Mutational analysis based on pharmacological differences between mammalian and amphibian angiotensin II receptors (AT receptors) previously led to construction of a mutant receptor that gained >25000‐fold affinity for the biphenylimidazole, Losartan. This variant frog receptor also bound with high affinity other nonpeptides in the biphenylimidazole chemical class according to the following rank order of potency (expressed in Fmut values = mutant IC50/rAT1b 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‐51,316, 3.9. In contrast, the imidazoleacrylic acids, SKF‐108,566 (Fmut = 160) and SB‐203,220 (Fmut = 170), bound with markedly less affinity. Thus, nonconserved residues determining the molecular requirements for biphenylimidazole recognition are conserved in general, but are not identical to nonconserved residues necessary for high affinity binding of imidazoleacrylic acids.