AJP - Regulatory, Integrative and Comparative Physiology, Vol 268, Issue 3 820-R823, Copyright © 1995 by American Physiological Society
Discovery of L-162,313: a nonpeptide that mimics the biological actions of angiotensin II
S. D. Kivlighn, W. R. Huckle, G. J. Zingaro, R. A. Rivero, V. J. Lotti, R. S. Chang, T. W. Schorn, N. Kevin, R. G. Johnson Jr, W. J. Greenlee and al. et
Department of Cardiovascular Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486.
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.
