Solution-structure of a Peptide Designed to Mimic the C-terminal Hexapeptide of Endothelin

The peptide: Ac‐cyclo(Cys‐His‐Leu‐Asp‐Cys)‐Ile‐Trp‐OH, has been designed by computer‐aided molecular‐modelling techniques to mimic the proposed α‐helical conformation of the C‐terminal hexapeptide of endothelin. Two‐dimensional proton nuclear magnetic resonance spectra were acquired for the peptide dissolved in d6‐DMSO or D2O‐H2O and the distance and angle constraints incorporated into simulated annealing experiments. Conformers generated from the D2O‐H2O data superposed on the corresponding main‐chain atoms in the crystal structure of endothelin 1 and the solution structure of BQ‐123 with root mean square co‐ordinate differences of 0·9 Å and 0·77 Å, respectively. The peptide did not elicit antagonism of endothelin‐induced in‐vitro contractions of rabbit aorta (endothelin A receptor) or rabbit bronchus (endothelin B receptor) preparations. Because the peptide can adopt a conformer which closely matches the equivalent residues in the endothelin 1 crystal structure and in BQ‐123, we suggest BQ‐123 does not necessarily mimic the endothelin C‐terminal region to achieve its antagonism, and that a helical conformation of the endothelin C‐terminal hexapeptide does not favour its interaction at the endothelin B receptor.