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

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

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish
Pages (from-to)370-384
Number of pages15
JournalJournal of Medicinal Chemistry
Volume64
Issue number1
DOIs
StatePublished - 14 Jan 2021

Fingerprint

Dive into the research topics of 'Discovery of Benzopyridone-Based Transient Receptor Potential Vanilloid 1 Agonists and Antagonists and the Structural Elucidation of Their Activity Shift'. Together they form a unique fingerprint.

Cite this