Discovery of Novel Dual Adenosine A2A and A1 Receptor Antagonists with 1H-Pyrazolo[3,4-d]pyrimidin-6-amine Core Scaffold as Anti-Parkinson's Disease Agents

New compounds with 1H-pyrazolo [3,4-d]pyrimidin-6-amine core scaffolds were synthesized and characterized in vitro to determine their affinity for human A(2A) and A(1) receptors. Among the tested compounds, a few compounds displayed nanomolar binding affinities for both receptors. One particular compound, 11o, showed high binding activities (hA(2A) K-i = 13.3 nM; hA(1) K-i = 55 nM) and full antagonism (hA(2A) IC50 = 136 nM; hA(1) IC50 = 98.8 nM) toward both receptors. Further tests showed that 11o has low hepatic clearance and good pharmacokinetic properties in mice, along with high bioavailability and a high brain plasma ratio. In addition, 11o 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, 11o tended to improve behavior. Moreover, 11o dose-dependently reversed haloperidol-induced catalepsy in female rats, with graded ED50 of between 3 and 10 mg/kg. Taken together, these results suggest that this potent dual A(2A)/A(1) receptor antagonist, 11o, is a good candidate for the treatment of Parkinson's disease with an excellent metabolic and safety profile.

Automated summary

This study synthesized new compounds and discovered one compound with potential for treating Parkinson's disease, showing good pharmacokinetic properties and low safety risk in vivo.