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引起无意识方面取得了重大进展，但 健忘症和固定化，确切的机制仍然很少理解。此外，所有镇静剂 - 催眠药会引起不良的不良反应。那是有必要发现新的镇静催眠术 并促进我们对他们行动机制的了解。我们以前发现麻醉剂， 提案，在辅酶Q（COQ）水平上干扰线粒体内的电子转移并诱导 质子泄漏过多。这些“两击”合并以损害线粒体膜电位（Δψm） 通过降解质子动力并防止电子通量中的必要坡道再生它。 初步工作，我们观察到合成COQ类似物（1,4-苯醌类的成员）导致 线粒体泄漏的类似增加和沉淀导致Δψm的下降。扩展这些观察结果，我们 发现短链COQ类似物泛素酮-5（UB5）的尾静脉注射立即诱导 小鼠无意识。这些挑衅性的发现使我们得出了我们的全球假设：1,4-奔驰Quinones 代表一类新型的镇静催眠术。我们特别假设UB5引起了潜意识 通过妥协Δψm。这是为了：1）表征UB5和2的麻醉作用） 确定UB5如何防止前脑线粒体产生足够的Δψm。第三个目标是 旨在识别神经元天冬氨酸 - 谷氨酸线粒体载体Aralar作为一种新颖 药理学相关的麻醉靶标。这个目的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。在特定目标3中，我们将确定Aralar在 介导UB5引起的无意识。该提案的成功将建立UB5作为一种新颖的麻醉 代理和阐明离散的线粒体作用机制。获得的知识将使我们发现 在未来工作中具有精确的线粒体靶标的镇静催眠术；最大化目标疗法 生物活性并最大程度地减少靶向毒性作用。