Pharmacological characterization of 3-azabicyclo[3,2,1]octane-1-yl-L-leucyl-D-tryptophanyl-D-4-Cl-phenylalanine: A novel ETA receptor-selective antagonist

Background and objectives: Pulmonary hypertension is a kind of disease associated with a very high rate of mortality. There are not many effective drugs for the treatment of pulmonary hypertension. Treatment with ET-1 receptor antagonists was proved to be effective in the treatment of pulmonary hypertension. Aiming at developing new endothelin A receptor (ETA) antagonist for treatment of pulmonary hypertension, 242 peptide compounds were synthesized by structural optimization of a selective ETA receptor antagonist BQ-123. Among these, -azabicyclo[3,2,1]octane- 1-yl-t-Leucyl-D-tryptophanyl-D-4-Cl-phenylalanine, named ETP-508, was selected for further harmacological characterization. Methods: Radioligand binding assay was performed to study the binding affinity of ETP-508 for ETA and ETB receptors. The biological activity of ETP-508 was evaluated in isolated rat aortic ring experiment and in systemic arterial pressure experiment. In addition, hypotensive effect of ETP-508 was investigated on hypoxia-induced pulmonary hypertension. Results: ETP-508 binds to endothelin ETA receptor with beta 10,000-fold higher affinity than to endothelin B receptor in rat lung tissue preparation. ETP-508 inhibited endothelin-1 (ET-1)-induced contraction of isolated rat aortic ring and shifted the cumulative concentration-contraction response curve to ET-1 to right with no change in the maximal response. In vivo, ETP-508 inhibited the increased effect of ET-1 on mean systemic arterial pressure. Pre-treatment with ETP-508 by intravenous infusion significantly inhibited chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy. ETP-508 also significantly inhibited the increase in lung ET-1 expression level, hemoglobin, red-cell count and red-cell hematocrit as induced by hypoxia. Furthermore, ETP-508 partially reversed pre-established pulmonary hypertension and right ventricle hypertrophy by chronic hypoxia. Conclusion: These results indicated that ETP-508 is a novel highly selective ETA receptor antagonist and may have a great potential to be developed as a drug of anti-pulmonary hypertension. 2008 Elsevier Ltd. All rights reserved.