Study on Affinity Profile toward Native Human and Bovine Adenosine Receptors of a Series of 1,8-Naphthyridine Derivatives

A new series of 1,8-naphthyridine derivatives (29−44 and 46−52) bearing various substituents in different positions on the heterocyclic nucleus were synthesized in order to analyze the effects produced on the affinity toward the bovine adenosine receptors. These derivatives represent an extension of our previous work on this class of compounds with high affinity toward A1 adenosine receptors. The results of radioligand binding assays indicate that a large number of the 1,8-naphthyridine derivatives proved to be A1 selective, with a high affinity toward bovine adenosine receptors in the low nanomolar range, and one (29) in the subnanomolar range. Furthermore, the new series of 1,8-naphthyridine derivatives (29−44 and 46−52), together with the analogous derivatives 1−28 previously studied, were tested to evaluate their affinity toward human cortical A1 receptors and human striatal A2A receptors. The results indicate that all the 1,8-naphthyridine compounds generally possess a higher affinity toward the bovine A1 receptor compared with the human A1 receptor. As regards the affinity toward the A2A bovine receptor, only a few compounds possess a moderate affinity, which for some compounds remained approximately the same toward the A2A human receptor. A molecular modeling study of the docking of the 1,8-naphthyridine compounds with both the bovine and the human A1 adenosine receptors was carried out with the aim of explaining the marked decrease in the affinity toward human A1 adenosine receptors in comparison with bovine A1 adenosine receptors. This study indicated that the structural differences, albeit small, of the active sites of the two receptors make differences in the dimensions of the site and this influenced the ability of the title compounds to interact with the two A1 receptors.