RECEPTOR INTERACTIONS OF ABBOTT-81988, A HIGHLY POTENT, NONPEPTIDE ANGIOTENSIN-II ANTAGONIST SELECTIVE FOR TYPE-1 RECEPTORS

Abbott-81988 (A-81988) was selected from a series of related compounds as a highly potent and selective antagonist of angiotensin receptors. In the rabbit aorta, A-81988 exhibited a pA(2) of 10.12 (+/- 0.08) vs . angiotensin-II, for type 1 receptors (AT(1)), and the antagonism app eared competitive. These results agreed with radioligand assays in whi ch A-81988 inhibited the binding of [I-125]-Sar(1)-Ile(8)-Angiotensin- II to rat liver membranes with a pK(I) of 9.12 (+/- 0.63). A-81988 was selective for AT(1) receptors based on its lack of activity at other sites, such as aortic al receptors. Moreover, A-81988 lacked affinity for AT(2) receptors of bovine cerebellar membranes or for alpha or bet a adrenergic receptors in binding assays. A-81988 lowered blood pressu re significantly in vivo in renal artery-ligated rats at doses of 0.3 mg/kg administered either i.v. or p.o. The compound was rapidly and al most completely absorbed from the duodenum of anesthetized rats and de monstrated very low first-pass metabolism in the rat liver. These prop erties of selectivity toward and potency for antagonizing AT(1) recept ors activity in lowering blood pressure In experimental animals, and f avorable pharmacokinetic properties indicate that A-81988 should be a useful antihypertensive agent in man.