Tricyclic oxazolo[2,3-f]purinediones: potency as adenosine receptor ligands and anticonvulsants Original Research Article

Synthesis and physicochemical properties of 7-mono- and 6,7-disubstituted dihydrooxazolo-[3,2-f]purinediones are described. Oxazolo[2,3-f]purinediones were synthesized by cyclization of 8-bromotheophylline with oxiranes. The obtained compounds (1–22) were evaluated for their affinity at adenosine A1 and A2A receptors. They showed mainly adenosine A2A receptor affinity at low micromolar concentrations and A2A selectivity, for example, compound 9 with an octyl substituent at the oxazole ring displayed adenosine A2A receptor affinity (Ki = 0.998 μM) and at least 25-fold A2A versus A1 selectivity. This compound was less selective (5-fold) towards human recombinant A2B and A3 adenosine receptors. In this group of compounds active adenosine A1 receptor antagonists were also identified. Oxazolopurinediones were evaluated in vivo as anticonvulsants in MES and ScMet tests and examined for neurotoxicity in mice (ip). Compounds with long alkyl chains showed anticonvulsant activity in both tests (in 100 and 300 mg/kg doses), accompanied by significant neurotoxicity. The anticonvulsant activity in rats (po) was higher and without signs of neurotoxicity. SAR and QSAR studies stressed the importance of lipophilic 7-substituents for both types of pharmacological activity. The volume of the substituent is, however, limited at the A2A AR, an n-octyl group being optimal.