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 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.
The latter compounds (9–12) showed that they reduce
oxaliplatin-induced neuropathic pain by a mechanism involving the
alpha7 subtype of nAchRs, similar to the nonselective AR antagonist
caffeine, taken as the reference compound. Along with the pharmacological
evaluation, chemical stability of 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
structure–activity relationships.