title: In vitro pharmacology of an angiotensin AT1 receptor antagonist with balanced affinity for AT2 receptors.
abstract: L-163,017 (6-[benzoylamino]-7-methyl-2-propyl-3-[[2'-(N-(3-methyl-1-butoxy) carbonylaminosulfonyl) [1,1']-biphenyl-4-yl]methyl]-3H-imidazo[4,5-b]pyridine) inhibited specific 125I-[Sar1, Ile8]angiotensin II binding to angiotensin AT1 receptor (Ki = 0.11-0.20 nM) in rabbit aorta, rat adrenal and human angiotensin AT1 receptor in CHO (Chinese hamster ovary transformed) cells and to AT2 receptor (Ki = 0.14-0.23 nM) in rat adrenal and brain receptors. L-163,017 also had a high affinity in the presence of bovine serum albumin (2 mg/ml), for angiotensin AT1 and AT2 receptors on human adrenal (Ki 3.9 and 4.3 nM), aorta (Ki 0.45 and 0.96 nM) and kidney (Ki 3.6 and 2.3 nM). The much higher Ki values in human tissues were likely due to the presence of bovine serum albumin in the binding assay buffer since L-163,017 had Ki values of 0.13 +/- 0.04 and 2.0 +/- 0.04 nM in the absence and presence of bovine serum albumin, respectively, in inhibiting 125I-[Sar1,Ile8]angiotensin II binding to angiotensin AT1 receptor in rat adrenal membranes. Scatchard analysis of 125I-[Sar1,Ile8]angiotensin II binding in the presence of bovine serum albumin (2 mg/ml) in rabbit aorta and bovine cerebellum indicated a competitive interaction of L-163,017 with angiotensin AT1 and AT2 receptors (Ki values 2.5 and 2.1 nM respectively). L-163,017 inhibited angiotensin II-induced aldosterone release in rat adrenal demonstrating that L-163,017 acted as a competitive antagonist (pA2 = 9.9) and lacked agonist activity. L-163,017 also inhibited angiotensin II responses in rat vascular tissues. The specificity of L-163,017 was shown by its lack of activity on the above functional responses produced by other agonists and in several binding assays.
authors: Merck Research Laboratories, West Point, PA 19486-0004, USA.
authors: R S
authors: RS
authors: Chang
authors: V J
authors: VJ
authors: Lotti
authors: T B
authors: TB
authors: Chen
authors: S S
authors: SS
authors: O'Malley
authors: R J
authors: RJ
authors: Bendesky
authors: P J
authors: PJ
authors: Kling
authors: S D
authors: SD
authors: Kivlighn
authors: P K
authors: PK
authors: Siegl
authors: D
authors: D
authors: Ondeyka
authors: W J
authors: WJ
authors: Greenlee
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; C098860:L 163017; D011725:Pyridines; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D000450:Aldosterone