Synthesis of analogs of [8 isoleucine]angiotensin II with variations in position 1

Article abstract of DOI:10.1021/jm00250a013

[Des Asp¹,Ile⁸], [Pro¹,Ile⁸], [MePhe¹,Ile⁸], [Me₂Gly¹,Ile⁸], [MeAla¹,Ile⁸], [MeIle¹,Ile⁸] and [Gac¹,Ile⁸]angiotensin II, synthesized by Merrifield's solid phase procedure, possess 0.4, 0.7, 0.9, 0.6, 1.0, 0.7 and 0.7% pressor activity of angiotensin II (vagotomized, ganglion blocked rats) and pA₂ values (rabbit aortic strips) of 8.04, 8.52, 8.34, 8.87, 9.03, 8.73, and 9.21, respectively. The comparative pA₂ value obtained for [Sar¹,Ile⁸]angiotension II was 9.17. These results suggest that antagonism to contractile response of angiotensin II was reduced when position 1 in [Sar¹,Ile⁸]angiotensin II was replaced by a hydrogen atom or a cyclic imino acid (proline). Antagonistic activity was also reduced when the α carbon atom of sarcosine was substituted with an aromatic side chain (N methylphenylalanine). In contrast, the presence of a branched aliphatic residue at the α carbon atom (N methylisoleucine), an additional methyl group at the nitrogen atom of sarcosine (dimethylglycine), or replacement of sarcosine by a highly basic moiety (guanidineacetic acid) had little effect on the in vitro antagonistic potency of the parent compound.