INVITRO BIOLOGICAL PROFILE OF A HIGHLY POTENT NOVEL ENDOTHELIN (ET) ANTAGONIST BQ-123 SELECTIVE FOR THE ET(A) RECEPTOR
INVITRO BIOLOGICAL PROFILE OF A HIGHLY POTENT NOVEL ENDOTHELIN (ET) ANTAGONIST BQ-123 SELECTIVE FOR THE ET(A) RECEPTOR
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DOI：
10.1097/00005344-199204002-00005
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发表时间：
1992-01-01
影响因子：
3
通讯作者：
YANO, M
中科院分区：
文献类型：
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作者：
IHARA, M;ISHIKAWA, K;YANO, M
从味色链霉菌的发酵产物中分离得到新型内皮素(ET)受体拮抗剂BE-18257A和BE-18257B。上述化合物对猪血管平滑肌细胞(VSMCs)上[I-125]ET-1与ET(A)受体的结合有抑制作用，IC50值分别为1.4和0.47微米。[I-125]ET-1与小脑膜上的ET(B)受体(对ET异肽不具选择性)的结合即使在100微米时也不受这两种化合物的抑制。合成的类似物BQ-123对[I-125]ET-1与ET(A)受体的结合有极强的抑制作用(IC50为7.3 nM)，但对[I-125]ET-1与ET(B)受体的结合(IC50为18微米)以及其他各种多肽与其受体的结合几乎没有抑制作用。BQ-123使猪冠状动脉ET-1的量效曲线右移，提示对ET(A)受体具有竞争性拮抗作用。然而，有少量的BQ-123不敏感的血管收缩，与血管平滑肌层膜上[I-125]ET-1结合的不完全抑制相平行。这些数据表明，动脉通过ET(A)和ET(B)受体收缩，BQ-123选择性地抑制ET(A)介导的收缩。此外，BQ-123还显示了ET(A)受体在组织和物种分布上的巨大差异。因此，有效的ET(A)拮抗剂BQ-123在阐明ET(A)受体的(病理)生理作用方面应该是有用的。
The novel endothelin (ET) receptor antagonists BE-18257A and BE-18257B were isolated from the fermentation products of Streptomyces misakiensis. The above-mentioned compounds inhibited [I-125]ET-1 binding to ET(A) receptors (selective for ET-1) on porcine aortic vascular smooth muscle cells (VSMCs) with IC50 values of 1.4 and 0.47 muM, respectively. [I-125]ET-1 binding to ET(B) receptors (nonselective to ET isopeptides) in cerebellar membranes was not inhibited by either of these compounds even at 100 muM. The synthesized analogue BQ-123 induced extremely potent inhibition of [I-125]ET-1 binding to ET(A) receptors (IC50 of 7.3 nM), but it barely inhibited [I-125]ET-1 binding to ET(B) receptors (IC50 of 18 muM) and binding of various other peptides to their receptors. BQ-123 shifted the concentration-response curve for ET-1 toward the right in porcine isolated coronary arteries, indicative of competitive antagonism for the ET(A) receptor. However, there was a small amount of BQ-123-insensitive vasocontraction that paralleled the incomplete inhibition of [I-125]ET-1 binding in the membrane of the vascular smooth muscle layer. These data suggest that the artery contracts via both ET(A) and ET(B) receptors and that BQ-123 selectively inhibits ET(A)-mediated contraction. Furthermore, BQ-123 revealed large tissue and species differences in the distribution of ET(A) receptors. Thus, the potent ET(A) antagonist BQ-123 should be useful in clarifying the (patho)physiological roles of ET(A) receptors.