title: In vitro pharmacology of L-158,809, a new highly potent and selective angiotensin II receptor antagonist.
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.
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania.
authors.forename: R S
authors.initials: RS
authors.lastname: Chang
authors.forename: P K
authors.initials: PK
authors.lastname: Siegl
authors.forename: B V
authors.initials: BV
authors.lastname: Clineschmidt
authors.forename: N B
authors.initials: NB
authors.lastname: Mantlo
authors.forename: P K
authors.initials: PK
authors.lastname: Chakravarty
authors.forename: W J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: A A
authors.initials: AA
authors.lastname: Patchett
authors.forename: V J
authors.initials: VJ
authors.lastname: Lotti
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D046508:Culture Techniques; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D019808:Losartan; D008253:Macaca mulatta; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D000450:Aldosterone; C070967:L 158809; C066026:losartan carboxylic acid; D019808:Losartan