Dynamic mechanisms of non-classical antagonism by competitive AT(1) receptor antagonists.
Selective competitive angiotensin AT(1) receptor antagonists exhibit diverse patterns of antagonism of angiotensin-II-mediated responses in functional assays. These range from the classical parallel rightward shift of agonist concentration-response curves with no depression of the maximum response to an apparently straightforward insurmountable antagonism with complete depression of the maximum response and no rightward shift. This article reviews some earlier equilibrium-based models that have been used to explain the insurmountable antagonism, and suggests that a kinetic model might provide a more satisfactory account of the observations. Such a model might provide deeper insights into the pharmacology of G-protein-coupled receptors than the more popular equilibrium models.
Lew
M J
MJ
Department of Pharmacology, University of Melbourne, Victoria 3010, Australia. m.lew@pharmacology.unimelb.edu.au
Ziogas
J
J
Christopoulos
A
A
D000804:Angiotensin II / Q000493:pharmacokinetics*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D008956:Models, Chemical; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000804:Angiotensin II