Masuda Y, Sugo T, Kikuchi T, Satoh M, Fujisawa Y, Itoh Y, Wakimasu M, Ohtaki T
Discovery Research Laboratories I, Takeda Chemical Industries, Ltd., Tsukuba, Ibaraki, Japan.
Eur J Pharmacol. 1997 May 1;325(2-3):263-70. doi: 10.1016/s0014-2999(97)00130-1.
Receptor binding and antagonist properties of endothelin-1 analogues, [Thr18,gamma-methylleucine19]endothelin-1, [Thr18,Leu19]endothelin-1 and [Thr18,cyclohexylalanine19]endothelin-1, were investigated using cloned human endothelin ET(A) and ET(B) receptors expressed in Chinese hamster ovary cells. Among them, [Thr18,gamma-methylleucine19]endothelin-1 had a high affinity for endothelin ET(A) and ET(B) receptors with respective Kd values of 300 and 110 pM and had no agonist activity on the stimulation of arachidonic acid release in endothelin ET(A) and ET(B) receptor-expressing cells. [Thr18,gamma-methylleucine19]Endothelin-1 had potent antagonist activity in endothelin-1-induced arachidonic acid release in endothelin ET(A) and ET(B) receptor-expressing cells with respective pA2 values of 8.2 and 8.5. In an inositol phosphates accumulation assay, [Thr18,gamma-methylleucine19]endothelin-1 also exhibited potent antagonist activity for endothelin ET(A) and ET(B) receptors with respective pA2 values of 8.0 and 8.4. In conclusion, [Thr18,gamma-methylleucine19]endothelin-1 acts as a potent and nonselective antagonist with no agonist activity for cloned human endothelin ET(A) and ET(B) receptors.
使用在中国仓鼠卵巢细胞中表达的克隆人内皮素ET(A)和ET(B)受体，研究了内皮素-1类似物[Thr18,γ-甲基亮氨酸19]内皮素-1、[Thr18,亮氨酸19]内皮素-1和[Thr18,环己基丙氨酸19]内皮素-1的受体结合及拮抗剂特性。其中，[Thr18,γ-甲基亮氨酸19]内皮素-1对内皮素ET(A)和ET(B)受体具有高亲和力，其Kd值分别为300和110 pM，并且对表达内皮素ET(A)和ET(B)受体的细胞中花生四烯酸释放的刺激没有激动剂活性。[Thr18,γ-甲基亮氨酸19]内皮素-1在表达内皮素ET(A)和ET(B)受体的细胞中，对内皮素-1诱导的花生四烯酸释放具有强效拮抗剂活性，其pA2值分别为8.2和8.5。在肌醇磷酸积累试验中，[Thr18,γ-甲基亮氨酸19]内皮素-1对内皮素ET(A)和ET(B)受体也表现出强效拮抗剂活性，其pA2值分别为8.0和8.4。总之，[Thr18,γ-甲基亮氨酸19]内皮素-1对克隆的人内皮素ET(A)和ET(B)受体起强效非选择性拮抗剂作用，且无激动剂活性。
