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（例如Allopregnanolone（Allop））强烈增强GABAA受体功能，驱动视图 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的行动似乎是一种唯一的GABA能力机制。了解其他机制 NAS将允许下一代治疗的进化。我们试图通过 Allop可以促进治疗益处，并通过拥有额外的NA来提高这些利益 和/或替代机制。该中心利用了独特的NAS类似物。这个项目的第一个目标 是为了评估这些类似物对NAS的离子通道目标不足的影响：电压门控 Ca2+通道和NMDA受体。这个目标将与项目1协同合作，以确定行动部位 NMDA受体。此外，此目标将重新评估天然中NAS的GABAA受体亚型选择性 细胞。该研究的第二个目的是将NAS作用限制为使用新型束缚的质膜受体 配体接近。这将在没有细胞内靶标的情况下揭示NAS效应，我们将在 AIM 3通过评估化合物对神经炎性细胞因子和自噬途径的活性。这 AIM遵循初步数据，表明NAS不自然的对映异构体会影响 这些细胞内靶标，项目1将探索介导这些靶标的潜在相关蛋白质靶标 效果。最终目的是评估各种NAS类似物对离体功能微电路的影响 脑电路。该项目将在项目3中确定评估最有趣的化合物集， 探索体内生理和电路。