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

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posted on 01.01.2021, 14:05 by Shivaji A. Thorat, Yoonji Lee, Aeran Jung, Jihyae Ann, Songyeon Ahn, Jisoo Baek, Dongxu Zuo, Nayeon Do, Jin Ju Jeong, Peter M. Blumberg, Timothy E. Esch, Noe A. Turcios, Larry V. Pearce, Hee-Jin Ha, Young Dong Yoo, Sunhye Hong, Sun Choi, Jeewoo Lee
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.