Fancy bioisosteres: novel paracyclophane derivatives as super-affinity dopamine D3 receptor antagonists.
Fancy bioisosteres: novel paracyclophane derivatives as super-affinity dopamine D3 receptor antagonists.
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奇特的生物等排体：作为超亲和力多巴胺 D3 受体拮抗剂的新型对环芳烷衍生物。
DOI：
10.1021/jm060138d
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发表时间：
2006
影响因子：
7.3
通讯作者：
P. Gmeiner
中科院分区：
文献类型：
--
作者：
Karin Schlotter;F. Boeckler;H. Hübner;P. Gmeiner
化学多样性空间的探索依赖于新的生物电子等排元素的发现。作为我们关于双层芳烃替代物的项目的延续，我们在此报告[2.2]对环芳衍生的4型和6型多巴胺D3受体拮抗剂。对于带有2-甲氧基苯基取代基的最有希望的测试化合物6a，当对映异构体（R）-6a（FAUC 418）和（S）-6a的平面手性引起D3结合的显著差异时，进行立体控制制备，这分别由0.19和3.0 nM的K（i）值表示。功能性实验表明，D3拮抗剂的性质paracyclophane衍生物的类型6。为了阐明推定的生物活性低能量构象，DFT为基础的研究，包括诊断磁屏蔽性能的计算进行。与铅化合物3b的单层苯并呋喃相比，[2.2]对环芳烷部分的体积增加了89%，表明GPCR结合区域的可塑性比通常预期的更高。
The exploration of the chemical diversity space depends on the discovery of novel bioisosteric elements. As a continuation of our project on bilayered arene surrogates, we herein report on [2.2]paracyclophane-derived dopamine D3 receptor antagonists of type 4 and 6. For the most promising test compound 6a, bearing a 2-methoxyphenyl substituent, a stereocontrolled preparation was performed when the planar chirality of enantiomers (R)-6a (FAUC 418) and (S)-6a caused a considerable differentiation of D3 binding, which is indicated by K(i) values of 0.19 and 3.0 nM, respectively. Functional experiments showed D3 antagonist properties for the paracyclophane derivatives of type 6. To elucidate putative bioactive low-energy conformations, DFT-based studies including the calculation of diagnostic magnetic shielding properties were performed. An 89% increase in volume for the [2.2]paracyclophane moiety compared to that of the monolayered benzofurane of lead compound 3b indicates higher plasticity of GPCR binding regions than usually expected.