Influence of polyfluorination of the phenylalanine ring of angiotensin II on conformation and biological activity.
[Phe(F5)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 Phe8 ring quadrupole moment in angiotensin II decreases agonist activity and invokes antagonist properties. 1H-NMR studies at 400 MHz in DMSO-d6 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 C2 and C4 protons in [Phe(F5)]ANG II compared to ANG II suggest that the Phe(F5) 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(F5) ring occur at relatively long range.
Bovy
P R
PR
Searle Research and Development, Monsanto Life Sciences Research Center, Chesterfield, MO.
Getman
D P
DP
Matsoukas
J M
JM
Moore
G J
GJ
D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005461:Fluorine / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010649:Phenylalanine / Q000737:chemistry*; D011487:Protein Conformation; D011817:Rabbits; D051381:Rats; D014599:Uterus / Q000737:chemistry
D000804:Angiotensin II; D005461:Fluorine; D010649:Phenylalanine