The substitution of an unnatural amino acid, 1-aminocyclopentanecarboxylic acid (Acpc), for each of the eight amino acids of angiotensin (AT) has been used to study the relationship between chemical structure and biological activities of angiotensin. The pressor and the myotropic activities of the various ATII derivatives have been tested on the rat blood pressure and on three isolated organs: rat isolated colon, rat stomach strip, and rabbit isolated kidney.The results indicate that 6-His and 8-Phe are essential for the activities of angiotensin II. Moreover, (8-Acpc)-ATII, but not (6-Acpc)-ATII, antagonizes the pressor and myotropic effects of ATII and ATI. αE and pD2 of all analogues have been estimated on the isolated rat stomach strip to evaluate intrinsic activity and affinity for the receptors. (1-, (2-, (3-, (4-, and (5-Acpc)-ATII have the same intrinsic activities as ATII, while those of (6-, (7-, and (8-Acpc)-ATII are much lower.Analogues of ATII substituted in position 8 antagonize specifically the myotropic and pressor effects of ATII and ATI. On the contrary, the effects of other smooth muscle stimulating agents (acetylcholine, 5-hydroxytryptamine, bradykinin, and vasopressin) are not modified.Log dose response curves of ATII and ATI are shifted to the right in the presence of antagonists, but remain parallel. The antagonism is rapidly reversible and may be competitive.
