Identification of a new class of prostaglandin transporter inhibitors and characterization of their biological effects on prostaglandin E2 transport
Identification of a new class of prostaglandin transporter inhibitors and characterization of their biological effects on prostaglandin E2 transport
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DOI：
10.1124/jpet.105.091975
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发表时间：
2006-03-01
影响因子：
3.5
通讯作者：
Schuster, VL
中科院分区：
文献类型：
--
作者：
Chi, YL;Khersonsky, SM;Schuster, VL
前列腺素(PG)参与多种重要的信号转导途径。当它们穿过细胞膜并在细胞内氧化时，它们的作用就终止了。前列腺素代谢的转运步骤是由前列腺素转运体(PGT)完成的。因此，抑制前列腺素T有望改变前列腺素的局部或循环浓度，从而改变它们的生物学效应。为了开发高亲和力的PGT特异性抑制剂，我们设计了一个三嗪类化合物文库，并利用稳定表达大鼠PGT的Madin-Darby犬肾细胞筛选了1842个小分子。我们发现了几种有效的PGT抑制剂。其中最有效的抑制剂的K-I为3.7+/-0.2 mU M。这些抑制剂使我们能够分离PGE(2)的外排过程，并证明在生理条件下PGT不向外转运PGE(2)。
Prostaglandins (PGs) are involved in several major signaling pathways. Their effects are terminated when they are transported across cell membranes and oxidized intracellularly. The transport step of PG metabolism is carried out by the prostaglandin transporter (PGT). Inhibition of PGT would therefore be expected to change local or circulating concentrations of prostaglandins, and thus their biological effects. To develop PGT-specific inhibitors with high affinity, we designed a library of triazine compounds and screened 1842 small molecules by using Madin-Darby canine kidney cells stably expressing rat PGT. We found several effective PGT inhibitors. Among them, the most potent inhibitor had a K-i of 3.7 +/- 0.2 mu M. These inhibitors allowed us to isolate the efflux process of PGE(2) and to demonstrate that PGT does not transport PGE(2) outwardly under physiological conditions.