Neurosteroids as a standard medical countermeasure for OP poisoning

神经类固醇作为 OP 中毒的标准医疗对策

• 批准号: 9352480
• 负责人: KELVIN W. GEE
• 金额: $ 43.46万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9352480
• 关键词: Acute; Advanced Development; Affinity; Anticonvulsants; Applications Grants; Atropine; Back; Benchmarking; Benzodiazepines; Biological; Blood drug level result; Brain; Chemical Warfare Agents; Chemical Weapons; Chemicals; Companions; Complex; Data; Dependency; Dose; Exposure to; Female; Hour; Human; In Vitro; Lead; Liver Microsomes; Mediating; Medical; Metabolic; Metabolic Biotransformation; Metabolic Clearance Rate; Metabolism; Microsomes; Midazolam; Military Personnel; Mission; Modeling; Modification; Molecular Weight; Neuraxis; Peripheral Nervous System; Pharmacology; Poisoning; Population; Rattus; Research; Research Support; Rodent Model; Seizures; Sex Characteristics; Site; Solubility; Soman; Specificity; Spottings; Status Epilepticus; Synapses; Testing; Therapeutic; Therapeutic Effect; Time; Toxic effect; United States National Institutes of Health; Unspecified or Sulfate Ion Sulfates; analog; base; central nervous system injury; design; drug development; gamma-Aminobutyric Acid; improved; in vivo; meetings; nerve agent; neurosteroids; neurotransmission; prevent; programs; receptor; response; screening; small molecule; steroid analog; therapeutic development

Acute organophosphorous poisoning is a military and civilian threat that causes a complex cascade of lethal central and peripheral nervous system toxicities. Identifying new and improved therapeutics to treat and/or prevent central nervous system (CNS) injuries resulting from exposure to chemical threats is a mission for the NIH Countermeasures Against Chemical Threats (CounterACT) program. This grant proposal seeks support for research on the identification of a small molecule lead candidate compound to block status epilepticus (SE) seizures caused by chemical warfare agent exposure. The objective of this proposal is to test the anticonvulsant efficacy of synthetic neuroactive steroids as an adjunct to standard medical countermeasures for soman-induced SE in a delayed treatment rodent model. Our studies will result in synthetically feasible compounds that are biologically active with specificity, affinity, potency, efficacy and target selectivity towards extrasynaptic α4β3δ subunit containing γ-aminobutyric acid-A receptors (GABAARs) for counteracting CNS toxicities arising from OP nerve agent exposure. We propose to demonstrate in vivo proof-of-concept efficacy data of one lead optimization compound ready for advanced therapeutic development plus a suitable backup molecule. The impact of the proposed research will be to understand if pharmacological targeting of extrasynaptic GABAARs is a strategy for designing effective medical countermeasures to chemical weapons exposure.

急性有机中毒是一种军事和平民威胁，导致一系列复杂的致命级联 中央和周围神经系统的毒性。确定新的和改进的治疗治疗和/或 预防中枢神经系统（CNS）受到化学威胁导致的伤害是该任务的任务 NIH针对化学威胁（抵消）计划的对策。该赠款提案寻求支持 用于鉴定小分子铅候选化合物以堵塞状态癫痫持续性（SE）的研究（SE） 化学战剂暴露引起的癫痫发作。该提议的目的是测试 合成神经活性类固醇作为标准医学对策的抗惊厥效率 在延迟的治疗啮齿动物模型中，用于SOMAN诱导的SE。我们的研究将导致合成可行 具有特异性，亲和力，效力，效率和目标选择性的生物学活跃化合物对 含有γ-氨基丁酸-A受体（GABAARS）的肌外α4β3δ亚基，用于抵消CNS 由OP神经毒剂暴露引起的毒性。我们建议证明体内概念验证效率 一个铅优化化合物的数据准备高级治疗开发以及合适的备份 分子。拟议研究的影响将是了解药物的靶向是否 外智GABAARS是为化学武器设计有效的医学对策的策略 接触。