Small molecules with similar structures exhibit agonist, neutral antagonist or inverse agonist activity toward angiotensin II type 1 receptor

• Published in: PloS one Vol. 7; no. 6; p. e37974
• Main Authors: Miura, Shin-ichiro, Kiya, Yoshihiro, Hanzawa, Hiroyuki, Nakao, Naoki, Fujino, Masahiro, Imaizumi, Satoshi, Matsuo, Yoshino, Yanagisawa, Hiroaki, Koike, Hiroyuki, Komuro, Issei, Karnik, Sadashiva S, Saku, Keijiro
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.06.2012; Public Library of Science (PLoS)
• Subjects: Angiotensin; Angiotensin II; Angiotensin II Type 1 Receptor Blockers - pharmacology; Angiotensins; Binding sites; Biochemistry; Biology; Cardiology; Chemistry; Cysteine; G protein-coupled receptors; Imidazoles - pharmacology; Ligands; Medicine; Models, Molecular; Molecular Conformation; Proteins; R&D; Receptor, Angiotensin, Type 1 - agonists; Receptor, Angiotensin, Type 1 - drug effects; Receptors; Research & development; Tetrazoles - pharmacology; Trends; Japan; Ohio
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0037974

Small differences in the chemical structures of ligands can be responsible for agonism, neutral antagonism or inverse agonism toward a G-protein-coupled receptor (GPCR). Although each ligand may stabilize the receptor conformation in a different way, little is known about the precise conformational differences. We synthesized the angiotensin II type 1 receptor blocker (ARB) olmesartan, R239470 and R794847, which induced inverse agonism, antagonism and agonism, respectively, and then investigated the ligand-specific changes in the receptor conformation with respect to stabilization around transmembrane (TM)3. The results of substituted cysteine accessibility mapping studies support the novel concept that ligand-induced changes in the conformation of TM3 play a role in stabilizing GPCR. Although the agonist-, neutral antagonist and inverse agonist-binding sites in the AT(1) receptor are similar, each ligand induced specific conformational changes in TM3. In addition, all of the experimental data were obtained with functional receptors in a native membrane environment (in situ).