Interaction of biphenylimidazole and imidazoleacrylic acid nonpeptide antagonists with valine 108 in TM III of the AT₁ angiotensin receptor

Abstract

Interspecies amino acid exchange, based on pharmacological differences between mammalian AT1 and amphibian xAT angiotensin II receptors, previously demonstrated that Val108 in transmembrane III (ValIII:08) is a critical structural requirement for binding the biphenylimidazole, losartan. Here, we investigated a series of biphenylimidazole and imidazoleacrylic acid nonpeptides to determine the general role of Val108 in nonpeptide recognition. Substitution of Val108 in the rAT1b receptor with Ile, the corresponding residue in xATa, significantly reduced ligand affinities from both nonpeptide classes (Fmut values (mutant IC50/rAT1bIC50): losartan > L-162,389 > L-16,313 > L-162,017 = L-163,491 > SB-203,220 > SK&F-108,566). While distinct molecular requirements exist for biphenylimidazole and imidazoleacrylic acid binding, these results suggest that Val108 is a common structural determinant of nonpeptide recognition on the AT1 receptor.