Navigating in chromone chemical space: discovery of novel and distinct A3 adenosine receptor ligands

Abstract

One of the major hurdles in the development of safe and effective drugs targeting G-protein coupled receptors (GPCRs) is finding ligands that are highly selective for a specific receptor subtype. The search for novel compounds with therapeutic value by targeting the A₃ adenosine receptor (A₃AR) is still in its early stages. The increasing knowledge about the biological, physiological and pathological role of the A₃AR subtype was accompanied by the design and development of the A₃AR ligands, but the particular role of A₃AR agonists and antagonists is still an open issue. Among the large variety of chemical classes screened towards ARs flavonoids have been indicated as remarkable A₃AR antagonists. However, the search of A₃AR ligands based on this framework seems to be discontinued. In this context, our research group focused its investigation into the discovery and development of novel, potent and selective AR ligands based on the chemical core of flavonoids, the chromone scaffold. The ongoing research has shown that chromone-2-phenylcarboxamide derivatives display a remarkable preference for hA₃AR. In this work we report stimulating results, supported by A_2A/A₃ molecular docking simulations and structure–affinity-relationship (SAR) studies by which N-(4,5-methylthiazol-2-yl)-4-oxo-4H-chromene-2-carboxamide (compound 31) emerged as the most potent and selective compound, displaying an hA₃ K_i of 167 nM and a selectivity ratio of 590 vs. the hA₁ and 480 vs. the hA_2AAR subtypes. The chromone-based ligand was obtained by a simple synthetic approach and will enter in a lead optimization program to enhance its potency and drug-like properties.