Non-peptide angiotensin receptor antagonists bind to tachykinin NK 3 receptors of rat and guinea pig brain

Abstract

[ 3H]Senktide, a highly selective tachykinin NK 3 receptor agonist, was used to study tachykinin NK 3 receptors of rat and guinea pig brain. Guinea pig brain membranes had a K d of 3.9 ± 0.5 nM and a B max of 42 fmol/mg. Dose-displacement experiments with neurokinins and selective tachykinin receptor agonists revealed the following order of potency: [MePhe 7]neurokinin B > neurokinin B > substance P > neurokinin A. This order is typical for a tachykinin NK 3 receptor. To further characterize the specificity of this receptor, the effects of unrelated compounds such as: bradykinin, angiotensin II, bombesin and their structural analogs were also evaluated on the binding of [ 3H]senktide. Unexpectedly, the angiotensin AT 1 receptor antagonists DuP 753 (2- n-butyl-4-chloro-5-hydroxymethyl-1[2′-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole potassium salt), L-158,809 (5,7-dimethyl-2-ethyl-3-[2′-(1 H-tetrazol-5-yl) [1,1′-biphenyl-4-yl) methyl]-3 H-imidazo[4,5-β]pyridine H 2O) and EXP 3174 (2- n-butyl-4-chloro-1-[2′-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid), inhibited the binding of [ 3H]senktide to its receptor in the guinea pig brain membranes with IC 50 values of 18 μM, 25 μM and 50 μM, respectively. Similar effects were also observed with rat brain membranes. Angiotensin II, saralasin ([Sar 1,Val 5,Ala 8]angiotensin II, a peptide angiotensin AT 1 receptor antagonist) and PD 123,319 (1-[4-(dimethylamino)3-methylaphenyl]methyl-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1 H imidazo[4,5- c]pyridine-6-carboxylic acid, a known non-peptide angiotensin AT 2 receptor antagonist) did not inhibit the binding of [ 3H]senktide to either type of membrane. Furthermore DuP 753, L-158,809 and EXP 3174 did not show any effect on the binding of the tachykinin NK 1 selective receptor agonist, [ 3H][Sar 9, Met (O) 2 11]SP, to guinea pig and rat brain membranes, thus eliminating a possible interaction of these angiotensin AT 1 receptor antagonists with the tachykinin NK 1 receptors. These studies constitute the first evidence of a non-selective interaction of DuP 753, L-158,809 and EXP 3174 with tachykinin NK 3 receptors.