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

Abstract

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, A_2A and A₃ receptors and for A_2B by adenylyl cyclase assay. Compound 26 was found to be the most remarkable, with a hA₁/hA₃ and hA_2A/hA₃ selectivity of 42, for the A₃ AR (K_i = 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.

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A series 3-phenylcarboxamidocoumarins were synthesised and their affinity for the human ARs subtypes was screened for A₁, A_2A and A₃ and A_2B receptors Compound 26 was found to be the most remarkable, with a hA₁/hA₃ and hA_2A/hA₃ selectivity of 42, for the A₃ AR (K_i = 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.

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