Dibasic biphenyl H3 receptor antagonists: Steric tolerance for a lipophilic side chain
Dibasic biphenyl H3 receptor antagonists: Steric tolerance for a lipophilic side chain
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DOI：
10.1016/j.ejmech.2011.12.019
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发表时间：
2012-02-01
影响因子：
6.7
通讯作者：
Mor, Marco
中科院分区：
文献类型：
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作者：
Bordi, Fabrizio;Rivara, Silvia;Mor, Marco
在一系列以联苯核心和两个碱性基团为特征的组胺H-3-拮抗剂中，我们鉴定了（S）-1-{[4 '-（（2-甲基吡咯烷-1-基）甲基）联苯-4-基]甲基}哌啶作为在靠近吡咯烷环的苄基碳处引入额外的亲脂链的先导支架。合成了一系列衍生物，并测试了它们对人和大鼠组胺H-3受体的结合亲和力及其拮抗剂效力。对于具有两个手性中心的化合物，合成过程提供了非对映体对的混合物，通过快速色谱法将其分离。实验NMR数据和分子动力学模拟的组合允许绝对立体化学的分配，基于每个非对映体对内检测到的特征差异。额外的亲脂性基团被受体耐受，支持H-3受体结合位点内描述的两个区域可以同时被拮抗剂占据的假设。在苄基碳上具有相反手性的非对映异构体在人和大鼠受体上均表现出有限的立体选择性或没有立体选择性。(C)2011年Elsevier Masson SAS。All rights reserved.
Within a series of histamine H-3-antagonists characterized by a biphenyl core and two basic groups, we identified (S)-1-{[4'-((2-methylpyrrolidin-1-yl)methyl)biphenyl-4-yl]methyl}piperidine as a lead scaffold to introduce an additional lipophilic chain at the benzylic carbon close to the pyrrolidine ring. A series of derivatives was synthesized and tested for their binding affinity at human and rat histamine H-3 receptors, and for their antagonist potency. For compounds with two chiral centers, the synthetic procedure provided mixtures of diastereomeric couples, which were separated by flash chromatography. Combination of experimental NMR data and molecular dynamics simulation allowed the assignment of absolute stereochemistry, based on characteristic differences detected within each diastereomeric couple. The additional lipophilic group was tolerated by the receptor, supporting the hypothesis that the two regions described within the H-3 receptor binding site can be simultaneously occupied by antagonists. Diastereoisomers with opposite chirality at the benzylic carbon showed limited or no stereo-selectivity at both human and rat receptors. (C) 2011 Elsevier Masson SAS. All rights reserved.