title: In vitro pharmacological characterization of UP 269-6, a novel nonpeptide angiotensin II receptor antagonist.
abstract: f1p4in vitro pharmacology of UP 269-6, a novel nonpeptide angiotensin II antagonist, was examined in radioligand binding and functional isolated tissue assays. UP 269-6 bound selectively to AT1 receptors as evidenced by the inhibition of specific [125I] Sar1, Ile8-AII binding in rat adrenal membranes (IC50 = 35.8 nM) and in cultured vascular smooth muscle cells (IC50 = 23.8 nM). UP 269-6 displayed a very high selectivity for the AT1 compared to the AT2 receptor subtype (IC50 > 10,000 nM). UP 269-6 inhibited the AII-induced contraction of isolated rabbit aortic strips. The pattern of AII antagonism suggested competitive antagonism at low concentrations (10(-10), 3 x 10(-10), 10(-9) M) of UP 269-6 and insurmountable antagonism at higher concentrations (3 x 10(-9), 10(-8), 3 x 10(-8) M). Based on the calculated pA2 values, UP 269-6 (9.86 +/- 0.25) was an angiotensin II receptor antagonist as potent as L-158,809 (9.82 +/- 0.37) and much more potent than losartan (7.96 +/- 0.38). UP 269-6 was devoid of affinity (IC50 > 10,000 nM) for many other receptors, ion channels and uptake sites, demonstrating its high specificity for AII receptors. Furthermore, this compound did not affect the contractile response to KCl or phenylephrine in rabbit aorta and exhibited no effect on angiotensin converting enzyme activity. These data demonstrate that UP 269-6 is a highly potent, selective and specific AT1 receptor antagonist.
authors.affiliation: Laboratoires UPSA, Rueil-Malmaison, France.
authors.forename: F
authors.initials: F
authors.lastname: Caussade
authors.forename: A
authors.initials: A
authors.lastname: Virone-Oddos
authors.forename: C
authors.initials: C
authors.lastname: Delchambre
authors.forename: M
authors.initials: M
authors.lastname: Cazes
authors.forename: A
authors.initials: A
authors.lastname: Versigny
authors.forename: A
authors.initials: A
authors.lastname: Cloarec
mesh_terms: D000313:Adrenal Medulla / Q000187:drug effects; D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D019808:Losartan; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D011743:Pyrimidines; D013777:Tetrazoles; D000804:Angiotensin II; C088791:UP 269-6; C070967:L 158809; D019808:Losartan