X.-M. Cheng, S.S. Nikam and A.M. Doherty* Pages 271 - 312 ( 42 )
Due partly to a greater understanding of the role of regulatory peptides and proteins in the pathophysiology of human disease there is considerable interest in designing agents that will modulate their effects. Endothelin-1 and its isopeptides belong to a family of novel vasoconstrictor agents first isolated from porcine aortic endothelial cells and subsequently found to be secreted from a variety of cell types. These peptides have potent biological effects on cardiovascular, renal, endocrine and neurological function. The rational design of receptor agonists and antagonists or proce ssing inhibitors from a ligand of interest, requires an understanding of the binding mode of the natural ligand(s) to the receptor(s) or enzyme and the relative importance of individual residues to binding. Screening of compound libraries and lead optimization techniques have also lead to pote'lt antagonists and processing enzyme inhibitors. This review will describe the progress achieved to date using both of these techniques to discover novel and potent endothelin agonists and antagonists of differing selectivity for the known ET receptor subtypes. Progress towards to design of endothelin converting enzyme inhibitors is also discussed. the discovery of agents to modulate the effects of endothelin will prove useful in elucidating the role of the endothelin family of peptides in human physiology and pathophysiology.