Scaglione Jamie B, Manion Brad D, Benz Ann, Taylor Amanda, DeKoster Gregory T, Rath Nigam P, Evers Alex S, Zorumski Charles F, Mennerick Steven, Covey Douglas F
Department of Molecular Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Med Chem. 2006 Jul 27;49(15):4595-605. doi: 10.1021/jm0602920.
Benz[f]indenes are tricyclic compounds with a linear 6-6-5 fused carbocyclic ring system. When properly substituted, benz[f]indenes can satisfy the pharmacophore requirements of the critical hydrogen-bond donor and acceptor groups found in neuroactive steroids that modulate gamma-aminobutyric acidA (GABAA) receptor function. Thus, the benz[f]indene ring system provides an opportunity to extend the previously well-studied GABAA receptor structure-activity relationships (SAR) of neuroactive steroids to a different ring system. Depending on whether the stereochemistry of the 6-6-5 ring fusions are trans-trans or cis-trans, either planar or nonplanar benz[f]indenes are obtained. We found that the planar trans-trans benz[f]indenes are active, but less active than the steroids they were designed to mimic, whereas the nonplanar cis-trans compounds have little, if any, activity. The results provide new insight into the importance of the steroid framework for the actions of neuroactive steroids at GABAA receptors.
苯并[f]茚是具有线性6-6-5稠合碳环系统的三环化合物。当进行适当取代时，苯并[f]茚可以满足调节γ-氨基丁酸A（GABAA）受体功能的神经活性甾体中关键氢键供体和受体基团的药效团要求。因此，苯并[f]茚环系统为将先前深入研究的神经活性甾体与GABAA受体的构效关系（SAR）扩展到不同的环系统提供了机会。根据6-6-5环稠合的立体化学是反式-反式还是顺式-反式，可以得到平面或非平面的苯并[f]茚。我们发现平面反式-反式苯并[f]茚具有活性，但比它们设计模仿的甾体活性低，而非平面顺式-反式化合物几乎没有活性（如果有活性的话）。这些结果为甾体骨架对神经活性甾体在GABAA受体上作用的重要性提供了新的见解。
