Influence of polyfluorination of the phenylalanine ring of angiotensin II on conformation and biological activity

• Published in: Biochimica et biophysica acta Vol. 1079; no. 1; pp. 23 - 28
• Main Authors: Bovy, Philippe R., Getman, Daniel P., Matsoukas, John M., Moore, Graham J.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 09.08.1991; Elsevier
• Subjects: Amino Acid Sequence; Aminoacids, peptides. Hormones. Neuropeptides; Analytical, structural and metabolic biochemistry; Angiotensin II; Angiotensin II - chemistry; Angiotensin II - isolation & purification; Angiotensin II - metabolism; Animals; Aorta - chemistry; Biological and medical sciences; Chromatography, High Pressure Liquid; Conformation by NMR; Female; Fluorine - chemistry; Fundamental and applied biological sciences. Psychology; Humans; Magnetic Resonance Spectroscopy; Molecular Sequence Data; Pentafluorophenylalanine; Phenylalanine - chemistry; Protein Conformation; Proteins; Rabbits; Rats; Receptor mechanism; Uterus - chemistry; RP-HPLC; Receptor mechanism; Angiotensin II; NOE; Conformation by NMR; Pentafluorophenylalanine; Phenylalanine; Rat; Peptide hormone; Rodentia; Overhauser effect; Rabbit; Smooth muscle; NMR spectrometry; Lagomorpha; Muscle contraction; Biological activity; Two dimension spectrometry; Vertebrata; Mammalia; Structure activity relation; Analog; Antagonist; Fluorination; Conformational transition
• ISSN: 0167-4838; 0006-3002; 1879-2588
• DOI: 10.1016/0167-4838(91)90019-V

[Phe(F 5) 8]angiotensin II was synthesized by the solid phase method and purified by reverse-phase HPLC. In rat uterus and rabbit aorta bioassays the analogue had 10 and 50%, respectively, of the contractile activity of angiotensin II and demonstrated antagonist properties. These findings illustrate that inversion of the Phe 8 ring quadrupole moment in angiotensin II decreases agonist activity and invokes antagonist properties. 1H-NMR studies at 400 MHz in DMSO-d 6 demonstrated the presence of cis and trans isomers in the ratio 1 : 3 due to restricted rotation of the His-Pro bond. Downfield shifts of the His C 2 and C 4 protons in [Phe(F 5)]ANG II compared to ANG II suggest that the Phe(F 5) residue may be involved in a parallel-plate ring pairing interaction with the imidazole group. However heteronuclear NOE studies, carried out by measuring the proton difference spectrum before and after saturation of the fluorine resonances, showed the absence of any NOE enhancement illustrating that electrostatic influences of the Phe(F 5) ring occur at relatively long range.