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- Title
Discovery of Novel Dual Adenosine A 2A and A 1 Receptor Antagonists with 1 H -Pyrazolo[3,4 -d ]pyrimidin-6-amine Core Scaffold as Anti-Parkinson's Disease Agents.
- Authors
Jung, Juyoung; Lee, Yoonsuk; Moon, An-Na; Ann, Jihyae; Jeong, Jin Ju; Do, Nayeon; Lee, Jeewoo
- 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.
- Subjects
ADENOSINES; PARKINSON'S disease; CARDIOVASCULAR diseases risk factors
- Publication
Pharmaceuticals (14248247), 2022, Vol 15, Issue 8, p922
- ISSN
1424-8247
- Publication type
Article
- DOI
10.3390/ph15080922