Novel adenosine receptor ligands as potential antiarrhythmic and cardioprotective agents

The human heart is maintained by various factors; a critical endogenous modulator is adenosine, with its effects on the cardiac electrophysiology fundamental. With the ability to reduce oxygen demand by decreasing myocardial contractility, increase oxygen supply through coronary vasodilation and control the sinus/atrioventricular node responses. However, its short half-life and non-specificity make pharmaceutical intervention necessary; there is great precedence for more specific and metabolically stable agonists. With suitable drugs only starting to reach the market it has called for further investigations to deliver viable drug candidates. EnAdo (9) was found to be a potent and selective A1 receptor agonist (EC50 = 1.0 nM),1-2 in an efforts to further investigate the structure activity relationship an investigation into the removal of the 3 membered ring, yet maintain the conformational arrangement of atoms, a series of 3-substituted bicyclo[3.2.1]octanes was envisaged. Synthesis of an asymmetric series of N6-3-substituted bicyclo[3.2.1]octane substituted adenosine analogues (49), incorporating the heteroatom moiety were synthesised through a variety of approaches, in addition other polycyclic analogues were synthesised to further explore large lipophilic N6 substituents. Affinities were tested at all four AR subtypes to determine the selectivity, N6-(3-thiobicyclo[3.2.1]octane)adenosine (102) and N6-(1-methylcubane)adenosine (119) displayed low nanomolar potency and very high selectivity (EC50 values of 2.3 and 1.1 nM, respectively). Furthermore, these compounds were tested in a functional assay where the preconditioning capacity of A1R agonists are tested in a dose dependant survival study of cells placed under ischaemia. A proposed model from A1R agonist and antagonist SAR studies have suggested relationship between the N6 and C-8 substituents of both ligands give rise to highly potent and selective A1R ligands. To explore this theory and further investigate the ENX (20) scaffold, a complementary series of 8-substituted bicyclo[3.2.1]octane xanthenes were synthesised via both linear and convergent pathways. Initial affinity assays showed low nanomolar Ki values that are undergoing further testing to determine the potency and selectivity against the other AR.