MOLECULAR PHARMACOLOGY OF LR-B 081, A NEW NONPEPTIDE ANGIOTENSIN AT(1) RECEPTOR ANTAGONIST/

This report describes the molecular pharmacological properties of LR-B /081 (methyl [[4-butyl-2-methyl-6-oxo-5-[[2'-(1H-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl]-1 (6H)-pyrimidinyl]methyl]-3-thiophenecarboxila te), a novel non-peptide angiotensin II receptor antagonist. This comp ound potently displaced [H-3]angiotensin II from angiotensin AT(1) (K- i = 1.4 nM, rat adrenal cortex), but not from angiotensin AT(2) (K-i > 1 mu M, bovine cerebellar cortex) receptors and did not show affinity for other receptor systems (K-i > 10 mu M). In saturation studies, LR -B/081 both increased K-D and decreased B-max values in a dose-depende nt fashion. The rate of dissociation of [H-3]angiotenin II from angiot ensin AT(1) receptors was not affected by the presence of 1 mu M LR-B/ 081 and the association rate of [H-3]angiotensin II was not decreased by the presence of 1 or 30 nM LR-B/081, indicating that the B-max redu ction was not due to an allosteric interaction or to a delay in reachi ng the steady-state conditions. These data underline the complexity of the antagonistic nature of LR-B/081, presenting features of both comp etitive and noncompetitive antagonism.