Identifying specific conformations by using a carbohydrate scaffold: discovery of subtype-selective LPA-receptor agonists and an antagonist.
Identifying specific conformations by using a carbohydrate scaffold: discovery of subtype-selective LPA-receptor agonists and an antagonist.
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DOI：
10.1002/anie.200454065
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发表时间：
2004-05
影响因子：
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通讯作者：
Yoko Tamaruya;Masato Suzuki;Goshu Kamura;M. Kanai;K. Hama;K. Shimizu;J. Aoki;H. Arai;M. Shibasaki
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文献类型：
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作者：
Yoko Tamaruya;Masato Suzuki;Goshu Kamura;M. Kanai;K. Hama;K. Shimizu;J. Aoki;H. Arai;M. Shibasaki
2895安徽。化学。2004,116,2894-2897 www.安格万特。2004年Wiley-VCH Verlag GmbH&Co.KGaA，Weinheim发现了LPA2受体。由于化合物2-14对LPA1没有明显的激动剂活性，我们尝试在六元环上引入取代基，通过微调环的构象来调节LPA1识别基序的相对位置。因此，我们合成了15-17，发现15相对于1-油酰基LPA具有同等或更强的LPA1激动剂活性(图1b)。[14，16]由于15不激活LPA2，[10]它是第一个可用于区分LPA1和LPA2激动剂活性的化合物。[15，17]亚型选择性激动剂活性2，13(LPA3选择性)和15(LPA1选择性)可能部分合理地基于特定的LPA受体区分识别基序的特定三维排列的假设。为了验证这一假设，我们用核磁共振技术测定了溶液状态下的环构象。所有的NOE数据和耦合常数值都表明，2以斜船构象存在，在假赤道位置上既有磷酸基团，又有油酰基(图2a)。另一方面，15以椅子构象存在，甲基和油酰基在赤道位置，磷酸基团在轴向位置(图2b)。[18]2和15中观察到的识别基序排列可能分别对应于柔性2-油酰基LPA与LPA1和LPA3的活性结合结构，这些排列可能被每个受体选择性地识别。
2895 Angew. Chem. 2004, 116, 2894–2897 www. angewandte. de 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim presence of the LPA2 receptor. As compounds 2–14 had no significant agonist activity for LPA1, we attempted to introduce a substituent on the six-membered ring to adjust the relative position of the recognition motifs for LPA1 through fine-tuning of the ring conformation. Thus, we synthesized 15–17 and found that 15 had equivalent or stronger potency as an agonist for LPA1 relative to 1-oleoyl LPA (Figure 1 b).[14, 16] As 15 did not activate LPA2,[10] it is the first compound that can be used to distinguish between LPA1-and LPA2-agonist activity.[15, 17] The subtype-selective agonist activity of 2, 13 (LPA3-selective), and 15 (LPA1-selective) might be partly rationalized based on the hypothesis that a specific LPA receptor distinguishes a specific three-dimensional arrangement of the recognition motifs. To test this hypothesis, we determined the ring conformation in a solution state by using NMR techniques. All NOE data and coupling constant values suggested that 2 exists in a skewed-boat conformation with both the phosphate and oleoyl groups in pseudoequatorial positions (Figure2a). On the other hand, 15 exists in a chair conformation with the methyl and oleoyl groups in equatorial positions and the phosphate group in an axial position (Figure 2 b).[18] The observed recognition-motif arrangements in 2 and 15 might correspond to the active binding structures of flexible 2-oleoyl LPA to LPA1 and LPA3, respectively, and the arrangements might be recognized selectively by each receptor.