Discovery and Development of a Benzoquinone Molecule as a Novel Anesthetic

苯醌分子作为新型麻醉剂的发现和开发

• 批准号: 10732956
• 负责人: Richard J Levy
• 金额: $ 45.26万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732956
• 关键词: Adverse effects; Amnesia; Anesthesia procedures; Anesthetics; Aspartate; Behavioral; Benzoquinones; Binding; Biochemical; Biological Assay; Biological Response Modifier Therapy; Body Temperature; Calcium; Closure by clamp; Conscious; Consumption; Coupled; Critical Illness; Data; Day Surgery; Development; Dose; Electroencephalography; Electron Transport; Electrons; Fluorescence; Foundations; Future; General Anesthesia; Genetic; Glutamates; Hypnosis; Image; Immobilization; In Vitro; Injections; Inner mitochondrial membrane; Intravenous; Ion Cotransport; Kinetics; Knockout Mice; Knowledge; Lasers; Link; Measures; Mediating; Membrane Potentials; Mitochondria; Modernization; Multienzyme Complexes; Mus; Natural regeneration; Neurons; Patients; Polarography; Process; Propofol; Prosencephalon; Proton Pump; Proton-Motive Force; Protons; Quinones; Ramp; Reflex action; Respiration; Role; Sedation procedure; Siblings; Source; Specificity; Spectrophotometry; Synaptosomes; Tail; Testing; Time; Toxic effect; Transgenic Mice; Ubiquinone; Unconscious State; Veins; Vitamin K 2; Work; analog; clinical practice; clinically relevant; design; falls; genetic approach; heart function; hypnotic; in vivo; inhibitor; insight; member; mitochondrial membrane; movement analysis; multi-photon; neurophysiology; novel; oxidation; para-benzoquinone; pharmacodynamic model; pharmacokinetics and pharmacodynamics; pharmacologic; prevent; proteoliposomes; response; sedative; solute; success; targeted treatment

Although the field has made substantial progress in understanding how anesthetics induce unconsciousness, amnesia, and immobilization, the exact mechanisms remain poorly understood. Furthermore, all sedative- hypnotic agents cause undesirable adverse effects. Thus, there is a need to discover new sedative-hypnotics and to advance our knowledge of their mechanism(s) of action. We previously found that the anesthetic, propofol, interfered with electron transfer within mitochondria at the level of coenzyme Q (CoQ) and induced excessive proton leak. These “two-hits” combined to compromise the mitochondrial membrane potential (ΔΨm) by degrading the proton motive force and preventing the requisite ramp up in electron flux to regenerate it. In preliminary work, we observed that synthetic CoQ analogs (members of the 1,4-benzoquinone class) cause a similar increase in mitochondrial leak and precipitate a decline in ΔΨm. Extending these observations, we found that tail vein injection of the short-chain CoQ analog, ubiquinone-5 (Ub5), immediately induced unconsciousness in mice. These provocative findings led us to our global hypothesis: 1,4-benzoquinones represent a novel class of sedative-hypnotics. We specifically hypothesize that Ub5 induces unconsciousness by compromising ΔΨm. Thus, the aims are designed to: 1) characterize the anesthetic effects of Ub5 and 2) determine how Ub5 prevents forebrain mitochondria from generating an adequate ΔΨm. The third aim is designed to identify the neuronal aspartate-glutamate mitochondrial carrier, Aralar, as a novel pharmacologically relevant anesthetic target. The basis for this aim is our preliminary data demonstrating that Aralar is a major source of Ub5-mediated proton leak. In specific aim #3 we will determine the role of Aralar in mediating Ub5-induced unconsciousness. Success of the proposal will establish Ub5 as a novel anesthetic agent and elucidate discrete mitochondrial mechanisms of action. Knowledge gained will permit us to discover sedative-hypnotics with precise mitochondrial targets in future work; maximizing on-target therapeutic biological activity and minimizing off-target toxic effects.

尽管该领域在理解麻醉剂如何导致意识丧失方面取得了实质性进展， 失忆症和固定，确切的机制仍然知之甚少。此外，所有镇静剂。 催眠药会引起不良副作用，因此需要发现新的镇静催眠药。 并增进我们对其作用机制的了解。我们之前发现麻醉剂， 异丙酚在辅酶 Q (CoQ) 水平上干扰线粒体内的电子转移并诱导 过多的质子泄漏。这些“两次打击”结合起来损害了线粒体膜电位（ΔΨm）。 通过降低质子动力并阻止电子通量重新产生所需的斜坡。 在初步工作中，我们观察到合成 CoQ 类似物（1,4-苯醌类成员）会导致 线粒体渗漏的类似增加并导致 ΔΨm 的下降，我们扩展了这些观察结果。 发现尾静脉注射短链 CoQ 类似物泛醌 5 (Ub5)，立即诱导 这些令人兴奋的发现使我们得出了我们的总体假设：1,4-苯醌。 我们特地爬升了 Ub5 会导致意识丧失 因此，目标是：1) 表征 Ub5 的麻醉效果，2) 确定 Ub5 如何阻止前脑线粒体产生足够的 ΔΨm 第三个目标是。 旨在鉴定神经元天冬氨酸-谷氨酸线粒体载体 Aralar，作为一种新型 药理学相关的麻醉目标的基础是我们的初步数据表明： Aralar 是 Ub5 介导的质子泄漏的主要来源，在具体目标#3 中，我们将确定 Aralar 在其中的作用。 介导 Ub5 引起的无意识。该提案的成功将使 Ub5 成为一种新型麻醉剂。 剂并阐明离散的线粒体作用机制。获得的知识将使我们能够发现。 未来工作中具有精确线粒体靶标的镇静催眠药； 生物活性并最大限度地减少脱靶毒性作用。