Properties of [3H]LF 7-0156, a new nonpeptide antagonist radioligand for the type 1 angiotensin II receptor

S Nouet, P Dodey, P Renaut, J Marie, D Pruneau, R Larguier, C Lombard and JC Bonnafous

INSERM U 401, Montpellier, France.

LF 7-0156 (2-[[[2-butyl-1-[(4-carboxyphenyl)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 competitively antagonized angiotensin II- induced contractile responses, with a pA2 value of 8.44. The synthesis of the radiolabeled compound [3H]LF 7-0156 has allowed direct binding studies with several membrane or cell preparations. Consistent with competition experiments, the binding of [3H]LF 7-0156 to purified rat liver membranes was characterized by a Kd value of 12.6 nM and very low pseudospecific or nonspecific binding; this latter characteristic confers to this compound an advantage over the structurally different compound [3H]DuP 753, which is the only commercially available nonpeptide radioligand. [3H]LF 7-0156 also bound to the type 1A angiotensin receptor expressed in Chinese hamster ovary cells, with high affinity (Kd = 3.5 nM) and a total absence of nonspecific binding. Functional antagonism in this cell system was assessed by the ability of LF 7-0156 to reverse angiotensin II-induced inositol phosphate production. These properties make [3H]LF 7-0156 an interesting pharmacological tool and should allow future evaluation of recognition of the nonpeptide ligand by mutated receptors expressed in Chinese hamster ovary cells; it will facilitate the analysis of possible differences in receptor amino acids involved in the binding of peptide and nonpeptide ligands, as well as the extent of spatial overlap between several nonpeptide antagonists displaying different structural properties.

Volume 46, Issue 4, pp. 693-701, 10/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics