Molecular Pharmacology, Vol 12, 217-224, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Analogues of Angiotensin II with Restricted Conformational Freedom, Including a New Antagonist

¹ Departments of Biological Chemistry, Pharmacology, and Physiology and Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110

Two analogues of angiotensin II (AII) and one analogue of the AII antagonist [1-sarcosine, 8-valine]-angiotensin II ([Sar¹, Va1⁸]-AII) have been synthesized which contain a methyl group in the place of a proton on -carbon 4 or 8. Theoretical studies indicate that these analogues should have restricted conformational freedom. The relatively high activity of the position 4 analogue in the rat uterus and blood pressure assays, when interpreted in the light of previous structure-activity studies, allows the tentative assignment of the torsional angles and at position 4 in the receptor-bound conformation of AII. These values differ from those determined for AII in solution. The position 8 analogue, [Sar¹, Val(Me)⁸]-AII is itself an antagonist and is 7 times more potent in vivo than [Sar¹, Val⁸]-AII.