Mechanistic studies of Neurosteroid Analogues

神经类固醇类似物的机制研究

• 批准号: 10456974
• 负责人: STEVEN J MENNERICK
• 金额: $ 53.92万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10456974
• 关键词: Acute; Allopregnanolone; Amygdaloid structure; Antidepressive Agents; Automobile Driving; Autophagocytosis; Behavior; Behavioral; Binding Sites; Biological Assay; Brain; Calcium Channel; Cell membrane; Cells; Cellular Stress; Characteristics; Chemicals; Clinical; Data; Development; Engineering; Evaluation; Evolution; Exhibits; Frequencies; Hippocampus (Brain); Ion Channel; Knowledge; Ligands; Mediating; Membrane; Molecular; Molecular Target; N-Methyl-D-Aspartate Receptors; Neurons; Nuclear; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Actions; Pharmacology; Physiology; Proteins; Psychiatric therapeutic procedure; Recombinants; Research; Signal Transduction; Site; Steroid Receptors; Steroids; Stress; Synapses; Techniques; Testing; Therapeutic; Viral; Work; analog; antagonist; base; cellular targeting; cytokine; drug candidate; enantiomer; improved; in vivo; innovation; mouse model; mutant; neural circuit; neuroinflammation; neuropsychiatry; neurosteroids; next generation; novel; novel therapeutics; positive allosteric modulator; programs; receptor; receptor function; relating to nervous system; steroid analog; tool; voltage

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.

项目摘要 神经类固醇如别孕烯醇酮（AlloP）强烈增强GABAA受体功能， 这些作用介导神经活性类固醇（NAS）的精神活性作用。快速抗抑郁药 AlloP的作用似乎掩盖了一个单独的GABA能机制。了解其他机制 NAS将允许下一代治疗的发展。我们试图通过以下方式来理解机制： 其中AlloP促进治疗益处，并且使用具有额外的 和/或替代机制。该中心利用了一套独特的NAS类似物。该项目的第一个目标 是评估这些类似物对NAS的未被充分认识的离子通道靶点的影响：电压门控 Ca 2+通道和NMDA受体。这一目标将与项目1协同工作，以确定以下方面的行动地点： NMDA受体。此外，本研究还将重新评估NAS对天然GABAA受体亚型的选择性。 细胞本研究的第二个目的是使用新的栓系受体将NAS作用限制于质膜受体。 配体接近。这将揭示在没有细胞内靶点的情况下NAS的作用，我们将在 目的3评价化合物对神经炎性细胞因子和自噬通路的活性。这 目的是跟进初步数据，表明NAS非天然对映体影响的功能， 这些细胞内的目标，和项目1将探索潜在的相关蛋白质的目标，介导这些 方面的影响.最后一个目的是评估各种NAS类似物对离体细胞功能微电路的影响。 大脑回路该项目将确定最有趣的一组化合物，用于项目3的评估， 探索体内生理学和电路。