Novel peptide-based endothelin (ET) receptor antagonists were designed and synthesized in our laboratory. BQ-485, HIM-CO-Leu-d-Trp-d-Trp-OH, was selected as the leading compound. The primary structures of these new tripeptides were ABO-CO-Leu-d-Trp-d-AA(X)-OH. The introduction of unnatural aromatic amino acids into these tripeptides was useful in the structure-activity relationship studies. Among the 20 tripeptides, 16 of them showed high activities against the contraction of rat aortic smooth muscles induced by ET-1.