INTERACTION OF BIPHENYLIMIDAZOLE AND IMIDAZOLEACRYLIC ACID NONPEPTIDEANTAGONISTS WITH VALINE-108 IN TM-III OF THE AT(1) ANGIOTENSIN RECEPTOR

Interspecies amino acid exchange, based on pharmacological differences between mammalian AT(1) and amphibian xAT angiotensin II receptors, p reviously demonstrated that Val(108) in transmembrane III (ValIII:08) is a critical structural requirement for binding the biphenylimidazole , losartan. Here, we investigated a series of biphenylimidazole and im idazoleacrylic acid nonpeptides to determine the general role of Val(1 08) in nonpeptide recognition. Substitution of Val(108) in the rAT(1b) receptor with Ile, the corresponding residue in xAT(a), significantly reduced ligand affinities from both nonpeptide classes (F-mut values (mutant IC50/rAT(1b)IC(50)): L-162,389>L-162,313>L-162,017=L-163,491>S B-203,220 >SK&F-108,566). While distinct molecular requirements exist for biphenylimidazole and imidazoleacrylic acid binding, these results suggest that Va1(108) is a common structural determinant of nonpeptid e recognition on the AT(1) receptor.