Discovery of l-162,313: a nonpeptide that mimics the biological actions of
angiotensin-ii.
Kivlighn, Salah D., William R. Huckle, Gloria J. Zingaro, Ralph A. Rivero,
Victor J. Lotti, Raymond S. L. Chang, Terry W. Schorn, Nancy Kevin, Robert G.
Johnson, Jr, William J. Greenlee, & Peter K. S. Siegl.
Department of Cardiovascular Pharmacology, Merck Research Laboratories,
West Point Pennsylvania 19486, Department of Exploratory Chemistry, Merck
Research Laboratories, Rahway, New Jersey 07065, Department of New Lead
Pharmacology, Merck Research Laboratories, West Point Pennsylvania 19486
APStracts 2:0001R, 1995.
L-162,313, 5,7-dimethyl-2-ethyl-3-[[4-[2(n-butyloxycarbonyl
sulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imadazo[4,5-6]
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 following 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 ACE-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.
Received 13 October 1994; accepted in final form 6 January 1995.
APS Manuscript Number R596-4RC.
Article publication pending Am. J. Physiol. (Regulatory Integrative Comp.
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 25 February 1995.