Discovery of Benzopyridone-Based Transient Receptor Potential Vanilloid 1 Agonists and Antagonists and the Structural Elucidation of Their Activity Shift
- Authors
- Thorat, S.A.; Lee, Y.; Jung, A.; Ann, J.; Ahn, S.; Baek, J.; Zuo, D.; Do, N.; Jeong, J.J.; Blumberg, P.M.; Esch, T.E.; Turcios, N.A.; Pearce, L.V.; Ha, H.-J.; Yoo, Y.D.; Hong, S.; Choi, S.; Lee, J.
- Issue Date
- 14-Jan-2021
- Publisher
- American Chemical Society
- Citation
- Journal of Medicinal Chemistry, v.64, no.1, pp 370 - 384
- Pages
- 15
- Journal Title
- Journal of Medicinal Chemistry
- Volume
- 64
- Number
- 1
- Start Page
- 370
- End Page
- 384
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/62609
- DOI
- 10.1021/acs.jmedchem.0c00982
- ISSN
- 0022-2623
1520-4804
- Abstract
- 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. ©
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