ANGIOTENSIN-II ANALOGS .12. ROLE OF THE AROMATIC RING OF POSITION-8 PHENYLALANINE IN PRESSOR ACTIVITY

To evaluate the relative contributions to pressor activity of lipophilic and aromatic character for the phenyl ring of position 8 phenylalanine in [Asn1, lie5] angiotensin II, the benzyl side chain was replaced by a variety of normal or branched aliphatic and substituted aromatic residues. A conformationally constrained analogue in which the 2-aminoindane-2-carboxylic acid (Ind) replaced the phenylalanine residue was prepared in order to examine the steric requirement for the aromatic ring for pressor activity. The analogues were synthesized by the solid-phase method and had the following pressor activities in the rat: Ahp8. 11.5%, Nle8, 7.3%; Leu8, 1.2%; Ind8, 0.1%; Phe(4-NH2)8, 52.5%; Phe(4-NO2)8, 15%; and the disubstituted analogues [SarLeu8]AII, 2.5%; [des-Asp1. D-Ala2, Leu8]AII, 1.4%; [Tyr(3-Bzl)4, Phe(4-NO2)8]AII, 0.2%. In the absence of aromatic character, higher lipophilicity of the analogues resulted in higher pressor activity. However, aromaticity was more important than lipophilic character and was necessary for full activity. Steric interference, caused by a bulky substituent on the ring or by branching of the aliphatic residue, resulted in reduced potency. When the sizes of the substituents were comparable, the aromatic, 7r-electron-enriched analogues were more active than the-r-electron-deficient analogues. The spatial orientation of the ring relative to the peptide backbone was critical for the pressor effect. [Ind8]AII was essentially lacking in pressor activity and was more potent than [Leu8]AII as an All antagonist, in spite of its aromatic nature. Substitution of sarcosine in position 1 greatly enhanced the potency and duration of antagonist activity. [SarLeu8]AII was more potent and longer acting than [Ind8]AII as an angiotensin II inhibitor. These results suggest that incorporation of a conformationally constrained aromatic ring in position 8 of angiotensin analogues can be an effective approach to the development of potent inhibitors with low pressor activity. © 1979, American Chemical Society. All rights reserved.