DISCOVERY OF L-162,313 - A NONPEPTIDE THAT MIMICS THE BIOLOGICAL ACTIONS OF ANGIOTENSIN-II

L-162,313 l-3-thienyl]phenyl]methyl]-imadazo[4,5-b]pyridine} is a nonp eptide that mimics the biological actions of angiotensin II (ANG II). The intravenous administration of L-162,313 increased blood pressure i n the rat. The maximum increase in mean arterial pressure (MAP) was no t different from the maximum response to ANG II in the same preparatio n. However, the duration of the presser response after L-162,313 great ly exceeded that of ANG II. Pretreatment with ANG II receptor antagoni sts, L-158,809 (AT(1) selective) or saralasin, blocked the L-162,313-i nduced 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 muscl e 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.