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The current treatment paradigm for these diseases entails the preferred use of inverse agonist AT<jats:sub>1<\/jats:sub> receptor blockers (ARBs). However, variability in the inverse agonist activities of common biphenyl\u2010tetrazole ARBs for the active state of AT<jats:sub>1<\/jats:sub> receptors often leads to treatment failure. Therefore, characterization of robust inverse agonist ARBs for the active state of AT<jats:sub>1<\/jats:sub> receptors is necessary.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>To identify the robust inverse agonist for active state of AT<jats:sub>1<\/jats:sub> receptors and its molecular mechanism, we performed site\u2010directed mutagenesis, competition binding assay, inositol phosphate production assay and molecular modelling for both ground\u2010state wild\u2010type AT<jats:sub>1<\/jats:sub> receptors and active\u2010state N111G mutant AT<jats:sub>1<\/jats:sub> receptors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Although candesartan and telmisartan exhibited weaker inverse agonist activity for N111G\u2010 compared with WT\u2010AT<jats:sub>1<\/jats:sub> receptors, only eprosartan exhibited robust inverse agonist activity for both N111G\u2010 and WT\u2010 AT<jats:sub>1<\/jats:sub> receptors. Specific ligand\u2013receptor contacts for candesartan and telmisartan are altered in the active\u2010state N111G\u2010 AT<jats:sub>1<\/jats:sub> receptors compared with the ground\u2010state WT\u2010AT<jats:sub>1<\/jats:sub> receptors, suggesting an explanation of their attenuated inverse agonist activity for the active state of AT<jats:sub>1<\/jats:sub> receptors. In contrast, interactions between eprosartan and N111G\u2010AT<jats:sub>1<\/jats:sub> receptors were not significantly altered, and the inverse agonist activity of eprosartan was robust.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>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\u2010independent, AT<jats:sub>1<\/jats:sub> receptor activation are warranted.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14213","type":"journal-article","created":{"date-parts":[[2018,3,23]],"date-time":"2018-03-23T18:37:29Z","timestamp":1521830249000},"page":"2454-2469","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The non\u2010biphenyl\u2010tetrazole angiotensin AT<sub>1<\/sub> receptor antagonist eprosartan is a unique and robust inverse agonist of the active state of the AT<sub>1<\/sub> receptor"],"prefix":"10.1111","volume":"175","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9703-3284","authenticated-orcid":false,"given":"Takanobu","family":"Takezako","sequence":"first","affiliation":[{"name":"Department of Advanced Heart Research Saga University  Saga Japan"},{"name":"Department of 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