INVESTIGATIONS OF STRUCTURAL REQUIREMENTS FOR ENDOTHELIN ANTAGONISM

Following the isolation of the vasoactive peptide, endothelin (ET), co nsiderable effort has been expended in the development of ET antagonis ts, some of which have recently been proved to be promising therapeuti c agents. Their clinical potential, however, is often limited because of a peptidic nature or a non-selective ETA/ETB receptor antagonism. W hile many non-peptide ET antagonists are optimised ad hoc from a lead compound found during a compound screening program, directing the deve lopment of a molecule towards a selectivity for the ETA or ETB recepto r rests upon the elucidation of the respective receptor-binding confor mation of ET-1 and ET-3, or a template structure derived from a peptid e antagonist whose structure/activity relationship is well characteris ed. This review focuses on peptide ET antagonists whose structure/acti vity relationships are well characterised and so provides some insight to the conformational criteria required of putative ETA or ETB recept or selective antagonists. Although the conformation of ET has been pre viously reported in depth on many occasions a brief summary is provide d here in order to relate the structure/activity relationships of the ET antagonists to the structure of ET. The list of ET antagonists disc ussed here is not comprehensive, since the emphasis for the review has been to focus on studies where structural data were obtained which sh ed light on the receptor binding conformation(s) of endothelin.