Monocyclic Endothelins

Monocyclic fragment analogues of endothelin-1 (ET-1) were prepared by standard solid-phase peptide synthetic methods. The analogues were designed to determine the importance of the unique bicyclic structure of the endothelins, vasoactive intestinal contractor, and the sarafotoxins to their binding affinity and functional activity. The binding affinity of the monocyclic analogues to the endothelin receptor was examined in three tissue preparations: (a) rabbit pulmonary artery, (b) rabbit aorta, and (c) rat heart ventricle. Functional activity was assessed in two tissues: (a) rabbit pulmonary artery and (b) rat left atria. Binding was not observed for the disulfide bridged cyclic 3-11 loop of ET-1 at concentrations of up to 100 microM. Attachment of the weakly binding 16-21 C-terminal hexapeptide of ET-1 to the cyclic 3-11 loop did not significantly enhance the observed receptor binding over that of the hexapeptide. Monocyclic Cys-Ser-Aoc-Val-Tyr-Phe-Cys-His-Leu-Asp-Ile-Ile-Trp (Aoc = 8-aminooctanoic acid) exhibited the greatest binding affinity (1.0 to 1.6 microM) in all three tissues, but was still approximately 1,000-fold less effective than ET-1. At concentrations of up to 30 microM, none of the analogues exhibited any functional activity.