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Abstract

In vitro pharmacology of L-158,809, a new highly potent and selective angiotensin II receptor antagonist.

R S Chang, P K Siegl, B V Clineschmidt, N B Mantlo, P K Chakravarty, W J Greenlee, A A Patchett and V J Lotti
Journal of Pharmacology and Experimental Therapeutics July 1992, 262 (1) 133-138;
R S Chang
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P K Siegl
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B V Clineschmidt
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N B Mantlo
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P K Chakravarty
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W J Greenlee
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A A Patchett
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V J Lotti
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Abstract

L-158,809 interacted in a competitive manner with rabbit aortic angiotensin II (AII) receptors as determined by Scatchard analysis of the specific binding of [125I]Sar1Ile8-AII. The affinity of L-158,809 (IC50 = 0.3 nM) for AII receptors in this tissue was appreciably greater than that of other reported nonpeptide AII antagonists such as DuP-753 (IC50 = 54 nM) and EXP3174 (IC50 = 6 nM) and similar to the natural ligand, AII. L-158,809 also exhibited a high potency at AII receptors in several other tissues from different animal species (IC50 = 0.2-0.8 nM). In vitro functional assays utilizing AII-induced aldosterone release in rat adrenal cortical cells demonstrated further that L-158,809 acts as a competitive, high affinity antagonist of AII (pA2 = 10.5) and lacks agonist activity. L-158,809 also potently inhibited AII-induced inositol phosphate accumulation in vascular smooth muscle cells and contractile responses to AII in isolated blood vessels. The specificity of L-158,809 for AII receptors was demonstrated by its lack of activity (IC50 greater than 1 microM) in several other receptor binding assays and its inability to affect in vitro functional responses produced by other agonists. L-158,809 demonstrated a very high selectivity for the AT1 compared to the AT2 receptor subtype (AT2 IC50 greater than or equal to 10 microM). The high affinity and selectivity makes L-158,809 a valuable new tool for investigating the physiological and pharmacological actions of AII.

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Journal of Pharmacology and Experimental Therapeutics
Vol. 262, Issue 1
1 Jul 1992
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Abstract

In vitro pharmacology of L-158,809, a new highly potent and selective angiotensin II receptor antagonist.

R S Chang, P K Siegl, B V Clineschmidt, N B Mantlo, P K Chakravarty, W J Greenlee, A A Patchett and V J Lotti
Journal of Pharmacology and Experimental Therapeutics July 1, 1992, 262 (1) 133-138;

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Abstract

In vitro pharmacology of L-158,809, a new highly potent and selective angiotensin II receptor antagonist.

R S Chang, P K Siegl, B V Clineschmidt, N B Mantlo, P K Chakravarty, W J Greenlee, A A Patchett and V J Lotti
Journal of Pharmacology and Experimental Therapeutics July 1, 1992, 262 (1) 133-138;
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