IDENTIFICATION OF NONCONSERVED AMINO-ACIDS IN THE AT(1) RECEPTOR WHICH COMPRISE A GENERAL BINDING-SITE FOR BIPHENYLIMIDAZOLE ANTAGONISTS

Mutational analysis based on pharmacological differences between mamma lian and amphibian angiotensin II receptors (AT receptors) previously led to construction of a mutant receptor that gained >25 000-fold affi nity for the biphenylimidazole, Losartan. This variant frog receptor a lso bound with high affinity other nonpeptides in the biphenylimidazol e chemical class according to the following rank order of potency (exp ressed in F-mut values = mutant IC50/rAT(1b) IC50): Losartan, 0.91; L- 162,389, 1.0; L-163,491, 1.9; L-158,809, 3.5; L-163,017, 3.9; SC-51,31 6, 3.9. In contrast, the imidazoleacrylic acids, SKF-108,566 (F-mut = 160) and SE-203,220 (F-mut = 170), bound with markedly less affinity. Thus, nonconserved residues determining the molecular requirements for biphenylimidazole recognition are conserved in general, but are not i dentical to nonconserved residues necessary for high affinity binding of imidazoleacrylic acids.