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Discovery of Benzopyridone-Based Transient Receptor Potential Vanilloid 1 Agonists and Antagonists and the Structural Elucidation of Their Activity Shift
- Title
- Discovery of Benzopyridone-Based Transient Receptor Potential Vanilloid 1 Agonists and Antagonists and the Structural Elucidation of Their Activity Shift
- Authors
- Thorat, Shivaji A.; Lee, Yoonji; Jung, Aeran; Ann, Jihyae; Ahn, Songyeon; Baek, Jisoo; Zuo, Dongxu; Do, Nayeon; Jeong, Jin Ju; Blumberg, Peter M.; Esch, Timothy E.; Turcios, Noe A.; Pearce, Larry, V; Ha, Hee-Jin; Yoo, Young Dong; Hong, Sunhye; Choi, Sun; Lee, Jeewoo
- Ewha Authors
- 최선; 이윤지
- SCOPUS Author ID
- 최선; 이윤지
- Issue Date
- 2021
- Journal Title
- JOURNAL OF MEDICINAL CHEMISTRY
- ISSN
- 0022-2623
1520-4804
- Citation
- JOURNAL OF MEDICINAL CHEMISTRY vol. 64, no. 1, pp. 370 - 384
- Publisher
- AMER CHEMICAL SOC
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- 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.
- DOI
- 10.1021/acs.jmedchem.0c00982
- Appears in Collections:
- 약학대학 > 약학과 > Journal papers
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