Different types of receptor interaction of peptide and nonpeptide angiotensin II antagonists revealed by receptor binding and functional studies
The pharmacological effects of angiotensin II (AII) are potently inhibited by several peptide and recently synthesized nonpeptide AII receptor antagonists. The interaction of sarcosine1, isoleucine8-AII (sarile), sarcosine1,O-methyltyrosine4-AII (sarmesin), and the nonpeptide AII antagonists 2-n-but...
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Veröffentlicht in: | Molecular pharmacology 1992-06, Vol.41 (6), p.1081-1088 |
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Zusammenfassung: | The pharmacological effects of angiotensin II (AII) are potently inhibited by several peptide and recently synthesized nonpeptide
AII receptor antagonists. The interaction of sarcosine1, isoleucine8-AII (sarile), sarcosine1,O-methyltyrosine4-AII (sarmesin),
and the nonpeptide AII antagonists 2-n-butyl-4-chloro-5- hydroxymethyl-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-yl)- methyl]imidazole
(DuP 753, Losartan potassium) and its metabolite 2-n-butyl-4-chloro-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-yl)methyl]imidaz
ole - 5-carboxylic acid (EXP3174) with AII binding sites was investigated in radioligand binding and functional studies. Sarile,
sarmesin, DuP 753, and EXP3174 inhibited 125I-AII binding to rat lung tissue, with Ki values of 3.5, 16.1, 23.7, and 10.4
nM, respectively. The Hill coefficients of all displacement curves, except for sarile (nH, 1.45), were not significantly different
from unity. In functional experiments using rabbit aorta, sarmesin and DuP 753 competitively inhibited the contractile response
to AII, with pA2 values of 6.75 and 8.01, respectively. Sarile, in contrast, revealed noncompetitive antagonism, i.e., the
maximum contractile force and the slope of the concentration-contractile force curve were significantly and concentration-dependently
depressed. The concentration-contractile response curve for AII was shifted to the right in a parallel fashion in the presence
of EXP3174 (3 nM to 1 microM); however, the maximum contractile force was significantly decreased, by 24%. The marked noncompetitive
antagonism of sarile (3 nM) was reversed in the presence of increasing concentrations of sarmesin (30 nM to 30 microM) or
DuP 753 (10 nM to 1 microM), whereas in the presence of increasing concentrations of EXP3174 (3-300 nM) a 25% depression in
maximum contractile force persisted. Moreover, the reduction of the maximum contractile force by EXP3174 (10 nM) was concentration-dependently
restored in the presence of increasing concentrations of DuP 753 (10 nM to 1 microM), indicating interaction with the same
binding site. Whereas sarile (0.3-10 nM) did not affect the 125I-AII binding capacity in radioligand saturation experiments,
a 54% reduction of Bmax was observed in the presence of 100 nM EXP3174. The data provide evidence that all antagonists inhibit
the functional response to AII by interacting with a common binding site at the receptor. The noncompetitive behavior of sarile
seems to be due to slow dissociation from this receptor site. An additi |
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ISSN: | 0026-895X 1521-0111 |