title: Molecular pharmacology of LR-B/081, a new non-peptide angiotensin AT1 receptor antagonist.
abstract: 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 (Ki = 1.4 nM, rat adrenal cortex), but not from angiotensin AT2 (Ki > 1 microM, bovine cerebellar cortex) receptors and did not show affinity for other receptor systems (Ki > 10 microM). In saturation studies, LR-B/081 both increased KD and decreased Bmax 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 microM 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 Bmax 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.
authors.affiliation: Department of Pharmacology, Laboratori Guidotti, Pisa, Italy.
authors.forename: A R
authors.initials: AR
authors.lastname: Renzetti
authors.forename: M
authors.initials: M
authors.lastname: Criscuoli
authors.forename: A
authors.initials: A
authors.lastname: Salimbeni
authors.forename: A
authors.initials: A
authors.lastname: Subissi
mesh_terms: D000302:Adrenal Cortex / Q000187:drug effects; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D002531:Cerebellum / Q000187:drug effects; D006801:Humans; D008297:Male; D015394:Molecular Structure; D011744:Pyrimidinones / Q000494:pharmacology*; D051381:Rats; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; C094835:LR B-081; D011744:Pyrimidinones; D013876:Thiophenes