Among
a series of benzopyridone-based scaffolds investigated as
human transient receptor potential vanilloid 1 (TRPV1) ligands, two
isomeric benzopyridone scaffolds demonstrated a consistent and distinctive
functional profile in which 2-oxo-1,2-dihydroquinolin-5-yl analogues
(e.g., 2) displayed high affinity and potent antagonism,
whereas 1-oxo-1,2-dihydroisoquinolin-5-yl analogues (e.g., 3) showed full agonism with high potency. Our computational models
provide insight into the agonist–antagonist boundary of the
analogues suggesting that the Arg557 residue in the S4–S5 linker
might be important for sensing the agonist binding and transmitting
signals. These results provide structural insights into the TRPV1
and the protein–ligand interactions at a molecular level.
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.
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