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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
- Source :
- Pharmaceuticals, Vol 15, Iss 8, p 922 (2022)
- Publication Year :
- 2022
- Publisher :
- MDPI AG, 2022.
-
Abstract
- 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 A2A and A1 receptors. Among the tested compounds, a few compounds displayed nanomolar binding affinities for both receptors. One particular compound, 11o, showed high binding activities (hA2A Ki = 13.3 nM; hA1 Ki = 55 nM) and full antagonism (hA2A IC50 = 136 nM; hA1 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 A2A/A1 receptor antagonist, 11o, is a good candidate for the treatment of Parkinson’s disease with an excellent metabolic and safety profile.
Details
- Language :
- English
- ISSN :
- 14248247
- Volume :
- 15
- Issue :
- 8
- Database :
- Directory of Open Access Journals
- Journal :
- Pharmaceuticals
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.14e94f352b4c16911dc9fc9a6902fb
- Document Type :
- article
- Full Text :
- https://doi.org/10.3390/ph15080922