Core A: Analytical and Medicinal Chemistry Core

项目摘要-分析和药物化学(AMC)核心-核心A 加州大学戴维斯分校新的对抗卓越中心的总体目标是识别和推动小说 治疗策略，当作为现场护理标准(SOC)的辅助时，对急性 有机磷(OP)中毒，将减轻长期不良神经系统疾病的发病和/或严重程度 后果。目前的医学对策，包括毒碱受体拮抗剂，阿托品， 联合用来激活乙酰胆碱酯酶和苯二氮卓类药物来终止癫痫持续状态， 没有充分预防自发性反复发作(SRS)和认知能力的发展 除非在暴露后的第一个15分钟内给药，否则会造成身体缺陷。因此，迫切需要确定 新的治疗策略，可以在暴露后的延迟时间部署，以缓解慢性、 急性有机磷农药中毒的神经后遗症。还迫切需要确定可量化的和 适用于评估潜在治疗的预测生物标志物，并允许预测 患者患持续性癫痫障碍和认知功能障碍的风险增加， 大多数人受益于暴露后治疗。 分析和药物化学核心(核心A)将通过以下方式作为该中心的一个组成部分发挥作用 支持并与所有三个项目和神经成像核心合作。在总体上支持整个 中心，核心A将执行质量控制，并确认所有商业获得的密钥的身份和纯度 化学资源和威胁剂氟磷二异丙酯(DFP)。如果有必要，化合物将被 在发布到项目之前在内部进行纯化。核心A将通过开发Liquid进一步支持这些项目 抗癫痫药物、抗癫痫药物的LC/MS检测方法 血浆和组织中的炎剂和神经保护剂及其代谢物，并产生药代动力学 为剂量选择和演示目标参与提供信息的数据。核心A将使用其药物化学 项目所需的合成小分子探针和潜在的新疗法的专业知识。 此外，核心A将与项目密切合作，识别和量化生物标记物 癫痫发作活动、神经炎症和血脑屏障通透性的变化及其改善作用 潜在的治疗方法。对核心的监督和管理将由核心领导Heike Wulff博士、 加州大学戴维斯分校药理学教授，在药理学和药物化学方面拥有广泛的专业知识；以及 核心联合领导，杨军，博士，加州大学戴维斯分校研究科学家，在质谱学方面拥有丰富的专业知识 以及全球代谢组学和靶向代谢组学，特别是脂类介体。通过提供分析和医疗 化学专业知识，以及探针和试剂设计、化学资源验证、生物标记物的专门服务 识别/检测和PK/PD分析，核心A将确保一致性、科学严谨性、效率和 加州大学戴维斯分校对抗中心所有项目研究的重复性。

Project Summary – Analytical and Medicinal Chemistry (AMC) Core – Core A The overall goal of the new UC Davis CounterACT Center of Excellence is to identify and advance novel therapeutic strategies that, when administered as an adjunct to in-field standard-of-care (SOC) for acute organophosphate (OP) intoxication, will mitigate the onset and/or severity of long-term, adverse neurological consequences. Current medical countermeasures, which include the muscarinic receptor antagonist, atropine, combined with an oxime, to reactivate acetylcholinesterase and a benzodiazepine to terminate status epilepticus, do not sufficiently protect against the development of spontaneous recurrent seizures (SRS) and cognitive deficits unless administered in the first 15-min after exposure. Therefore, there exists an urgent need to identify novel therapeutic strategies that can be deployed at delayed times post-exposure to mitigate the chronic, adverse neurological sequelae of acute OP intoxication. There is also a critical need to identify quantifiable and predictive biomarkers that are suitable for evaluating potential therapeutics and that allow prediction of which patients are at increased risk of developing persistent seizure disorders and cognitive dysfunction and would most benefit from post-exposure treatment. The Analytical and Medicinal Chemistry Core (Core A) will function as an integral component of the Center by supporting and collaborating with all three Projects and the Neuroimaging Core. In general support of the entire Center, Core A will perform quality control and confirm the identity and purity of all commercially obtained key chemical resources and the threat agent diisopropylfluorophosphate (DFP). If necessary, compounds will be purified in-house before release to the Projects. Core A will further support the Projects by developing liquid chromatography–mass spectrometry (LC/MS) methods for the detection of antiseizure drugs, anti- inflammatories and neuroprotectants and their metabolites in plasma and tissues, and generate pharmacokinetic data to inform dose selection and demonstrate target engagement. Core A will use its medicinal chemistry expertise to synthesize small molecule probes and potential novel therapeutics as required by the Projects. Additionally, Core A will closely work with the Projects on the identification and quantification of biomarkers for seizure activity, neuroinflammation and changes in blood-brain-barrier permeability and their amelioration by potential therapeutics. Oversight and management of the Core will be provided by Core Lead, Heike Wulff, PhD, Professor of Pharmacology at UC Davis with broad expertise in pharmacology and medicinal chemistry; and Core Co-Lead, Jun Yang, PhD, Research Scientist at UC Davis, with extensive expertise in mass spectrometry and both global and targeted metabolomics, particularly lipid mediators. By providing analytical and medicinal chemistry expertise, and dedicated services of probe and reagent design, chemical resource verification, biomarker identification/detection and PK/PD analysis, Core A will ensure consistency, scientific rigor, efficiency, and reproducibility in research across the Projects of the UC Davis CounterACT Center.