Synthesis and evaluation of [des-Asp1]angiotensin I as a precursor for [des-Asp1]angiotensin II (angiotensin III)

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Abstract
The nonapeptide [des-Asp1]angiotensin I (IV), synthesized by Merrifield''s solid-phase procedure, was tested as a possible substrate for the converting enzymes from porcine lung and plasma. IV, [des-Asp1]angiotensin II (III), [des-(Asp1,Arg2)]angiotensin II (V), [des-(Asp1,Arg2,Val3)]angiotensin II (VI), [Sar1,Ile8]angiotensin II (VII) and [des-Asp1,Ile8]angiotensin II (VIII) possessed 0.5, 20, 2, 0, < 0.1 and < 0.01% of the inotropic activity (rabbit atria), 1, 15, 5, 0, 3 and 0% secretory activity of the cat adrenal medulla and 0.0, 150, 1, 0.5, 3 and 10% of the adrenal steroidogenic activity of angiotensin II, respectively. When tested for their antagonistic activity in the above tissues, only VII and VIII inhibited responses to angiotensin II. The pA2 values for VII and VIII were 8.31 and 10.0 in the adrenal cortex and 9.31 and 9.16 in the adrenal medulla, respectively. All these peptides were tested as product inhibitors for the plasma and lung converting enzymes. With the plasma enzyme, median inhibitory dose (ID50) values were II, 1.6 .times. 10-4 M; III, 5 .times. 10-5 M; V, 1.2 .times. 10-4 M; VI, 5 .times. 10-4 M; VII, 5 .times. 10-5 M; VIII, 5 .times. 10-4 M. IV is a good substrate for converting enzymes from lung and plasma while all other compounds were inhibitors of these enzymes. The most potent inhibitors of converting enzyme were III followed by VII and VIII. With the exception of II and III all the other analogs had very low intrinsic activities. These results suggest an alternate pathway for the formation of the heptapeptide III, i.e., by the action of converting enzyme on the nonapeptide IV and that III may also be acting as inhibitor of the converting enzyme by the feedback mechanism.

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