Investigations of Structural Requirements for Endothelin Antagonism

Abstract

Following the isolation of the vasoactive peptide, endothelin (ET), considerable effort has been expended in the development of ET antagonists, some of which have recently been proved to be promising therapeutic agents. Their clinical potential, however, is often limited because of a peptidic nature or a non-selective ETA/ETB receptor antagonism. While many non-peptide ET antagonists are optimised ad hoc from a lead compound found during a compound screening program, directing the development of a molecule towards a selectivity for the ETA or ETB receptor rests upon the elucidation of the respective receptor-binding conformation of ET-1 and ET-3, or a template structure derived from a peptide antagonist whose structure/activity relationship is well characterised. This review focuses on peptide ET antagonists whose structure/activity relationships are well characterised and so provides some insight to the conformational criteria required of putative ETA or ETB receptor selective antagonists. Although the conformation of ET has been previously reported in depth on many occasions a brief summary is provided here in order to relate the structure/activity relationships of the ET antagonists to the structure of ET. The list of ET antagonists discussed here is not comprehensive, since the emphasis for the review has been to focus on studies where structural data were obtained which shed light on the receptor binding conformation(s) of endothelin.