PHARMACOLOGICAL CHARACTERIZATION OF ABBOTT-81282, A NOVEL, NONPEPTIDEANGIOTENSIN-II ANTAGONIST SELECTIVE FOR TYPE-1 RECEPTORS

Abbott-81282 (A-81282) has been identified among a series of related c ompounds as being a highly potent and selective antagonist of angioten sin receptors. At AT1 receptors of the rabbit aorta, A-81282 exhibited a pA2 Of 9.64 (+/- 0.33) vs. angiotensin-II, and demonstrated charact eristics consistent with competitive antagonism of this receptor. Thes e results were supported in radioligand binding assays in which A-8128 2 inhibited the binding of [I-125]-Sar1-Ile8-Angiotensin-II to rat liv er membranes with a pK(I) of 8.505 (+/- 0.102). Selectivity of this ag ent for AT1 receptors was validated by its lack of activity at other r eceptor sites, such as al receptors of isolated rabbit aorta. Moreover , A-81282 lacked affinity for AT2 receptors of bovine cerebellar membr anes or for alpha or beta adrenergic receptor sites in radioligand bin ding assays. A-81282 lowered blood pressure significantly in vivo in r enal artery-ligated rats at doses of 1 mg/kg i.v. or 5 mg/kg p.o. The compound was slowly and moderately absorbed from the duodenum of anest hetized rats and demonstrated low first-pass metabolism in the rat liv er. Because of its selectivity and potency for antagonizing AT1 recept ors, and its activity in lowering blood pressure in experimental anima ls, A-81282 has the potential to be a useful antihypertensive agent in man.