DESIGN, SYNTHESIS, AND BIOLOGICAL-ACTIVITIES OF 4 ANGIOTENSIN-II RECEPTOR LIGANDS WITH GAMMA-TURN MIMETICS REPLACING AMINO-ACID-RESIDUES-3-5

Disulfide cyclization is a powerful method for reducing the conformati onal space of a peptide. This in turn may enable the study of its bioa ctive conformation. Several analogues of angiotensin II (Ang II) conta ining a disulfide bridge between amino acids 3 and 5 have been reporte d. Among these the cyclic octapeptides c[Hcy(3,5)]-Ang II, c[Cys(3,5)] -Ang II, and c[Pen(3,5)]Ang II showed significant activity at Ang II r eceptors. We have performed conformational analysis studies using theo retical calculations and H-1-NMR spectroscopy on tripeptide model comp ounds of these cyclic octapeptides which show that the cyclic moieties of c[Cys(3,5)]-Ang II and c[Pen(3,5)]-Ang II preferentially assume an inverse gamma-turn conformation. On the basis of these results, we su bstituted amino acid residues 3-5 in Ang II with two different gamma-t urn mimetics giving four diastereomeric Ang II analogues. Interestingl y, two of these are equipotent to Ang II in binding to AT(1) receptors . In the contractile test using rabbit aorta rings, one of the analogu es is an agonist with full contractile activity approximately equipote nt to c[Pen(3,5)]-Ang II but 300-fold less potent than Ang II. This lo w potency may suggest that Ang II does not adopt a gamma-turn in the 3 -5 region when interacting with the receptor.