title: Discovery of L-162,313: a nonpeptide that mimics the biological actions of angiotensin II.
abstract: L-162,313 (5,7-dimethyl-2-ethyl-3-[[4-[2(n- butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]- imadazo[4,5-b]pyridine) is a nonpeptide that mimics the biological actions of angiotensin II (ANG II). The intravenous administration of L-162,313 increased blood pressure in the rat. The maximum increase in mean arterial pressure (MAP) was not different from the maximum response to ANG II in the same preparation. However, the duration of the pressor response after L-162,313 greatly exceeded that of ANG II. Pretreatment with ANG II receptor antagonists, L-158,809 (AT1 selective) or saralasin, blocked the L-162,313-induced increase in MAP. Enalaprilat, an angiotensin-converting enzyme inhibitor, failed to block the MAP response to L-162,313. In vitro, L-162,313-activated phosphoinositide turnover in rat aortic smooth muscle cell cultures was also blocked by L-158,809 and losartan (DuP-753). Therefore, L-162,313 is the first reported nonpeptide ANG II receptor agonist.
authors.affiliation: Department of Cardiovascular Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: S D
authors.initials: SD
authors.lastname: Kivlighn
authors.forename: W R
authors.initials: WR
authors.lastname: Huckle
authors.forename: G J
authors.initials: GJ
authors.lastname: Zingaro
authors.forename: R A
authors.initials: RA
authors.lastname: Rivero
authors.forename: V J
authors.initials: VJ
authors.lastname: Lotti
authors.forename: R S
authors.initials: RS
authors.lastname: Chang
authors.forename: T W
authors.initials: TW
authors.lastname: Schorn
authors.forename: N
authors.initials: N
authors.lastname: Kevin
authors.forename: R G
authors.initials: RG
authors.lastname: Johnson
authors.forename: W J
authors.initials: WJ
authors.lastname: Greenlee
mesh_terms: D000804:Angiotensin II / Q000819:agonists*; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D007093:Imidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D007275:Injections, Intravenous; D008024:Ligands; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000819:agonists / Q000145:classification / Q000502:physiology
chemical_list: D001713:Biphenyl Compounds; D007093:Imidazoles; C091630:L 162313; D008024:Ligands; D010716:Phosphatidylinositols; D011945:Receptors, Angiotensin; D000804:Angiotensin II