| Summary: | Adenosine receptors (ARs) play an important role in neurological and psychiatric disorders such as Alzheimer’s disease, Parkinson’s disease, epilepsy and schizophrenia. The different subtypes of ARs and the knowledge on their densities and status are important for understanding the mechanisms underlying the pathogenesis of diseases and for developing new therapeutics. Looking for new scaffolds for selective AR ligands, coumarin–chalcone hybrids were synthesized (compounds <strong>1</strong>–<strong>8</strong>) and screened in radioligand binding (<em>h</em>A<sub>1</sub>, <em>h</em>A<sub>2A</sub> and <em>h</em>A<sub>3</sub>) and adenylyl cyclase (<em>h</em>A<sub>2B</sub>) assays in order to evaluate their affinity for the four human AR subtypes (<em>h</em>ARs). Coumarin–chalcone hybrid has been established as a new scaffold suitable for the development of potent and selective ligands for <em>h</em>A<sub>1</sub> or <em>h</em>A<sub>3</sub> subtypes. In general, hydroxy-substituted hybrids showed some affinity for the <em>h</em>A<sub>1</sub>, while the methoxy counterparts were selective for the <em>h</em>A<sub>3</sub>. The most potent <em>h</em>A<sub>1</sub> ligand was compound <strong>7 </strong>(<em>K</em><sub>i</sub> = 17.7 µM), whereas compound <strong>4</strong> was the most potent ligand for <em>h</em>A<sub>3</sub> (<em>K</em><sub>i</sub> = 2.49 µM). In addition, docking studies with <em>h</em>A<sub>1</sub> and <em>h</em>A<sub>3</sub> homology models were established to analyze the structure–function relationships. Results showed that the different residues located on the protein binding pocket could play an important role in ligand selectivity.
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