Mechanistic studies of Neurosteroid Analogues

项目摘要 别孕酮等神经类固醇强烈增强GABAA受体功能，推动观点 这些效应介导了神经活性类固醇(NAS)的精神活性效应。快速抗抑郁药 AllP的作用似乎掩盖了一个单独的GABA能机制。了解以下附加机制 NAS将允许下一代治疗方法的演变。我们试图通过以下两种方式来理解机制 哪种allP可促进治疗优势，并通过拥有更多 和/或替代机制。该中心利用了一套独特的NAS类似产品。这个项目的首要目标是 是为了评估这些类似物对NAS被低估的离子通道靶标的影响：电压门控 钙通道和NMDA受体。这一目标将与项目1协同工作，以确定行动地点 NMDA受体。此外，这一目的将重新评估NAS的GABAA受体亚型选择性。 细胞。这项研究的第二个目的是利用新的系链将NAS的作用限制在质膜受体上 配基接近了。这将揭示在没有细胞内目标的情况下的NAS效应，我们将在 目的3评价化合物对神经炎性细胞因子和自噬途径的活性。这 AIM跟进了初步数据，表明NAS非天然对映体影响 这些细胞内靶点和项目1将探索潜在的相关蛋白质靶点，这些靶点介导这些 效果。最终目的是评估不同的NAS类似物对体外功能微电路的影响 大脑回路。本项目将在项目3中确定最感兴趣的一组化合物进行评估，其中 探索体内的生理学和电路。

Project Summary Neurosteroids such as allopregnanolone (AlloP) strongly potentiate GABAA receptor function, driving the view that these effects mediate psychoactive effects of neuroactive steroids (NAS). The rapid antidepressant actions of AlloP seem to belie a solely GABAergic mechanism. Understanding the additional mechanisms of NAS will allow evolution of the next generation of treatments. We seek to both understand mechanisms by which AlloP promotes therapeutic benefit and to improve on these benefits with NAS that possess additional and/or alternative mechanisms. The Center leverages a unique set of NAS analogues. This project's first Aim is to evaluate the impact of these analogues on underappreciated ion channel targets of NAS: voltage-gated Ca2+ channels and NMDA receptors. This aim will work in concert with Project 1 to identify sites of action on NMDA receptors. In addition, this aim will re-evaluate the GABAA receptor subtype selectivity of NAS in native cells. The second aim of the study is to limit NAS actions to plasma membrane receptors using novel tethered ligand approaches. This will reveal NAS effects in the absence of intracellular targets, which we will explore in Aim 3 with evaluation of compounds' activity on neuroinflammatory cytokines and autophagy pathways. This aim follows up on preliminary data that suggests that NAS unnatural enantiomers influence the function of these intracellular targets, and project 1 will explore potential relevant protein targets that mediate these effects. A final aim is to evaluate the impact of various NAS analogues on functional microcircuitry of ex vivo brain circuits. This project will identify the most interesting set of compounds for evaluation in project 3, which explores in vivo physiology and circuitry.