Design, synthesis and evaluation of amino-3,5-dicyanopyridines and thieno[2,3-b]pyridines as ligands of adenosine A receptors for the potential treatment of epilepsy.

Due to the implication of adenosine in seizure suppression, adenosine-based therapies such as adenosine receptor (AR) agonists have been investigated. This study aimed at investigating thieno[2,3-]pyridine derivatives as non-nucleoside A agonists that could be used in pharmaco-resistant epilepsy (PRE). Compound (thieno[2,3-]pyridine derivative), displayed good binding affinity to the rA AR (  = 61.9 nM). This could be a breakthrough for further investigation of this heterocyclic scaffold as potential ligand. In silico evaluation of this compound raised bioavailability concerns but performed well on drug-likeness tests. The effect of intramolecular cyclisation that occurs during synthesis of thieno[2,3-]pyridines from the lead compounds, amino-3,5-dicyanopyridine derivatives (-) in relation to AR binding was also evaluated. A significant loss of activity against rA/rA ARs with cyclisation was revealed. Amino-3,5-dicyanopyridines exhibited greater affinity towards rA ARs (  < 10 nM) than rA. Compound had the best rA affinity (  = 0.076 nM). Novel compounds (, , , , , , were highly selective towards rA AR ( between 0.179 and 21.0 nM). Based on their high selectivity for A ARs, amino-3,5-dicyanopyridines may be investigated further as AR ligands in PRE with the right structural optimisations and formulations. A decrease in rA AR affinity is observed with intramolecular cyclisation that occurs during synthesis of thieno[2,3-]pyridines (, , ) from amino-3,5-dicyanopyridine derivatives (, , ).