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Differential Bonding Interactions of Inverse Agonists of Angiotensin II Type 1 Receptor in Stabilizing the Inactive State

Department of Cardiology (S.-i.M., Y.K., S.I., M.F., Y.M., K.S.), Fukuoka University School of Medicine, Fukuoka 814-0180, Japan; Novartis Institute for BioMedical Research (T.K.), Tsukuba 300-2611, Japan; and Department of Molecular Cardiology (S.-i.M., S.S.K.), Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195

Address all correspondence and requests for reprints to: Shin-ichiro Miura, Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-Ku, Fukuoka 814-0180, Japan. E-mail: miuras{at}cis.fukuoka-u.ac.jp.

Although the sartan family of angiotensin II type 1 (AT₁) receptor blockers (ARBs), which includes valsartan, olmesartan, and losartan, have a common pharmacophore structure, their effectiveness in therapy differs. Although their efficacy may be related to their binding strength, this notion has changed with a better understanding of the molecular mechanism. Therefore, we hypothesized that each ARB differs with regard to its molecular interactions with AT₁ receptor in inducing inverse agonism. Interactions between valsartan and residues Ser¹⁰⁵, Ser¹⁰⁹, and Lys¹⁹⁹ were important for binding. Valsartan is a strong inverse agonist of constitutive inositol phosphate production by the wild-type and N111G mutant receptors. Substituted cysteine accessibility mapping studies indicated that valsartan, but not losartan, which has only weak inverse agonism, may stabilize the N111G receptor in an inactive state upon binding. In addition, the inverse agonism by valsatan was mostly abolished with S105A/S109A/K199Q substitutions in the N111G background. Molecular modeling suggested that Ser¹⁰⁹ and Lys¹⁹⁹ bind to phenyl and tetrazole groups of valsartan, respectively. Ser¹⁰⁵ is a candidate for binding to the carboxyl group of valsartan. Thus, the most critical interaction for inducing inverse agonism involves transmembrane (TM) V (Lys¹⁹⁹) of AT₁ receptor although its inverse agonist potency is comparable to olmesartan, which bonds with TM III (Tyr¹¹³) and TM VI (His²⁵⁶). These results provide new insights into improving ARBs and development of new G protein-coupled receptor antagonists.

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