Neuroactive steroids as novel psychiatric treatments: mechanistic studies

神经活性类固醇作为新型精神病治疗：机制研究

• 批准号: 10198240
• 负责人: STEVEN J MENNERICK
• 金额: $ 253.57万
• 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/10198240
• 关键词: Address; Allopregnanolone; Antidepressive Agents; Behavior; Behavioral; Biological; Biology; Brain; Calcium Channel; Catalogs; Cause of Death; Cell physiology; Cellular Stress; Chemistry; Collaborations; Complement; Data; Development; Disease; Enhancers; FDA approved; Formulation; Fostering; Funding; Future; GABA Agents; Glutamate Receptor; Goals; Hippocampus (Brain); Inflammation; Inflammatory; International; Ion Channel; Ketamine; Lead; Ligands; Major Depressive Disorder; Mass Spectrum Analysis; Mediating; Medical; Mental disorders; Modernization; Molecular; Molecular Target; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Oral; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Photoaffinity Labels; Positioning Attribute; Postpartum Depression; Psychiatric therapeutic procedure; Recording of previous events; Research; Research Personnel; Research Support; Resources; Role; Scientist; Seeds; Seminal; Site; Steroids; Stress; Structure; Synapses; Testing; Therapeutic; Therapeutic Effect; Translational Research; Woman; Work; analog; antidepressant effect; base; cell type; disability; drug development; experience; gamma-Aminobutyric Acid; improved; innovation; insight; member; men; mouse model; multidisciplinary; neural circuit; neural network; neuroinflammation; neurosteroids; novel; novel therapeutics; phase 3 study; programs; prototype; receptor; side effect; steroid analog; success; therapeutic development; tool; voltage

CONTE CENTER SUMMARY Neuroactive steroids (NAS) offer novel directions for psychiatric therapeutics. The prototypical NAS is allopregnanolone (AlloP), which under the formulation of brexanolone, has recently been approved by FDA for treatment of women with postpartum depression; a second, orally-active NAS has had a successful Phase 3 study for postpartum depression and a Phase 2B study for men and women with major depression. While AlloP is a potent and effective enhancer of GABAA receptors (GABAARs), it is not presently clear that the antidepressant effects of NAS are mediated solely by GABAergic effects, and recent data indicate that other mechanisms including effects on cellular stress and inflammatory pathways could also be involved. Members of our center have extensive experience studying the medicinal chemistry and mechanisms underlying the effects of AlloP-like NAS. In this Conte Center proposal we will leverage novel NAS compounds to probe varied molecular, synaptic, network and behavioral effects of NAS as clues to their therapeutic mechanisms and potential. Our center proposal is driven by unique NAS analogues synthesized in our Chemistry Core and involves three complementary and intertwined projects that will pursue three specific goals. First, we will test the hypothesis that selective actions of NAS on a class of GABAARs underlies effects on hippocampal electrical activity, network function and behavior in novel mouse lines and mouse models of postpartum and major depression. Second, we will examine the role of non-GABAA ion channels in mediating hippocampal and behavioral effects of NAS focusing on novel NAS that modulate NMDA glutamate receptors and low voltage activated calcium channels. These studies will use unique photoaffinity labeling approaches to elucidate sites of actions of NAS on NMDA receptors and other targets. Other studies will examine effects of NAS analogues on cellular function, neural network function, and behavior. Third, we will test the role of intracellular targets engaged by NAS on hippocampal circuits and behavior, focusing on the roles of neuroinflammation and cellular stress pathways. Our center is uniquely positioned to traverse the exploration of antidepressant NAS from molecules to sites of action and effects on dysfunctional circuits to identify potentially novel agents and targets for psychiatric therapeutic development.

孔戴中心摘要 神经活性类固醇（NAS）为精神病治疗提供了新的方向。原型NAS是 根据Brexanolone的配方，Allopregnanolone（Allop）最近已获得FDA批准 用于治疗产后抑郁症的妇女；第二个口头活跃的Nas成功了 对产后抑郁症的3阶段研究和针对重度抑郁症的男性和女性的2B期研究。 虽然Allop是GABAA受体（GABAARS）的有效增强剂，但目前尚不清楚 NAS的抗抑郁作用仅由GABAergic效应介导，最近的数据表明 还可能涉及其他机制，包括对细胞应激和炎症途径的影响。 我们中心的成员在研究药物化学和机制方面具有丰富的经验 基础类似于异形NA的效果。在这个孔戴中心提议中，我们将利用新颖的NAS 探测探测的化合物各种分子，突触，网络和NAS的行为影响作为其线索 治疗机制和潜力。我们的中心建议是由独特的NAS类似物驱动的 在我们的化学核心中合成，涉及三个互补和交织的项目 追求三个具体目标。首先，我们将测试NAS在一类中的选择性行动的假设 Gabaars是对新型海马电活动，网络功能和行为的影响 产后和重度抑郁症的小鼠线和小鼠模型。第二，我们将研究 NAS的介导海马和行为影响的非GABAA离子通道专注于新的NAS 调节NMDA谷氨酸受体和低压激活的钙通道。这些研究会 使用独特的光性标签方法来阐明NAS对NMDA受体和 其他目标。其他研究将检查NAS类似物对细胞功能，神经网络的影响 功能和行为。第三，我们将测试NAS参与海马的细胞内靶标的作用 电路和行为，重点是神经炎症和细胞应激途径的作用。我们的中心 是独特的位置，可以穿越从分子到作用部位的抗抑郁药的探索 以及对功能失调的电路的影响，以识别潜在的新型药物和精神病的目标 治疗发展。