Synthesis of a series of 8-(substituted-phenyl)xanthines and a study on the effects of substitution pattern of phenyl substituents on affinity for adenosine A1 and A2A receptors

A new series of 8-(substituted-phenyl)xanthines have been synthesized and compounds were evaluated for their affinity for A1 and A2 adenosine receptors (AR) using radioligand binding assays. The effects of varying the positions of 8-phenyl substituents on affinity and selectivity at A1 and A2A adenosine receptors have been studied. Isovanilloid 1,3-dimethyl-8-[4-methoxy-3-(2-morpholin-4-ylethoxy)phenylxanthine (9d) displayed the highest affinity and selectivity towards A2A AR subtypes with Ki = 100 nM over A1 receptors (Ki > 100 mM). It has been observed that substitution pattern on 8-phenyl group greatly affects the affinity and selectivity at adenosine receptors, with A2A tolerating bulkier substituents than did A1 receptors.

Graphical abstractA new series of 8-(substituted-phenyl)xanthines have been synthesized. On evaluation of the binding affinity of compounds for adenosine receptors, it was observed that substitution pattern on 8-phenyl group greatly affects the affinity and selectivity at various AR subtypes.Figure optionsDownload full-size imageDownload as PowerPoint slide