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.