Chemical Biology and Drug Design
Chemical Biology and Drug Design
5 years ago

Coumarins and adenosine receptors: new perceptions in structure-affinity relationships

Coumarins and adenosine receptors: new perceptions in structure-affinity relationships
Karl-Norbert Klotz, Sonja Kachler, Maria João Matos, André Fonseca, Eugenio Uriarte, Santiago Vilar, Fernanda Borges
Adenosine receptors (ARs) subtypes are involved in several physiological and pharmacological processes. Ligands able to selectively modulate one receptor subtype can delay or slow down the progression of diverse diseases. In this context, our research group focused its investigation into the discovery and development of novel, potent and selective ARs ligands based on coumarin scaffold. Therefore, a series 3-phenylcarboxamidocoumarins were synthesised and their affinity for the human ARs subtypes was screened by radioligand binding assays for A1, A2A and A3 receptors and for A2B by adenylyl cyclase assay. Compound 26 was found to be the most remarkable, with a hA1/hA3 and hA2A/hA3 selectivity of 42, for the A3 AR (Ki = 2.4 μM). Receptor-driven molecular modelling studies have provided valuable information on the binding/selectivity data of compound 26 and for the following optimization process. Moreover, compound 26 present drug-like properties according to the general guidelines linked to the concept. This article is protected by copyright. All rights reserved. A series 3-phenylcarboxamidocoumarins were synthesised and their affinity for the human ARs subtypes was screened for A1, A2A and A3 and A2B receptors Compound 26 was found to be the most remarkable, with a hA1/hA3 and hA2A/hA3 selectivity of 42, for the A3 AR (Ki = 2.4 µM). Receptor-driven molecular modelling studies have provided valuable information on the binding/selectivity data of compound 26 and for the following optimization process.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.13075

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