Organ selective angiotensin antagonists: Sarcosyl1-cysteinyl(s-methyl)8-angiotensin I

An angiotensin antagonist, Sarcosyl1-Cysteinyl(S-Methyl)8-angiotensin I [Sar1-Cys(Me)8-ANG I] was synthesized and its pharmacological properties evaluated in vivo (rat blood pressure assay) and in vitro (rabbit aortic strip, guinea-pig ileum and rat uterus assay). It was found to be an extremely potent angiotensin II (ANG II) antagonist in the rat pressor assay (dose ratio for ANG II of 1300 during infusion of 5.0 μg/kg/min Sar1-Cys-(Me)8-ANG I) and a moderately effective antagonist in guinea-pig ileum (pA2 ≅ 8.2). Moderate antagonism was also seen in the rabbit aortic strip preparation (pA2 ≅ 8.1) while the analog was inactive in the rat uterus assay. In each of the preparations where antagonist activity was observed there was evidence of non-competitive antagonism. Most striking was the inability of extremely high doses (up to 125 μg ANG II/kg) of ANG II to overcome the Sar1-Cys(Me)8-ANG I blockade. In both the rat pressor and guinea-pig ileum assays the Sar1-Cys(Me)8-ANG I antagonism is completely abolished in the presence of the converting enzyme inhibitor SQ14225 (Captopril®-Squibb). Organ selectivity of this analog is discussed in terms of the inherent activity of the active principle (i.e. the Sar1-Cys(Me)8-angiotensin II [Sar1-Cys(Me)8-ANG II] released by the action of converting enzyme) and the availability of converting enzyme in each bioassay.