The non‐biphenyl‐tetrazole angiotensin AT₁ receptor antagonist eprosartan is a unique and robust inverse agonist of the active state of the AT₁ receptor

Background and Purpose Conditions such as hypertension and renal allograft rejection are accompanied by chronic, agonist‐independent, signalling by angiotensin II AT 1 receptors. The current treatment paradigm for these diseases entails the preferred use of inverse agonist AT 1 receptor blockers (ARBs). However, variability in the inverse agonist activities of common biphenyl‐tetrazole ARBs for the active state of AT 1 receptors often leads to treatment failure. Therefore, characterization of robust inverse agonist ARBs for the active state of AT 1 receptors is necessary. Experimental Approach To identify the robust inverse agonist for active state of AT 1 receptors and its molecular mechanism, we performed site‐directed mutagenesis, competition binding assay, inositol phosphate production assay and molecular modelling for both ground‐state wild‐type AT 1 receptors and active‐state N111G mutant AT 1 receptors. Key Results Although candesartan and telmisartan exhibited weaker inverse agonist activity for N111G‐ compared with WT‐AT 1 receptors, only eprosartan exhibited robust inverse agonist activity for both N111G‐ and WT‐ AT 1 receptors. Specific ligand–receptor contacts for candesartan and telmisartan are altered in the active‐state N111G‐ AT 1 receptors compared with the ground‐state WT‐AT 1 receptors, suggesting an explanation of their attenuated inverse agonist activity for the active state of AT 1 receptors. In contrast, interactions between eprosartan and N111G‐AT 1 receptors were not significantly altered, and the inverse agonist activity of eprosartan was robust. Conclusions and Implications Eprosartan may be a better therapeutic option than other ARBs. Comparative studies investigating eprosartan and other ARBs for the treatment of diseases caused by chronic, agonist‐independent, AT 1 receptor activation are warranted.