Study on Affinity Profile toward Native 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 A(1) adenosine receptors.(19) The results of radioligand binding assays indicate that a large number of the 1,8-naphthyridine derivatives proved to be A(1) 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,(19) were tested to evaluate their affinity toward human cortical A(1) receptors and human striatal A(2A) receptors. The results indicate that all the 1,8-naphthyridine compounds generally possess a higher affinity toward the bovine A(1) receptor compared with the human A(1) receptor. As regards the affinity toward the A(2A) bovine receptor, only a few compounds possess a moderate affinity, which for some compounds remained approximately the same toward the A(2A) human receptor. A molecular modeling study of the docking of the 1,8-naphthyridine compounds with both the bovine and the human A(1) adenosine receptors was carried out with the aim of explaining the marked decrease in the affinity toward human A(1) adenosine receptors in comparison with bovine A(1) 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 A(1) receptors.