Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. Part 9: Synthesis, characterization and molecular modeling of pyridinyl isosteres of N-BPE-8-CAC (1), a high affinity ligand for opioid receptors
Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. Part 9: Synthesis, characterization and molecular modeling of pyridinyl isosteres of N-BPE-8-CAC (1), a high affinity ligand for opioid receptors
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DOI：
10.1016/j.bmcl.2013.01.117
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发表时间：
2013-04-01
影响因子：
2.7
通讯作者：
Bidlack, Jean M.
中科院分区：
文献类型：
--
作者：
VanAlstine, Melissa A.;Wentland, Mark P.;Bidlack, Jean M.
制备了先导化合物N-BPE-8-CAC（1）的衍生物，其中联苯基的每个CH被N单独取代，以期鉴定具有改善的水溶性的高亲和力配体。与1相比，五种可能的吡啶基衍生物对μ阿片受体的结合亲和力在三倍低至五倍高之间，最有效的化合物的Ki为0.064 nM。将8-CAC（2）对接到小鼠μ阿片受体（PDB：4DKL）的未配体结合位点中揭示了8-CAC和β-FNA（来自4DKL）与受体产生几乎相同的相互作用。然而，对于1和新的吡啶基衍生物4-8，由于大的N-取代基的空间限制，在8-CAC结合模式中不容许结合。替代结合模式或蛋白质重排以适应这些修饰可以解释它们的高结合亲和力。(C)2013爱思唯尔有限公司保留所有权利。
Derivatives of the lead compound N-BPE-8-CAC (1) where each CH of the biphenyl group was individually replaced by N were prepared in hopes of identifying high affinity ligands with improved aqueous solubility. Compared to 1, binding affinities of the five possible pyridinyl derivatives for the mu opioid receptor were between threefold lower to fivefold higher with the K-i of the most potent compound being 0.064 nM. Docking of 8-CAC (2) into the unliganded binding site of the mouse mu opioid receptor (pdb: 4DKL) revealed that 8-CAC and beta-FNA (from 4DKL) make nearly identical interactions with the receptor. However, for 1 and the new pyridinyl derivatives 4-8, binding is not tolerated in the 8-CAC binding mode due to the steric constraints of the large N-substituents. Either an alternative binding mode or rearrangement of the protein to accommodate these modifications may account for their high binding affinity. (C) 2013 Elsevier Ltd. All rights reserved.