Interaction of biphenylimidazole and imidazoleacrylic acid nonpeptide antagonists with valine 108 in TM III of the AT(1) angiotensin receptor

被引：21

作者：

Nirula, V ^{[1
]}

Zheng, W ^{[1
]}

Sothinathan, R ^{[1
]}

Sandberg, K ^{[1
]}

机构：

[1] GEORGETOWN UNIV,MED CTR,DEPT MED,DIV NEPHROL & HYPERTENS,WASHINGTON,DC 20007

来源：

BRITISH JOURNAL OF PHARMACOLOGY | 1996年 / 119卷 / 08期

关键词：

angiotensin; angiotensin receptors; nonpeptide antagonists; biphenylimidazoles; imidazoleacrylic acids; site-directed mutagenesis; ligand binding;

D O I：

10.1111/j.1476-5381.1996.tb16065.x

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 Ile, the corresponding residue in xAT(a), significantly reduced ligand affinities from both nonpeptide classes (F-mut values (mutant IC50/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 Va1(108) is a common structural determinant of nonpeptide recognition on the AT(1) receptor.

引用

页码：1505 / 1507

页数：3

共 6 条

[1]

CASCIERI MA, 1995, MOL PHARMACOL, V47, P660

[2]

JI H, 1994, J BIOL CHEM, V269, P16533

[3] GENETIC TRANSFER OF A NONPEPTIDE ANTAGONIST BINDING-SITE TO A PREVIOUSLY UNRESPONSIVE ANGIOTENSIN RECEPTOR [J].

JI, H ;

ZHENG, W ;

ZHANG, Y ;

CATT, KJ ;

SANDBERG, K .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (20) :9240-9244

[4]

SCHAMBYE HT, 1995, MOL PHARMACOL, V47, P425

[5]

Schwartz Thue W., 1994, Current Opinion in Biotechnology, V5, P434, DOI 10.1016/0958-1669(94)90054-X

[6]

TIMMERMANS PBMWM, 1993, PHARMACOL REV, V45, P205

← 1 →