All of the synthesized molecules exhibited high affinity at the hA 3 AR (K i values ranging from 1.46 to 44.8 nM), as well as remarkable selectivity versus A 1, A 2A, and A 2B AR subtypes. Compound (R)-4-allyl-8-ethyl-7,8-dihydro-2-(3-methoxy-1-methyl-1H- pyrazol-5-yl)-1H-imidazo[2,1-i]purin-5(4H)-one (R-33) was found to be the most potent and selective ligand of the series (K i hA 3 = 1.46 nM, K i hA 2A/K i hA 3 > 3425; IC 50 hA 2B/K i hA 3 > 3425; K i hA 1/K i hA 3 = 1729). Molecular modeling studies were helpful in rationalizing the available structure-activity relationships along with the selectivity profiles of the new series of ligands. © 2011 American Chemical Society.