Discovery of Benzopyridone-Based Transient Receptor Potential Vanilloid 1 Agonists and Antagonists and the Structural Elucidation of Their Activity Shift

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.