PROPERTIES OF [H-3] LF-7-0156, A NEW NONPEPTIDE ANTAGONIST RADIOLIGAND FOR THE TYPE-1 ANGIOTENSIN-II RECEPTOR

LF 7-0156 enyl)methyl]-1H-imidazol-5-yl]methyl]amino]benzoic acid) is a nonpeptide angiotensin II receptor antagonist selective for the type 1 angiotensin receptor. In rabbit aortic rings, LF 7-0156 competitive ly antagonized angiotensin II-induced contractile responses, with a pA (2) value of 8.44. The synthesis of the radiolabeled compound [H-3]LF 7-0156 has allowed direct binding studies with several membrane or cel l preparations. Consistent with competition experiments, the binding o f [H-3]LF 7-0156 to purified rat liver membranes was characterized by a K-d value of 12.6 nM and very low pseudospecific or nonspecific bind ing; this latter characteristic confers to this compound an advantage over the structurally different compound [H-3]DUP 753, which is the on ly commercially available nonpeptide radioligand. [H-3]LF 7-0156 also bound to the type 1A angiotensin receptor expressed in Chinese hamster ovary cells, with high affinity (K-d = 3.5 nM) and a total absence of nonspecific binding. Functional antagonism in this cell system was as sessed by the ability of LF 7-0156 to reverse angiotensin II-induced i nositol phosphate production. These properties make [H-3]LF 7-0156 an interesting pharmacological tool and should allow future evaluation of recognition of the nonpeptide ligand by mutated receptors expressed i n Chinese hamster ovary cells; it will facilitate the analysis of poss ible differences in receptor amino acids involved in the binding of pe ptide and nonpeptide ligands, as well as the extent of spatial overlap between several nonpeptide antagonists displaying different structura l properties.