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Lys 199 mutation of the human angiotensin type 1 receptor differentially affects the binding of surmountable and insurmountable non-peptide antagonists

Department of Molecular and Biochemical Pharmacology, Institute of Molecular Biology and Biotechnology, Free University of Brussels (VUB), B-1640 Sint-Genesius Rode, Belgium, ffierens@ vub.ac.be

Patrick ML Vanderheyden

Department of Molecular and Biochemical Pharmacology, Institute of Molecular Biology and Biotechnology, Free University of Brussels (VUB), B-1640 Sint-Genesius Rode, Belgium

Zsuzsanna Gáborik

Department of Physiology, Semmelweis University Medical School, H-1444 Budapest, PO Box 259, Hungary

Tam Le Minh

Department of Molecular and Biochemical Pharmacology, Institute of Molecular Biology and Biotechnology, Free University of Brussels (VUB), B-1640 Sint-Genesius Rode, Belgium

Jean-Paul De Backer

Department of Molecular and Biochemical Pharmacology, Institute of Molecular Biology and Biotechnology, Free University of Brussels (VUB), B-1640 Sint-Genesius Rode, Belgium

László Hunyady

Department of Physiology, Semmelweis University Medical School, H-1444 Budapest, PO Box 259, Hungary

Adriaan Ijzerman

Division of Medicinal Chemistry, Leiden/Amsterdam Centre of Drug Research, Universiteit Leiden, PO Box 9502, 230 RA Leiden, The Netherlands

Georges Vauquelin

Department of Molecular and Biochemical Pharmacology, Institute of Molecular Biology and Biotechnology, Free University of Brussels (VUB), B-1640 Sint-Genesius Rode, Belgium

Many slow dissociating (insurmountable) non-peptide angiotensin type 1 receptor (AT₁) 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 AT₁-receptor, wild-type and mutant receptors were transiently transfected in CHO-K1 cells and characterised by [³H]candesartan binding. Lys¹⁹⁹ 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). His²⁵⁶ Ala substitution had only minor effects. This suggests that Lys¹⁹⁹ is important for the tight binding of non-peptide antagonists.

Key Words: CHO cells • angiotensin II • human AT1-receptor • mutation • insurmountable non-peptide antagonist

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Journal of Renin-Angiotensin-Aldosterone System, Vol. 1, No. 3, 283-288 (2000)
DOI: 10.3317/jraas.2000.044


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