BIOLOGICAL PROFILES OF HIGHLY POTENT NOVEL ENDOTHELIN ANTAGONISTS SELECTIVE FOR THE ETA RECEPTOR
BIOLOGICAL PROFILES OF HIGHLY POTENT NOVEL ENDOTHELIN ANTAGONISTS SELECTIVE FOR THE ETA RECEPTOR
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DOI：
10.1016/0024-3205(92)90331-i
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发表时间：
1992-01-01
期刊：
影响因子：
6.1
通讯作者：
YANO, M
中科院分区：
文献类型：
--
作者：
IHARA, M;NOGUCHI, K;YANO, M
我们描述了新的有效的内皮素（ET）拮抗剂，其对ET（A）受体（对ET-1具有选择性）具有高度效力和选择性。 基于从链霉菌miskiensis分离的ET（A）拮抗剂BE-18257 A的合成类似物（对猪主动脉平滑肌细胞（VSMCs）上ET（A）受体的IC 50值; 1.4 μ M），化合物BQ-123和BQ-153极大地提高了[I-125]ET-1对VSMCs上ET（A）受体的结合亲和力（IC 50;分别为7.3和8.6 nM），而它们几乎不抑制[I-125]ET-1与小脑膜中ET（B）受体（对ET家族的异肽无选择性）的结合（IC 50;分别为18和54 μ M）。 这些肽与ET（A）受体的亲和力增加，拮抗ET-1诱导的离体猪冠状动脉收缩。 然而，有少量的ET-1诱导的血管收缩抵抗这些拮抗剂，这说明不完全抑制[I-125]ET-1结合在主动脉平滑肌层的膜。 这些数据表明，动脉有ET（A）和ET（B）受体负责ET-1诱导的血管收缩。 拮抗剂使ET-1在冠状动脉中的浓度-反应曲线右移，并在[I-125]ET-1与VSMCs结合的Scatchard分析中增加表观解离常数，而不影响结合容量，表明对ET（A）受体具有竞争性拮抗作用。 在清醒大鼠，预先给予拮抗剂可剂量依赖性地拮抗ET-1诱导的持续性升压反应，而不影响ET-1诱导的短暂性降压作用，提示升压作用由ET（A）受体介导，降压作用由ET（B）受体介导。 此外，用有效的拮抗剂预处理可防止ET-1诱导的小鼠猝死。 因此，这些有效的ET（A）拮抗剂应该为探索ET（A）拮抗剂在推定的ET-1相关疾病中的治疗用途提供强有力的工具。
We describe novel potent endothelin (ET) antagonists that are highly potent and selective for the ET(A) receptor (selective to ET-1). Of the synthetic analogs based on ET(A) antagonist BE-18257 A isolated from Streptomyces miskiensis (IC50 value for ET(A) receptor on porcine aortic smooth muscle cells (VSMCs); 1.4-mu-M), the compounds BQ-123 and BQ-153 greatly improved the binding affinity of [I-125]ET-1 for ET(A) receptors on VSMCs (IC50; 7.3 and 8.6 nM, respectively), whereas they barely inhibited [I-125]ET-1 binding to ET(B) receptors (nonselective with respect to isopeptides of ET family) in the cerebellar membranes (IC50; 18 and 54-mu-M, respectively). Associated with the increased affinity for ET(A) 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 [I-125]ET-1 binding in the membrane of the aortic smooth muscle layer. These data suggest that the artery has both ET(A) and ET(B) 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 [I-125]ET-1 binding on the VSMCs without affecting the binding capacity, indicative of the competitive antagonism for ET(A) 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 ET(A) receptors, while the depressor action is mediated by ET(B) receptors. In addition, pretreatment with the potent antagonists prevented ET-1-induced sudden death in mice. Thus, these potent ET(A) antagonists should provide a powerful tool for exploring the therapeutic uses of ET(A) antagonists in putative ET-1-related disorders.