Molecular characterisation of the interactions between olmesartan and telmisartan and the human angiotensin II AT₁ receptor

Abstract

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.

Effects of high dose olmesartan medoxomil plus hydrochlorothiazide on blood pressure control in patients with grade 2 and grade 3 hypertension

“…13 Such findings are inline with in vitro studies, which show that OM produces a strong blockade of the AT 1 receptor, with a high degree of insurmountable binding, slow dissociation and high affinity for the AT 1 receptor. 14 The clinical consequences of this robust inhibition of the AT 1 receptor appear as the sustained reductions in SBP and DBP over 24 h seen in the metaanalysis of Fabia et al 7 Direct clinical comparisons in which OM produced larger reductions in BP measured by ABPM than several other ARBs may also reflect stronger AT 1 receptor blockade [15][16][17] The 2009 re-appraisal of the ESH-ESC guidelines on hypertension management acknowledge that, in general, in up to 20% of patients with hypertension BP control cannot be achieved by a two-drug combination. 4 However, even treatment with an ARB with superior AT 1 receptor binding characteristics may not lead to high rates of BP goal achievement in a population that includes a high proportion of patients with severe hypertension.…”

Multivalent ligand–receptor interactions elicit inverse agonist activity of AT1 receptor blockers against stretch-induced AT1 receptor activation

“…11 Recently, it was reported that olmesartan showed a higher degree of insurmountable antagonism than did telmisartan against AngIIinduced IP accumulation in CHO-K1 cells expressing the AT 1 receptor. 12 In this study, we showed that olmesartan shows insurmountable antagonist activity against the AT 1 receptor and that the carboxyl and hydroxyl groups on the imidazole ring are required for the insurmountable inhibition of AngII-induced ERK activation and c-fos gene expression (Figure 1). The unique side-chain structure olmesartan possesses (its carboxyl group and hydroxyl group) contributes to its specific receptor-binding activity.…”

Significance of angiotensin II receptor blockers with high affinity to angiotensin II type 1 receptors for vascular protection in rats

“…4 In another study assessing binding to cultured Chinese hamster ovary cells expressing human AT 1 receptors, the dissociation rate constant of olmesartan and telmisartan was 0.0096 and 0.0237 min À1 , respectively, with corresponding half-lives of 65 and 29 min, respectively. 5 Miura et al 6 reported structural differences among ARBs, and these differences may explain why olmesartan can block AT 1 receptors to a greater degree than other ARBs. However, it is unclear whether the different binding affinities to the AT 1 receptor are reflected in the differences in protection against vascular dysfunction in in vivo experiments.…”

“…For example, although ARBs vary in their binding affinities in in vitro experiments, the significance of the different binding affinities of the various ARBs has rarely been discussed in in vivo studies. 4,5 In in vitro experiments that studied the angiotensin II time-dependent dissociation of telmisartan, olmesartan, candesartan, Exp3174 (an active metabolite of losartan) and valsartan from membrane components containing human AT 1 receptors, the dissociation rate constant of each ARB was 0.003248, 0.004171, 0.005203, 0.008561 and 0.009946 min À1 , respectively, with corresponding half-lives of 213, 166, 133, 81 and 70 min, respectively. 4 In another study assessing binding to cultured Chinese hamster ovary cells expressing human AT 1 receptors, the dissociation rate constant of olmesartan and telmisartan was 0.0096 and 0.0237 min À1 , respectively, with corresponding half-lives of 65 and 29 min, respectively.…”