Discovery of Novel Dual Adenosine A and A Receptor Antagonists with 1-Pyrazolo[3,4]pyrimidin-6-amine Core Scaffold as Anti-Parkinson's Disease Agents.

New compounds with 1-pyrazolo [3,4]pyrimidin-6-amine core scaffolds were synthesized and characterized in vitro to determine their affinity for human A and A receptors. Among the tested compounds, a few compounds displayed nanomolar binding affinities for both receptors. One particular compound, showed high binding activities (A K = 13.3 nM; A K = 55 nM) and full antagonism (A IC = 136 nM; A IC = 98.8 nM) toward both receptors. Further tests showed that has low hepatic clearance and good pharmacokinetic properties in mice, along with high bioavailability and a high brain plasma ratio. In addition, was associated with very low cardiovascular risk and mutagenic potential, and was well-tolerated in rats and dogs. When tested in an MPTP-induced mouse model of Parkinson's disease, tended to improve behavior. Moreover, dose-dependently reversed haloperidol-induced catalepsy in female rats, with graded ED of between 3 and 10 mg/kg. Taken together, these results suggest that this potent dual A/A receptor antagonist, , is a good candidate for the treatment of Parkinson's disease with an excellent metabolic and safety profile.