Small molecules with similar structures exhibit agonist, neutral antagonist or inverse agonist activity toward angiotensin II type 1 receptor.
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).
Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan. miuras@cis.fukuoka-u.ac.jp
Shin-ichiro
S
Miura
Yoshihiro
Y
Kiya
Hiroyuki
H
Hanzawa
Naoki
N
Nakao
Masahiro
M
Fujino
Satoshi
S
Imaizumi
Yoshino
Y
Matsuo
Hiroaki
H
Yanagisawa
Hiroyuki
H
Koike
Issei
I
Komuro
Sadashiva S
SS
Karnik
Keijiro
K
Saku
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; C576721:R239470; C576722:R794847; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C437965:olmesartan