Li Xin, Liu Ke-Liang, Zheng Jian-Quan, Chi Mu-Gen, Dong Jun-Jun, Dong Si-Jian, Gong Ze-Hui
Department of Pharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
Pulm Pharmacol Ther. 2008 Oct;21(5):780-7. doi: 10.1016/j.pupt.2008.06.001. Epub 2008 Jun 11.
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 (ET(A)) antagonist for treatment of pulmonary hypertension, 242 peptide compounds were synthesized by structural optimization of a selective ET(A) receptor antagonist BQ-123. Among these, -azabicyclo[3,2,1]octane-1-yl-l-Leucyl-d-tryptophanyl-d-4-Cl-phenylalanine, named ETP-508, was selected for further harmacological characterization.
Radioligand binding assay was performed to study the binding affinity of ETP-508 for ET(A) and ET(B) 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.
ETP-508 binds to endothelin ET(A) receptor with >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.
These results indicated that ETP-508 is a novel highly selective ET(A) receptor antagonist and may have a great potential to be developed as a drug of anti-pulmonary hypertension.
肺动脉高压是一种死亡率极高的疾病。治疗肺动脉高压的有效药物并不多。已证明用内皮素-1（ET-1）受体拮抗剂治疗肺动脉高压有效。为开发用于治疗肺动脉高压的新型内皮素A受体（ET(A)）拮抗剂，通过对选择性ET(A)受体拮抗剂BQ-123进行结构优化合成了242种肽化合物。其中，名为ETP-508的氮杂双环[3,2,1]辛烷-1-基-L-亮氨酰-D-色氨酰-D-4-氯苯丙氨酸被选用于进一步的药理学特性研究。
进行放射性配体结合试验以研究ETP-508对ET(A)和ET(B)受体的结合亲和力。在离体大鼠主动脉环实验和体循环动脉压实验中评估ETP-508的生物活性。此外，研究了ETP-508对缺氧诱导的肺动脉高压的降压作用。
在大鼠肺组织制备中，ETP-508与内皮素ET(A)受体的结合亲和力比对内皮素B受体高10000倍以上。ETP-508抑制内皮素-1（ET-1）诱导的离体大鼠主动脉环收缩，并使ET-1的累积浓度-收缩反应曲线右移，最大反应无变化。在体内，ETP-508抑制ET-1对平均体循环动脉压的升高作用。静脉输注ETP-508预处理可显著抑制慢性缺氧诱导引起的肺动脉高压和右心室肥厚。ETP-508还显著抑制缺氧诱导的肺ET-1表达水平、血红蛋白、红细胞计数和红细胞压积的升高。此外，ETP-508可部分逆转慢性缺氧预先建立的肺动脉高压和右心室肥厚。
这些结果表明ETP-508是一种新型的高选择性ET(A)受体拮抗剂，具有作为抗肺动脉高压药物开发的巨大潜力。
