Modifications on the amino-3,5-dicyanopyridine core to obtain multifaceted adenosine receptor ligands with antineuropathic activity

A new series of amino-3,5-dicyanopyridines (1-31) was synthesized and biologically evaluated in order to further investigate the potential of this scaffold to obtain adenosine receptor (AR) ligands. In general, the modifications performed have led to compounds having from high to good human (h) A1AR affinity and an inverse agonist profile. While most of the compounds are hA1AR selective, some derivatives behave as mixed hA1AR inverse agonists/A2A and A2B AR antagonists. These latter (compound 9-12) showed to reduce oxaliplatin-induced neuropathic pain by a mechanism involving the alpha7 subtype of nAchRs, similarly to the non-selective AR antagonist caffeine, taken as reference compound. Along with the pharmacological evaluation, chemical stability of the methyl 3-(((6-amino-3,5-dicyano-4-(furan-2-yl)pyridin-2-yl)sulfanyl)methyl)benzoate 10 was assessed in plasma matrices (rat and human), and molecular modeling studies were carried out to better rationalize the available SARs.