Mechanistic studies of Neurosteroid Analogues

神经类固醇类似物的机制研究

• 批准号: 10198243
• 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/10198243
• 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; Structure; Synapses; Techniques; Testing; Therapeutic; Viral; Work; analog; 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.

项目概要 Allopregnanolone (AlloP) 等神经类固醇可强烈增强 GABAA 受体功能，从而推动这一观点 这些作用介导了神经活性类固醇（NAS）的精神作用。快速抗抑郁药 AlloP 的作用似乎掩盖了纯粹的 GABA 能机制。了解附加机制 NAS 将促进下一代治疗方法的发展。我们寻求通过以下方式来理解机制： AlloP 可以促进治疗效果，并通过具有额外功能的 NAS 来改善这些效果 和/或替代机制。该中心利用一组独特的 NAS 类似物。该项目的第一个目标 是为了评估这些类似物对 NAS 未被充分重视的离子通道目标的影响：电压门控 Ca2+ 通道和 NMDA 受体。该目标将与项目 1 协同工作，以确定行动地点 NMDA 受体。此外，该目标将重新评估天然NAS中GABAA受体亚型的选择性 细胞。该研究的第二个目标是使用新型系留物来限制 NAS 对质膜受体的作用 配体方法。这将揭示在缺乏细胞内靶标的情况下 NAS 的影响，我们将在 目标 3 评估化合物对神经炎症细胞因子和自噬途径的活性。这 初步数据表明 NAS 非天然对映异构体影响 这些细胞内靶点，项目 1 将探索介导这些细胞内靶点的潜在相关蛋白质靶点 影响。最终目的是评估各种 NAS 类似物对离体功能微电路的影响 脑回路。该项目将确定项目 3 中最有趣的一组化合物进行评估，其中 探索体内生理学和电路。