Chalcone-based derivatives as new scaffolds for hA3 adenosine receptor antagonists

With the aim of finding new adenosine receptor (AR) ligands based on the chalcone scaffold, we report the synthesis of a new series of coumarin-chalcone hybrids and the pharmacological characterization of their actions at four subtypes of AR.

The synthesized compounds 5-10 were characterized in radioligand binding (A1 , A2A and A3 ) and adenylyl cyclase activity assays (A2B ) to determine the affinity of the compounds for the four human AR (hAR) subtypes.

Coumarin-chalcone hybrids were found to be ligands with a novel structure, not reported thus far, that showed varying affinity and selectivity for AR subtypes.

The coumarin-chalcone hybrids in which ring B of the chalcone scaffold was a thiophene (compounds 5 and 9) were found to be the most potent compounds of the series. Compound 9, in which ring A of the chalcone moiety was the phenyl ring of the coumarin, showed similar activity against hA1 , hA2A and hA3 ARs, while compound 5, in which ring A of the chalcone was substituted by the benzopyrone ring of the coumarin moiety, showed similar activity only at the hA3 AR and, therefore, was deemed to be selective (Ki (dissociation constant) = 5160 nm).