Ihara M, Noguchi K, Saeki T, Fukuroda T, Tsuchida S, Kimura S, Fukami T, Ishikawa K, Nishikibe M, Yano M
Central Research Labs., Banyu Pharmaceutical Co., Ltd., Tokyo, Japan.
Life Sci. 1992;50(4):247-55. doi: 10.1016/0024-3205(92)90331-i.
We describe novel potent endothelin (ET) antagonists that are highly potent and selective for the ETA receptor (selective to ET-1). Of the synthetic analogs based on ETA antagonist BE-18257A isolated from Streptomyces misakiensis (IC50 value for ETA receptor on porcine aortic smooth muscle cells (VSMCs); 1.4 microM), the compounds BQ-123 and BQ-153 greatly improved the binding affinity of [125I]ET-1 for ETA receptors on VSMCs (IC50; 7.3 and 8.6 nM, respectively), whereas they barely inhibited [125I]ET-1 binding to ETB receptors (nonselective with respect to isopeptides of ET family) in the cerebellar membranes (IC50; 18 and 54 microM, respectively). Associated with the increased affinity for ETA receptors, these peptides antagonized ET-1-induced constriction of isolated porcine coronary artery. However, there was a small amount of ET-1-induced vasoconstriction resistant to these antagonists, which paralleled the incomplete inhibition of [125I]ET-1 binding in the membrane of the aortic smooth muscle layer. These data suggest that the artery has both ETA and ETB receptors responsible for ET-1-induced vasoconstriction. The antagonists shifted the concentration-response curve to the right for ET-1 in the coronary artery, and increased the apparent dissociation constant in the Scatchard analysis of [125I]ET-1 binding on the VSMCs without affecting the binding capacity, indicative of the competitive antagonism for ETA receptor. In conscious rats, pretreatment with the antagonists markedly antagonized ET-1-induced sustained pressor responses in dose-dependent fashion without affecting ET-1-induced transient depressor action, suggesting that the pressor action is mediated by ETA receptors, while the depressor action is mediated by ETB receptors. In addition, pretreatment with the potent antagonists prevented ET-1-induced sudden death in mice. Thus, these potent ETA antagonists should provide a powerful tool for exploring the therapeutic uses of ETA antagonists in putative ET-1-related disorders.
我们描述了新型强效内皮素（ET）拮抗剂，它们对ETA受体具有高效力和选择性（对ET-1具有选择性）。从链霉菌中分离出的基于ETA拮抗剂BE-18257A的合成类似物（猪主动脉平滑肌细胞（VSMC）上ETA受体的IC50值；1.4 microM）中，化合物BQ-123和BQ-153极大地提高了[125I]ET-1与VSMC上ETA受体的结合亲和力（IC50分别为7.3和8.6 nM），而它们几乎不抑制[125I]ET-1与小脑膜中ETB受体（对ET家族的异肽无选择性）的结合（IC50分别为18和54 microM）。与对ETA受体亲和力的增加相关，这些肽拮抗ET-1诱导的离体猪冠状动脉收缩。然而，存在少量对这些拮抗剂有抗性的ET-1诱导的血管收缩，这与主动脉平滑肌层膜中[125I]ET-1结合的不完全抑制平行。这些数据表明，该动脉具有负责ET-1诱导血管收缩的ETA和ETB受体。拮抗剂使冠状动脉中ET-1的浓度-反应曲线向右移动，并在对VSMC上[125I]ET-1结合的Scatchard分析中增加了表观解离常数，而不影响结合容量，表明对ETA受体具有竞争性拮抗作用。在清醒大鼠中，用拮抗剂预处理以剂量依赖性方式显著拮抗ET-1诱导的持续升压反应，而不影响ET-1诱导的短暂降压作用，表明升压作用由ETA受体介导，而降压作用由ETB受体介导。此外，用强效拮抗剂预处理可预防ET-1诱导的小鼠猝死。因此，这些强效ETA拮抗剂应为探索ETA拮抗剂在假定的ET-1相关疾病中的治疗用途提供有力工具。
