title: Binding of KRH-594, an antagonist of the angiotensin II type 1 receptor, to cloned human and rat angiotensin II receptors.
abstract: We studied the binding properties of KRH-594, a new selective antagonist of angiotensin II (AII) type 1 (AT1) receptors, to rat liver membranes and to recombinant AT1 and AT2 receptors. Preincubation of rat liver membranes with KRH-594 produced maximal inhibition of [125I]-AII binding when the preincubation time was 1-2 h. Preincubation with KRH-594 for 2 h decreased the B(max) value and increased the Kd value. For human AT1, human AT2, rat AT1A and rat AT1B receptors, the Ki values for KRH-594 were 1.24, 9360, 0.67, and 1.02 nm, respectively. The rank order of K1 values for human AT1 receptors was KRH-594 >> EXP3174 > candesartan = AII. The order of specificities for human AT1 and AT2 receptors was candesartan > EXP3174 > KRH-594. Although a 2-h preincubation of human AT2 receptors with KRH-594 (30 microM) or CGP 42112 (a selective AT2 receptor antagonist; 0.3 nM) inhibited binding of [125I]-AII, the suppression by KRH-594 was not significant. These results indicate that KRH-594 binds potently to AT1 receptors in an insurmountable manner, and that at a very high dose (30 microM) it may also bind to AT2 receptors, but in a surmountable manner.
authors.affiliation: Department of Pharmacology, Shinshu University School of Medicine, Asahi, Matsumoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Inada
authors.forename: T
authors.initials: T
authors.lastname: Nakane
authors.forename: S
authors.initials: S
authors.lastname: Chiba
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D019556:COS Cells; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008566:Membranes; D009842:Oligopeptides / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D013830:Thiadiazoles / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; C108799:KRH 594; D009842:Oligopeptides; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D013830:Thiadiazoles; D000804:Angiotensin II; C060894:CGP 42112A; C066026:losartan carboxylic acid; D019808:Losartan; C081643:candesartan