New chromene scaffolds for adenosine A_2A receptors: Synthesis, pharmacology and structure-activity relationships

In silico screening of a collection of 1584 academic compounds identified a small molecule hit for the human adenosine A_2A receptor (pK _i = 6.2) containing a novel chromene scaffold (3a). To explore the structure-activity relationships of this new chemical series for adenosine receptors, a focused library of 43 2H-chromene-3-carboxamide derivatives was synthesized and tested in radioligand binding assays at human adenosine A ₁, A_2A, A_2B and A₃ receptors. The series was found to be enriched with bioactive compounds for adenosine receptors, with 14 molecules showing submicromolar affinity (pK_i ≥ 6.0) for at least one adenosine receptor subtype. These results provide evidence that the chromene scaffold, a core structure present in natural products from a wide variety of plants, vegetables, and fruits, constitutes a valuable source for novel therapeutic agents.