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

• Published in: RSC advances 2015-09, Vol.5 (96), p.78572-78585
• Main Authors: Cagide, F, Gaspar, A, Reis, J, Chavarria, D, Vilar, S, Hripcsak, G, Uriarte, E, Kachler, S, Klotz, K. N, Borges, F
• Format: Article
• Language: English
• Subjects: Adenosines; Chemical compounds; Derivatives; Flavonoids; Ligands; Optimization; Receptors; Searching
• ISSN: 2046-2069
• DOI: 10.1039/c5ra14988f

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 A 3 adenosine receptor (A 3 AR) is still in its early stages. The increasing knowledge about the biological, physiological and pathological role of the A 3 AR subtype was accompanied by the design and development of the A 3 AR ligands, but the particular role of A 3 AR agonists and antagonists is still an open issue. Among the large variety of chemical classes screened towards ARs flavonoids have been indicated as remarkable A 3 AR antagonists. However, the search of A 3 AR 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 h A 3 AR. In this work we report stimulating results, supported by A 2A /A 3 molecular docking simulations and structure-affinity-relationship (SAR) studies by which N -(4,5-methylthiazol-2-yl)-4-oxo-4 H -chromene-2-carboxamide (compound 31 ) emerged as the most potent and selective compound, displaying an h A 3 K i of 167 nM and a selectivity ratio of 590 vs. the h A 1 and 480 vs. the h A 2A AR 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. One of the major hurdles in the development of effective drugs targeting GPCRs is finding ligands selective for a specific receptor subtype. Here we describe a potent and selective hormone-based h A 3 AR ligand ( K i of 167 nM) with a remarkable selectivity.