| Summary: | Many slow dissociating (insurmountable) non-peptide angiotensin type 1 receptor (AT 1 ) antagonists contain, besides the acidic biphenyltetrazole substructure of losartan, a second acidic group to stabilise antagonist-receptor complexes. To investigate the involved basic amino-acids of the human AT 1 -receptor, wild-type and mutant receptors were transiently transfected in CHO-K1 cells and characterised by [ 3 H]candesartan binding. Lys 199 → Gln substitution decreased the affinity 45-fold for candesartan (95% insurmountable), 18-fold for EXP3174 (70% insurmountable), 10-fold for irbesartan (40% insurmountable) and 5-fold for losartan (surmountable). His 256 → Ala substitution had only minor effects. This suggests that Lys 199 is important for the tight binding of non-peptide antagonists.
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