IN-VITRO PHARMACOLOGY OF AN ANGIOTENSIN AT(1) RECEPTOR ANTAGONIST WITH BALANCED AFFINITY FOR AT(2) RECEPTORS

L-163,017 o]-7-methyl-2-propyl-3-[[2'-(N-(3-methyl-1-butoxy) ']-biphen yl-4yl]methyl]-3H-imidazo[4,5-b]pyridine) inhibited specific I-125-[Sa r(1),Ile(8)]angiotensin II binding to angiotensin AT(1) receptor (K-i = 0.11-0.20 nM) in rabbit aorta, rat adrenal and human angiotensin AT, receptor in CHO (Chinese hamster ovary transformed) cells and to AT(2 ) receptor (K-i = 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 album in (2 mg/ml), for angiotensin AT(1) and AT(2) receptors on human adren al (K-i 3.9 and 4.3 nM), aorta (K-i 0.45 and 0.96 nM) and kidney (K-i 3.6 and 2.3 nM). The much higher K-i values in human tissues were like ly due to the presence of bovine serum albumin in the binding assay bu ffer since L-163,017 had Ki values of 0.13 +/- 0.04 and 2.0 +/- 0.04 n M in the absence and presence of bovine serum albumin, respectively, i n inhibiting I-125-[Sar(1),Ile(8j)angiotensin II binding to angiotensi n AT, receptor in rat adrenal membranes. Scatchard analysis of I-125-[ Sar(1),Ile(8)]angiotensin II binding in the presence of bovine serum a lbumin (2 mg/ml) in rabbit aorta and bovine cerebellum indicated a com petitive interaction of L-163,017 with angiotensin AT(1) and AT(2) rec eptors (K-i values 2.5 and 2.1 nM respectively). L-163,017 inhibited a ngiotensin II-induced aldosterone release in rat adrenal demonstrating that L-163,017 acted as a competitive antagonist (pA(2) = 9.9) and la cked agonist activity. L-163,017 also inhibited angiotensin II respons es in rat vascular tissues. The specificity of L-163,017 was shown by its lack of activity on the above functional responses produced by oth er agonists and in several binding assays.