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Interaction of biphenylimidazole and imidazoleacrylic acid nonpeptide antagonists with valine 108 in TM III of the AT 1 angiotensin receptor
Author(s) -
Nirula Vaneet,
Zheng Wei,
Sothinathan Renuka,
Sandberg Kathryn
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb16065.x
Subject(s) - losartan , receptor , chemistry , angiotensin ii , stereochemistry , valine , amino acid , mutant , ligand (biochemistry) , transmembrane protein , biochemistry , gene
Interspecies amino acid exchange, based on pharmacological differences between mammalian AT 1 and amphibian xAT angiotensin II receptors, previously 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 imidazoleacrylic acid nonpeptides to determine the general role of Val 108 in nonpeptide recognition. Substitution of Val 108 in the rAT 1b receptor with He, the corresponding residue in xAT a , significantly reduced ligand affinities from both nonpeptide classes (F mut values (mutant IC 50 /rAT 1b IC 50 ): losartan > L‐162,389 > L‐162,313 > 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 Val 108 is a common structural determinant of nonpeptide recognition on the AT 1 receptor.