Pharmacological characterization of Abbott-81282, a novel, non-peptide angiotensin-II antagonist selective for type-1 receptors.
Abbott-81282 (A-81282) has been identified among a series of related compounds as being a highly potent and selective antagonist of angiotensin receptors. At AT1 receptors of the rabbit aorta, A-81282 exhibited a pA2 of 9.64 (+/- 0.33) vs. angiotensin-II, and demonstrated characteristics consistent with competitive antagonism of this receptor. These results were supported in radioligand binding assays in which A-81282 inhibited the binding of [125I]-Sar-Il8-Angiotensin-II to rat liver membranes with a pKI of 8.505 (+/- 0.102). Selectivity of this agent for AT1 receptors was validated by its lack of activity at other receptor sites, such as alpha 1 receptors of isolated rabbit aorta. Moreover, A-81282 lacked affinity for AT2 receptors of bovine cerebellar membranes or for alpha or beta adrenergic receptor sites in radioligand binding assays. A-81282 lowered blood pressure significantly in vivo in renal 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 anesthetized rats and demonstrated low first-pass metabolism in the rat liver. Because of its selectivity and potency for antagonizing AT1 receptors, and its activity in lowering blood pressure in experimental animals, A-81282 has the potential to be a useful antihypertensive agent in man.
Hancock
A A
AA
Abbott Laboratories, Division of Cardiovascular Research, Abbott Park, IL 60064.
Buckner
S A
SA
Lee
J Y
JY
Brune
M
M
Morse
P A
PA
Oheim
K
K
Warner
R B
RB
Winn
M
M
Zydowsky
T M
TM
De
B
B
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004341:Drug Evaluation; D066298:In Vitro Techniques; D008297:Male; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D013777:Tetrazoles; C082984:Abbott 81282