Design, synthesis and evaluation of amino-3,5-dicyanopyridines and thieno[2,3-b]pyridines as ligands of adenosine A1 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- b ]pyridine derivatives as non-nucleoside A 1 agonists that could be used in pharmaco-resistant epilepsy (PRE). Compound 7c (thieno[2,3- b ]pyridine derivative), displayed good binding affinity to the rA 1 AR ( K i = 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- b ]pyridines from the lead compounds, amino-3,5-dicyanopyridine derivatives ( 6a - s ) in relation to AR binding was also evaluated. A significant loss of activity against rA 1 /rA 2A ARs with cyclisation was revealed. Amino-3,5-dicyanopyridines exhibited greater affinity towards rA 1 ARs ( K i < 10 nM) than rA 2A . Compound 6c had the best rA 1 affinity ( K i = 0.076 nM). Novel compounds ( 6d , 6k , 6l , 6m , 6n , 6o , 6p) were highly selective towards rA 1 AR ( K i between 0.179 and 21.0 nM). Based on their high selectivity for A 1 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 1 AR affinity is observed with intramolecular cyclisation that occurs during synthesis of thieno[2,3- b ]pyridines ( 7a , 7d , 7c ) from amino-3,5-dicyanopyridine derivatives ( 6a , 6f , 6g ).