Molecular characterisation of the interactions between olmesartan and telmisartan and the human angiotensin II AT 1 receptor

Background and purpose: Whereas some angiotensin II (Ang II) type 1 receptor blockers (ARBs) produce surmountable antagonism of AT 1 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 AT 1 receptor, using well characterised in vitro methods and model systems. Experimental approach: CHO‐K1 cells that stably express human AT 1 receptors (CHO‐hAT 1 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 AT 1 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, [ 3 H] 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 [ 3 H] 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