STRUCTURE-ACTIVITY-RELATIONSHIPS OF C-TERMINAL ENDOTHELIN HEXAPEPTIDEANTAGONISTS

The discovery of selective endothelin (ET) receptor antagonists will f acilitate identification of the physiological and pathological roles f or ET and its isopeptides. Structure-activity studies of the C-termina l hexapeptide of ET have been carried out to elucidate those amino aci ds important for receptor binding and agonist or antagonist activity. Binding studies were performed in rat heart ventricle, rabbit renal ar tery vascular smooth muscle cells, and rat cerebellum. In addition, ma ny of the compounds have been evaluated functionally for their effects on endothelin-1-induced arachidonic acid release and inositol phospha te accumulation in specific cell lines. Selected compounds have been e valuated in a functional bioassay in tissue preparations specifically expressing either ET(A) or ET(B) receptors. We have previously describ ed the structure-activity relationships in the hydrophobic C-terminal hexapeptide of ET, a region known to be highly important for receptor recognition. A mono-D-amino acid scan of the ET[16-21] revealed that s ubstitution at His16 gave rise to analogs with significantly enhanced binding affinity. We have further evaluated the C-terminal region and will describe the design, synthesis, and pharmacological evaluation of several novel and potent ET peptide receptor antagonists.