A two-state model of antagonist-AT1 receptor interaction: further support by binding studies at low temperature.
The molecular mechanism of insurmountable antagonism was investigated to a large extent in Chinese hamster ovary cells transfected with the human angiotensin II receptor type 1 (AT(1)) receptor. It was proposed that AT(1) receptor antagonists interact with their receptor according to a two-state receptor model. Briefly, this theoretical model reveals that antagonist bound AT(1) receptor can adopt a fast and a slow reversible state. The first, fast reversible state is similar for all antagonists, while the slow reversible state displays the characteristics of each antagonist. In the present study, we performed competition experiments with the AT(1) receptor antagonists candesartan, EXP3174, irbesartan, losartan and ligand [3H]-angiotensin II at 0-4 degrees. This gave the opportunity to verify the two-state model for the first time with experimental data.
Verheijen
Ilse
I
Department of Molecular and Biochemical Pharmacology, Free University of Brussels (VUB), Building E, 2 Pleinlaan, Belgium. iverheij@minf.vub.ac.be
De Backer
Jean-Paul
JP
Vanderheyden
Patrick
P
Vauquelin
Georges
G
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000493:pharmacokinetics; D016466:CHO Cells; D003080:Cold Temperature; D003198:Computer Simulation; D006224:Cricetinae; D007093:Imidazoles / Q000493:pharmacokinetics*; D000077405:Irbesartan; D007700:Kinetics; D019808:Losartan / Q000493:pharmacokinetics; D008954:Models, Biological; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000235:genetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013777:Tetrazoles / Q000493:pharmacokinetics*; D013816:Thermodynamics; D014162:Transfection
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D011994:Recombinant Proteins; D013777:Tetrazoles; C066026:losartan carboxylic acid; D000077405:Irbesartan; D019808:Losartan