Enantiospecific Recognition at the A_2B Adenosine Receptor by Alkyl 2‑Cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates

A novel family of structurally simple, potent, and selective nonxanthine A_2BAR ligands was identified, and its antagonistic behavior confirmed through functional experiments. The reported alkyl 2-cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahy-dropyrimidine-5-carboxylates (<b>16</b>) were designed by bioisosteric replacement of the carbonyl group at position 2 in a series of 3,4-dihydropyrimidin-2-ones. The scaffold (<b>16</b>) documented herein contains a chiral center at the heterocycle. Accordingly, the most attractive ligand of the series [(±)<b>16b</b>, <i>K</i>_i <b>=</b> 24.3 nM] was resolved into its two enantiomers by chiral HPLC, and the absolute configuration was established by circular dichroism. The biological evaluation of both enantiomers demonstrated enantiospecific recognition at A_2BAR, with the (<i>S</i>)-<b>16b</b> enantiomer retaining all the affinity (<i>K</i>_i <b>=</b> 15.1 nM), as predicted earlier by molecular modeling. This constitutes the first example of enantiospecific recognition at the A_2B adenosine receptor and opens new possibilities in ligand design for this receptor