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标题：A Novel Sphingosine-1-Phosphate Receptor 1 Antagonist Prevents the Proliferation and Relaxation of Vascular Endothelial Cells by Sphingosine-1-Phosphate
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作者：Kiyoaki Yonesu ; Tsuyoshi Nakamura ; Yumiko Mizuno 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2010
卷号：33
期号：9
页码：1500-1505
DOI：10.1248/bpb.33.1500
出版社：The Pharmaceutical Society of Japan
摘要：A sphingosine-1-phosphate receptor 1 (S1P₁) antagonist is expected to be an anti-angiogenic compound; however, there are few reports that demonstrated that a S1P₁ inhibitor improved the disease state in an angiogenic animal model. Since we determined that a prototype S1P₁ antagonist was an in vivo angiogenesis inhibitor, we developed the derivatives to acquire more effective compounds. In this report, we show the S1P₁ antagonistic activity of some representatives, especially compound 5 {sodium 4-[(4-butoxyphenyl)thio]-2′-[{4-[(heptylthio)methyl]-2-hydroxyphenyl}(hydroxy)methyl]biphenyl-3-sulfonate}. The IC₅₀ values calculated from an intracellular cyclic AMP measurement assay and a [³³P]sphingosine-1-phosphate (Sph-1-P)/S1P₁ binding assay were 38 and 200 n M , respectively. A subtype specificity test for the other Sph-1-P receptors showed that compound 5 was the S1P₁-directional antagonist. It also inhibited the proliferation, migration, and tube formation of human umbilical vein endothelial cells stimulated by Sph-1-P with the IC₅₀ values of 18, 650, and 230 n M , respectively. A cytotoxicity assay concurrently performed with a tube formation assay supported the hypothesis that these biological effects were not due to its cytotoxicity. Furthermore, administration (10 mg/kg, intravenously) to anesthetized Sprague-Dawley rats inhibited Sph-1-P-induced hypotension by 100—90% for 30 min. This is presumably through the inhibition of Sph-1-P-induced vasorelaxation, mainly by the blocking of S1P₁ and/or S1P₃. Taken together, these results show that compound 5 is an inhibitor of in vitro and in vivo Sph-1-P signaling, and that it will be useful to elucidate the in vivo effect of Sph-1-P on vascular endothelial cells.
关键词：sphingosine-1-phosphate;human umbilical vein endothelial cell;hypotension;sphingosine-1-phosphate receptor 1 antagonist