Activity of 2-substituted lysophosphatidic acid (LPA) analogs at LPA receptors:: Discovery of a LPA1/LPA3 receptor antagonist
Activity of 2-substituted lysophosphatidic acid (LPA) analogs at LPA receptors:: Discovery of a LPA1/LPA3 receptor antagonist
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DOI：
10.1124/mol.60.6.1173
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发表时间：
2001-12-01
影响因子：
3.6
通讯作者：
Lynch, KR
中科院分区：
文献类型：
--
作者：
Heise, CE;Santos, WL;Lynch, KR
溶血磷脂酸占据单个受体的生理意义在很大程度上是未知的，因为目前还没有选择性激动剂/拮抗剂。三种高亲和力溶血磷脂酸受体LPA(1)、LPA(2)和LPA(3)的分子克隆为开发受体类型选择性配体提供了平台。从n -酰基乙醇酰胺磷酸LPA类似物开始，我们在第二个碳上进行了一系列取代，以生成具有不同空间，立体化学和电子特征的化合物。使用鸟苷5′- o -（3-[S-35]硫代）三磷酸（GTP[γ S-35]）结合试验分析该系列在每个重组LPA受体上的活性差异很大。我们的研究结果表明，这些受体具有一个空间限制性结合袋，与2取代基团相互作用，并倾向于小的疏水性基团和氢键功能。GTP[γ S-35]结合试验预测的激动剂活性反映在麻醉大鼠动脉压升高的一组化合物的活性上。其中一个具有庞大疏水性基团的化合物（VPC12249）是LPA(1)/LPA(3)双竞争性拮抗剂。一些具有较小侧链的化合物被发现是LPA(1)选择性激动剂。
The physiological implications of lysophosphatidic acid occupancy of individual receptors are largely unknown because selective agonists/antagonists are unavailable currently. The molecular cloning of three high-affinity lysophosphatidic acid receptors, LPA(1), LPA(2), and LPA(3), provides a platform for developing receptor type-selective ligands. Starting with an N-acyl ethanolamide phosphate LPA analog, we made a series of substitutions at the second carbon to generate compounds with varying spatial, stereochemical, and electronic characteristics. Analysis of this series at each recombinant LPA receptor using a guanosine 5'-O-(3-[S-35]thio)triphosphate (GTP[gamma S-35]) binding assay revealed sharp differences in activity. Our results suggest that these receptors have one spatially restrictive binding pocket that interacts with the 2-substituted moieties and prefers small hydrophobic groups and hydrogen bonding functionalities. The agonist activity predicted by the GTP[gamma S-35] binding assay was reflected in the activity of a subset of compounds in increasing arterial pressure in anesthetized rats. One compound with a bulky hydrophobic group (VPC12249) was a dual LPA(1)/LPA(3) competitive antagonist. Several compounds that had smaller side chains were found to be LPA(1)-selective agonists.