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- Title
Molecular characterisation of the interactions between olmesartan and telmisartan and the human angiotensin II AT<sub>1</sub> receptor.
- Authors
Le, M. T.; Pugsley, M. K.; Vauquelin, G.; Van Liefde, I.
- Abstract
Background and purpose:Whereas some angiotensin II (Ang II) type 1 receptor blockers (ARBs) produce surmountable antagonism of AT1 receptors, others such as olmesartan and telmisartan display varying degrees of insurmountability. This study compared the molecular interactions of olmesartan and telmisartan with the human AT1 receptor, using well characterised in vitro methods and model systems.Experimental approach:CHO-K1 cells that stably express human AT1 receptors (CHO-hAT1 cells) were used in several pharmacological studies of olmesartan and telmisartan, including direct radioligand binding and inhibition of Ang II-induced inositol phosphate (IP) accumulation.Key results:Both ARBs were found to be competitive antagonists that displayed high affinity, slow dissociation, and a high degree of insurmountability for the AT1 receptor (the latter greater with olmesartan). Their receptor interactions could be described by a two-step process with the initial formation of a loose complex (IR) and subsequent transformation into a tight binding complex (IR*). In washout experiments, [3H] telmisartan dissociated from the receptor with a half-life of 29 min and the Ang II-mediated IP accumulation response was 50% maximally restored within 24 min, whereas values for [3H] olmesartan were 72 min and 76 min, respectively.Conclusions and implications:The high degree of insurmountability, slow dissociation, and high affinity of olmesartan for its receptor may relate to its ability to stabilise IR* via the carboxyl group of its imidazole core. In comparison, telmisartan displays a less potent interaction with the receptor.British Journal of Pharmacology (2007) 151, 952–962; doi:10.1038/sj.bjp.0707323; published online 18 June 2007
- Publication
British Journal of Pharmacology, 2007, Vol 151, Issue 7, p952
- ISSN
0007-1188
- Publication type
Academic Journal
- DOI
10.1038/sj.bjp.0707323