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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

基本信息

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
项目类别：
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

项目摘要

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.

会议中心总结