Development of chemical biology tools for NMDA receptors

NMDA 受体化学生物学工具的开发

• 批准号: 9310158
• 负责人: DOUGLAS F COVEY
• 金额: $ 42.46万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9310158
• 关键词: Address; Affect; Alkynes; Binding; Binding Sites; Biochemical; Biological; Biology; Carrier Proteins; Cell membrane; Cells; Chemicals; Chemistry; Chemosensitization; Cholesterol; Clinical; Clinical Treatment; Development; Diazomethane; Disadvantaged; Future; Glutamates; Goals; Health; Hydroxycholesterols; Image; In Situ; Investigation; Leadership; Learning; Major Depressive Disorder; Medical; Memory; Modeling; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Neurotransmitter Receptor; Neurotransmitters; Pharmaceutical Preparations; Pharmacology; Photoaffinity Labels; Physiology; Positioning Attribute; Pregnanolone; Pregnenolone; Process; Reaction; Receptor Inhibition; Research; Resolution; Scientist; Steroids; Structure; Structure-Activity Relationship; Testing; Therapeutic; Time; Treatment Efficacy; Unspecified or Sulfate Ion Sulfates; analog; design; improved; innovation; insight; interest; neuropsychiatric disorder; neuroregulation; neurosteroids; novel; pregnenolone sulfate; protein transport; receptor; receptor binding; receptor function; steroid sulfate; tool; trafficking

Project Description This proposal has two specific aims unified by a common theme: the development of click chemistry probes to study the modulation of NMDA receptors (NMDARs), important targets for neuropsychiatric disease, by two structurally and mechanistically distinct classes of endogenous steroids. Nothing is known about how either class of steroids is trafficked or compartmentalized in neurons, even though compartmentalization can affect the ability of steroids to reach NMDA receptors and may aid identification of transport proteins involved in trafficking or other novel targets. Additionally, while some structure-activity studies have been interpreted to imply the existence of specific steroid binding sites for steroids on NMDA receptors, direct proof of direct binding is lacking. The novels probes developed in this proposal will address these two fundamental mechanistic questions. These NMDAR probes are significant because NMDA receptors, key receptors for the excitatory neurotransmitter glutamate, are of interest for medical reasons, i.e.: 1) NMDA receptor inhibition is a potential treatment for clinical depression and other neuropsychiatric disorders, and 2) modest increases in NMDA activation enhance memory and learning. Additionally, the click chemistry tools developed in the proposal will be of widespread use to scientists exploring the physiology and pharmacology of steroid modulators of NMDA receptors.

项目描述 这个建议有两个具体的目标统一的一个共同的主题：点击化学的发展 研究NMDA受体（NMDARs）调节的探针，神经精神病学的重要靶点 疾病，由两种结构和机制不同的内源性类固醇类。一无所知 关于类固醇是如何在神经元中被运输或划分的，即使 区室化可以影响类固醇到达NMDA受体的能力，并可能有助于鉴定 参与运输或其他新靶点的转运蛋白。此外，虽然一些结构活性 研究已被解释为暗示NMDA上存在类固醇的特异性类固醇结合位点 受体，缺乏直接结合的直接证据。本提案中开发的小说探测器将解决 这两个基本的机械问题。这些NMDAR探针是重要的，因为NMDA 受体，兴奋性神经递质谷氨酸的关键受体，由于医学原因而受到关注，即： 1)NMDA受体抑制是临床抑郁症和其他神经精神疾病的潜在治疗方法。 2）NMDA激活的适度增加增强记忆和学习。此外，点击 该提案中开发的化学工具将广泛用于科学家探索生理学和 NMDA受体的类固醇调节剂的药理学。