Latest QSAR study of adenosine A_{\mathrm{2B}} receptor affinity of xanthines and deazaxanthines

Adenosine, a widespread and endogenous nucleoside that acts as a powerful neuromodulator in the nervous system, is a promising therapeutic target in a wide range of conditions. The structural similarity between xanthine derivatives and neurotransmitter adenosine has led to the derivatives of the heterocyclic ring being among the most abundant chemical classes of ligand antagonists of adenosine receptor subtypes. Small changes in the xanthine scaffold have resulted in a wide array of adenosine receptor antagonists. In this work, we developed a QSAR model for the \(\hbox {A}_{\mathrm{2B}}\) subtype, which is, as yet, not well characterized, with two purposes in mind: to predict adenosine \(\hbox {A}_{\mathrm{2B}}\) antagonist activity and to offer a substructural interpretation of this group of xanthines. The QSAR model provided good classifications of both the test and external sets. In addition, most of the contributions to adenosine \(\hbox {A}_{\mathrm{2B}}\) receptor affinity derived by subfragmentation of the molecules in the training set agree with the relationships observed in the literature. These two factors mean that this QSAR ensemble could be used as a model to predict future adenosine \(\hbox {A}_{\mathrm{2B}}\) antagonist candidates.