Molecular pharmacology of LR-B/081, a new non-peptide angiotensin AT1 receptor antagonist

This report describes the molecular pharmacological properties of LR-B/081 (methyl 2-[[4-butyl-2-methyl-6-oxo-5-[ [2′-(1H-tetrazol-5-yl) [1,1′-biphenyl]-4-yl]methyl]-1 (6H)-pyrimidinyl]methyl]-3-thiophenecarboxilate), a novel non-peptide angiotensin II receptor antagonist. This compound potently displaced [³H]angiotensin II from angiotensin AT₁ (K_i = 1.4 nM, rat adrenal cortex), but not from angiotensin AT₂ (K_i > 1 ωM, bovine cerebellar cortex) receptors and did not show affinity for other receptor systems (K_i > 10 ωM). In saturation studies, LR-B/081 both increased K_D and decreased B_max values in a dose-dependent fashion. The rate of dissociation of [³H]angiotenin II from angiotensin AT₁ receptors was not affected by the presence of 1 ωM LR-B/081 and the association rate of [³H]angiotensin II was not decreased by the presence of 1 or 30 nM LR-B/081, indicating that the B_max reduction was not due to an allosteric interaction or to a delay in reaching the steady-state conditions. These data underline the complexity of the antagonistic nature of LR-B/081, presenting features of both competitive and noncompetitive antagonism.