Takahashi Masahiko, Taniguchi Takanobu, Tanaka Takashi, Kanamaru Hiroshi, Okada Kenichiro, Muramatsu Ikunobu
Department of Pharmacology, School of Medicine, Fukui Medical University, Matsuoka, Fukui 910-1193, Japan.
Eur J Pharmacol. 2003 Apr 25;467(1-3):185-9. doi: 10.1016/s0014-2999(03)01606-6.
The pharmacological profile of N-(6-(2-(5-bromopyrimidine-2-yloxy)ethoxy)-5-(4-methylphenyl)pyrimidin-4-yl)-4-(2-hydroxy-1,1-dimethylethyl) benzensulfonamide sodium salt sesquihydrate (TA-0201), a new antagonist of endothelin receptors, was examined, using human recombinant and prostate endothelin receptors. In binding experiments with [125I]endothelin-1, TA-0201 showed extremely high affinity for recombinant endothelin ET(A) receptors (pK(i)=10.7), as compared with that for recombinant endothelin ET(B) receptors (pK(i)=7.8). Endothelin ET(A) and ET(B) receptors coexisted in human prostate with different proportions (endothelin ET(A) receptor: approximately 70%), which were distinguished by TA-0201 in the same manner as with recombinant receptors. Human prostate strips contracted in response to endothelin-1 and sorafotoxin S6c, but the maximum contraction induced by endothelin-1 was approximately three times greater than that induced by sarafotoxin S6c. The response to endothelin-1, but not to sarafotoxin S6c, was inhibited by TA-0201 and cyclo(D-Asp-Pro-D-Val-Leu-D-Trp) (BQ123) (endothelin ET(A) receptor antagonist) but not by BQ788 (endothelin ET(B) receptor antagonist). These results suggest that TA-0201 is a highly selective endothelin ET(A) receptor antagonist and will be useful for understanding the physiological and pathological roles of the endothelin ET(A) receptor in human prostate and other tissues.
使用人重组内皮素受体和前列腺内皮素受体，对新型内皮素受体拮抗剂N-（6-（2-（5-溴嘧啶-2-基氧基）乙氧基）-5-（4-甲基苯基）嘧啶-4-基）-4-（2-羟基-1,1-二甲基乙基）苯磺酰胺钠盐倍半水合物（TA-0201）的药理特性进行了研究。在与[125I]内皮素-1的结合实验中，与重组内皮素ET（B）受体（pK（i）=7.8）相比，TA-0201对重组内皮素ET（A）受体显示出极高的亲和力（pK（i）=10.7）。内皮素ET（A）和ET（B）受体以不同比例共存于人前列腺中（内皮素ET（A）受体：约70%），TA-0201以与重组受体相同的方式区分它们。人前列腺条对内皮素-1和索拉毒素S6c有收缩反应，但内皮素-1诱导的最大收缩约为索拉毒素S6c诱导的最大收缩的三倍。TA-0201和环（D-天冬氨酸-脯氨酸-D-缬氨酸-亮氨酸-D-色氨酸）（BQ123）（内皮素ET（A）受体拮抗剂）可抑制对内皮素-1的反应，但不能抑制对索拉毒素S6c的反应，而BQ788（内皮素ET（B）受体拮抗剂）则无此作用。这些结果表明，TA-0201是一种高度选择性的内皮素ET（A）受体拮抗剂，将有助于了解内皮素ET（A）受体在人前列腺和其他组织中的生理和病理作用。
