An important subject of research has been how molecules bind to and change the conformation to activate or inactivate G-protein coupled receptors. Although only light-sensitive rhodopsin has been crystallized in different conformational states, the crystal structures of the ßadrenergic receptors ß 1 and ß 2-AR have recently been obtained for complexes of the receptors bound to inverse agonists. More recently, Rosenbaum et al., Rasmussen et al., and Warne et al. reported that structural, biophysical and computational studies could provide insight into the agonistinduced activation of ß1 and ß2-AR. Based on a comparison of the agonist-induced crystal structure to that in which ß2-AR is bound to an inverse agonist, it has been shown that the transition between the R* state and R state involves the repacking of hydrophobic amino acid residues with slight rotations of transmembrane 5 and 6. Nonetheless, the conformation range and dynamics of the effects of ligands on GPCRs may differ from one receptor to another. Angiotensin II type 1 receptor, which is a member of the GPCR superfamily, has a widespread tissue distribution and mediates most known cardiovascular functions including vasoconstriction, cardiovascular hypertrophy and hyperplasia. The AT1 receptor exhibits a low level of constitutive activity in the absence of any ligand. The data indicate that a small portion of the receptor is in the active state. The blockade of constitutive activity may confer resistance to diverse effects. Inverse agonists inhibit basal constitutive activity, and we previously reported that the AT1 receptor blocker olmesartan showed inverse agonism toward inositol phosphate production. We revealed that cooperative interactions between the hydroxyl group and Tyr113 and between the carboxyl group and His256 are crucial for the potent inverse agonist activity of olmesartan. In addition, the olmesartanrelated compound R239470, which has a non-acidic carbamoyl group instead of a carboxyl group, acts as a neutral antagonist. Each inverse agonist, neutral antagonist and agonist may induce a specific conformational change in TM3 as well as TM6 in the AT1 receptor. However, little is known about this topic, even though it should promote our understanding of the structural basis of ligandreceptor interaction. Small differences in the chemical structures of ligands are responsible for inducing agonism, neutral antagonism or inverse agonism in a GPCR. Although each agonist, neutral antagonist or inverse agonist may stabilize the receptor conformation in a different way, little is known about the precise differences in the AT1 receptor. Specifically, little is known about the structural basis for the functional versatility of the AT1 receptor, which switches from the R state to the R* state under the influence of ligands. Since the AT1 receptor has not yet been crystallized, we used an LEE011 alternate approach in this study. Structure-based drug-design methods rely on knowledge about the molecules that bind to the biological target AT1 receptor and the focus is on ligands, and is usually referred to as receptor-based drug design.