title: Pharmacological characterization of the nonpeptide angiotensin II receptor antagonist, SK&F 108566.
abstract: The angiotensin II (AII) antagonist activity of (E)-alpha-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5- yl]methylene]-2-thiophenepropanoic acid (SK&F 108566), was examined in a number of in vitro and in vivo assays. In rat and human adrenal cortical membranes, SK&F 108566 displaced specifically bound [125I]AII with IC50 of 9.2 and 3.9 nM, respectively. SK&F 108566 also inhibited [125I]AII binding to human liver membranes (IC50 = 1.7 nM) and to rat mesenteric artery membranes (IC50 = 1.5 nM). In rabbit aortic smooth muscle cells, SK&F 108566 caused a concentration-dependent inhibition of AII-induced increases in intracellular Ca++ levels. In rabbit aortic rings, SK&F 108566 produced parallel rightward shifts in the AII concentration-response curve without affecting the maximal contractile response. Schild analysis of the data yielded a KB value of 0.26 nM and a slope not different from 1, indicative of competition antagonism. SK&F 108566 had no effect on the contractile responses to KCl, norepinephrine or endothelin in rabbit aorta. In conscious normotensive rats, i.v. administration of SK&F 108566 (0.01-0.3 mg/kg) produced dose-dependent parallel shifts in the AII pressor dose-response curve. Administration of SK&F 108566 (3-10 mg/kg) intraduodenally or intragastrically to conscious normotensive rats resulted in a dose-dependent inhibition of the pressor response to AII (250 ng/kg, i.v.). At 10 mg/kg, i.d., significant inhibition of the pressor response to AII was observed for 3 hr. In this same rat model, SK&F 108566 had no effect on base-line pressure or on the pressor response to norepinephrine or vasopressin. The data demonstrate that SK&F 108566 is a potent, highly selective, competitive nonpeptide AII antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
authors.forename: R M
authors.initials: RM
authors.lastname: Edwards
authors.forename: N
authors.initials: N
authors.lastname: Aiyar
authors.forename: E H
authors.initials: EH
authors.lastname: Ohlstein
authors.forename: E F
authors.initials: EF
authors.lastname: Weidley
authors.forename: E
authors.initials: E
authors.lastname: Griffin
authors.forename: M
authors.initials: M
authors.lastname: Ezekiel
authors.forename: R M
authors.initials: RM
authors.lastname: Keenan
authors.forename: R R
authors.initials: RR
authors.lastname: Ruffolo
authors.forename: J
authors.initials: J
authors.lastname: Weinstock
mesh_terms: D000179:Acrylates / Q000494:pharmacology*; D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D003243:Consciousness; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013876:Thiophenes; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000179:Acrylates; D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D013876:Thiophenes; D000804:Angiotensin II; C068373:eprosartan; D007703:Peptidyl-Dipeptidase A; D002118:Calcium