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首页> 外文期刊>Journal of Medicinal Chemistry >Neurosteroid analogues. 11. Alternative ring system scaffolds: gamma-aminobutyric acid receptor modulation and anesthetic actions of benz[f]indenes
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Neurosteroid analogues. 11. Alternative ring system scaffolds: gamma-aminobutyric acid receptor modulation and anesthetic actions of benz[f]indenes

机译:神经甾体类似物。 11.替代环系统支架:γ-氨基丁酸受体的调节和苯并[f]茚的麻醉作用

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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 acid(A) (GABA(A)) receptor function. Thus, the benz[f] indene ring system provides an opportunity to extend the previously well- studied GABA(A) 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 GABA(A) receptors.
机译:苯并[f]茚满是具有线性6-6-5稠合碳环系统的三环化合物。经过适当取代后,苯并[f]茚满可以满足在调节γ-氨基丁酸(A)(GABA(A))受体功能的神经活性类固醇中发现的关键氢键供体和受体基团的药效团要求。因此,苯并[f]茚环系统提供了一个将先前广为研究的神经活性类固醇的GABA(A)受体结构-活性关系(SAR)扩展到不同环系统的机会。根据6-6-5环融合的立体化学是反式还是反式,获得平面或非平面的苯并[f]茚。我们发现,平面反式-反式苯并[f]茚满是有活性的,但比它们设计用来模拟的类固醇的活性低,而非平面式的顺式-反式化合物几乎没有活性。结果为类固醇骨架对于神经活性类固醇在GABA(A)受体上的作用的重要性提供了新的见解。

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