Synthesis, Biological Activity, and ¹⁹F Nuclear Magnetic Resonance Spectra of Angiotensin II Analogs Containing Fluorine

[Asp¹,p-fluoro-L-phenylalanine⁴]-angiotensin II ([pFPhe⁴]-AII) and [Asp¹,p-fluoro-L-phenylalanine8]-angiotensin II ([pFPhe⁸]]AII) were synthesized by the solid-phase procedure in order to study their biological activity and ¹⁹F nuclear magnetic resonance (nmr) spectra. p-Fluoro-D,L-phenylalanine was resolved by enzymatic hydrolysis of N-trifluoroacetyl-p-fluoro-D.L-phenylalanine with carboxy-peptidase A. [pFPhe⁸]-AII is at least as potent as angiotensin II and [pFPhe⁴]-AII is an antagonist of angiotensin II in the rat oxytocic, the rat blood pressure, and the prostaglandin release assay. The ¹⁹F nmr spectra of [pFPhe⁸]]AII show that the C-terminal carboxyl has a pK_a, of 3.1, that above pH 7 two conformations exist, and that the rate of exchange between these two conformations is slow on the nmr time scale. A conformational change with a pK of 6.1 is the most likely cause of the chemical shift change seen in the ¹⁹F nmr spectra of [pFPhe⁴]-AII.