Studies on angiotensin II and analogs: impact of substitution in position 8 on conformation and activity.

Abstract

Affinity, residual agonist activity, and inhibitor properties of a series of angiotensin II analogs modified at the COOH-terminal position (X8-substituted peptides) have been probed for structure/conformation-biological activity relationships. The results emphasize (t) the large impact that subtle conformational variations caused by structural alterations in the position 8 side chain have on biological properties, (it) the implication of the COOH-terminal carboxyl group in both affinity and intrinsic activity, and (Wi) the influence that the bulkiness of the side chain in position 8 of antagonists has on the local conformation at the COOH terminus and thus on the inhibitory properties. In the hormone, the phenylalanine-8 ring is required for its steric influence and aromaticity to ensure a fully active conformation at the COOH terminus. Especially, correct orientation of the position 8 carboxyl group relative to the phenyl group of the phenylalanine residue may be necessary for agonistic activation of the angiotensin receptor complex. Replacement of the aromatic ring on the COOHterminal residue by a nonaromatic group leads to incorrect orientation of the carboxyl group and causes the appearance of antagonist properties. Although the steric effects of the side chain can be modulated by specific interaction of its chemical groups (if any) with the peptide backbone, we found a good correlation between the size of the side chain-e.g., the steric parameter Vy (the van der Waals volume consisting of the C., Cp, and Cy atoms), the conformational properties in the backbone (3J HC.t-NH), and the binding capacities in all compounds tested.

Identification of Distinct Conformations of the Angiotensin-II Type 1 Receptor Associated with the Gq/11 Protein Pathway and the β-Arrestin Pathway Using Molecular Dynamics Simulations

“…The ability to insert in the hydrophobic core and elicit the conformational change could be unique to the phenyl moiety, as mutation of this residue to a tyrosine or diphenylalanine are the only tolerated changes that do not lead to an AngII analog with an antagonist profile on the G q/11 pathway. Indeed, substitution of Phe 8 for other hydrophobic residues, such as alanine, leucine, or isoleucine, turns the ligand into an antagonist on the G q/11 pathway (15,(63)(64)(65). However, a larger side chain such as (pentabromo)Phe-8 or a change of orientation from L-Phe-8 to D-Phe-8 also results in conferring an antagonistic nature on the G q/11 pathway (66,67).…”

Pathways of angiotensin formation and function in the brain.

“…Although our studies were carried out in the brain, the information is applicable to other organs that contain a functional RAS. It is quite possible [1][2][3][4][5][6][7][8][9][10][11][12][13][14] Supplement I Hypertension Vol 15, No 2, February 1990 that the production of biologically active angiotensin peptides in various tissues is accounted for by mechanisms that diverge from the accepted RAS cascade described in the peripheral circulation. 4 Biological Actions of Angiotensin II:…”

Loss of contractile activity of endothelin‐1 induced by electrical field stimulation‐generated free radicals

“…However, the EIA used in the present study can detect Met sulphoxide7 (Met(o)7) ET-1 as well as ET-1 (Suzuki, personal communication). Moreover, Met(o)7 ET-1 also has similar contractile activity to ET-1 (Kimura, unpublished data (Aumelas et al, 1985;Mann et al, 1986). Further study is required to determine whether EFS-derived hydroxyl radicals actually oxidize Trp2" of ET-1.…”