Novel treatment of posttraumatic stress disorder

创伤后应激障碍的新疗法

• 批准号: 8714528
• 负责人: Yvonne Y. Lai
• 金额: $ 34.87万
• 依托单位: ANAGIN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8714528
• 关键词: Address; Adult; Adverse effects; Affect; American; Amygdaloid structure; Anxiety Disorders; Attenuated; Auditory; Aversive Stimulus; Back; Biological Assay; Biological Neural Networks; Cells; Chemical Structure; Chemicals; Chronic; Clinical; Coupled; Coupling; Cues; Cyclic GMP-Dependent Protein Kinases; Development; Disease; Distress; Dose; Drug Formulations; Drug Kinetics; Enzyme Activation; Event; Exposure to; Extinction (Psychology); Financial compensation; Foundations; Functional disorder; Future; Genes; Glutamate Receptor; Glutamates; Goals; Guanylate Cyclase; Health Care Costs; Hippocampus (Brain); Human; Hyperalgesia; In Vitro; Knock-out; Lead; Long-Term Potentiation; Maintenance; Medical; Memory; Memory impairment; Methods; Modeling; Motor; Movement; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; Neurons; Neurotransmitters; Nitric Oxide; Nitric Oxide Synthase Type I; Oral; Parents; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase I Clinical Trials; Plasma; Post-Traumatic Stress Disorders; Pre-Clinical Model; Prefrontal Cortex; Presynaptic Terminals; Prevention strategy; Principal Investigator; Production; Proteins; Receptor Activation; Receptor Signaling; Role; Scaffolding Protein; Secondary Prevention; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Small Business Innovation Research Grant; Solubility; Stimulus; Stress; Symptoms; Synaptic plasticity; Testing; Therapeutic; Toxic effect; Trauma; Validation; Veterans; Work; analog; aspartate receptor; base; conditioned fear; cost; design; disability; drug candidate; drug development; drug discovery; effective therapy; experience; functional disability; improved; in vivo; inhibitor/antagonist; innovation; novel; phase 1 study; postsynaptic density protein; pre-clinical; preclinical efficacy; protein protein interaction; psychologic; public health relevance; receptor; relating to nervous system; response; retinal rods; small molecule; socioeconomics

DESCRIPTION (provided by applicant): The present application "Novel Treatment for Posttraumatic Stress Disorder" addresses the critical need for efficacious treatments for posttraumatic stress disorder (PTSD). A key neural signaling cascade activated by a trauma experience is initiated by the excitatory neurotransmitter glutamate. Activation of the NMDA receptor, a glutamate receptor subtype, results in subsequent activation of the enzyme neuronal nitric oxide synthase (nNOS) and, ultimately, an increase in the production of the signaling molecule nitric oxide (NO). These events trigger aberrant synaptic plasticity that is implicated in the initiation and maintenance of PTSD. Postsynaptic density protein 95 (PSD95) targets nNOS to the NMDA receptor and is, therefore, required for NMDA receptor activation of nNOS. Dr. Lai, Principal investigator for this project, first showed that the small molecule inhibitor IC87201 disrupts the functional protein-protein interaction between nNOS and PSD95 in vitro and attenuates NMDA receptor dependent hyperalgesia in vivo. Our preclinical team, led by Dr. Shekhar (Founder of Anagin), has now shown that IC87201 and a related analog, ZL006, block the long-term encoding of conditioned fear even after a fear conditioning session has occurred (i.e. post-trauma). Unlike NMDA receptor antagonists, these protein interaction inhibitors are efficacious without impairing motor movement or memory. Thus, disruption of signal compartmentalization represents an innovative approach to develop novel treatments for anxiety disorders with fewer side-effects. We have assembled a collaborative team with synergistic and complementary expertise to unite extensive combined experience in drug discovery (Lai), development of novel preclinical stress and memory models (Shekhar and Hohmann), chemical optimization of lead compounds (Thakur) and target validation (Lai and Hohmann) to conduct work proposed under two Specific Aims. Aim 1 of this proposal will characterize the pharmacokinetic profile and oral efficacy of our lead inhibitors. Aim 2 will then use a traditional drug medicinal chemistry approach to design and develop a back up chemical series with improved solubility and potency compared to the parent compounds. Results from this SBIR Phase I study will lay the foundation for further lead optimization and preclinical development of nNOS targeting inhibitors as novel treatments for PTSD in Phase II. These studies are expected to validate the disruption of signal protein compartmentalization as an innovative and feasible approach to drug development. The development of effective pharmacotherapies with novel chemical structures that possess limited side- effect profiles is expected to drive down escalating health care costs and alleviate unnecessary suffering in PTSD patients.

描述（由申请人提供）：本申请“创伤后应激障碍的新颖治疗”解决了对创伤后应激障碍（PTSD）的有效治疗的迫切需要。创伤经历激活的关键神经信号级联是由兴奋性神经递质谷氨酸启动的。 NMDA 受体（一种谷氨酸受体亚型）的激活会导致神经元一氧化氮合酶 (nNOS) 的随后激活，并最终导致信号分子一氧化氮 (NO) 的产生增加。这些事件会引发异常的突触可塑性，这与 PTSD 的发生和维持。突触后密度蛋白 95 (PSD95) 将 nNOS 靶向 NMDA 受体，因此是 NMDA 受体激活 nNOS 所必需的。该项目的首席研究员Lai博士首先表明，小分子抑制剂IC87201在体外破坏了nNOS和PSD95之间的功能性蛋白质-蛋白质相互作用，并在体内减弱了NMDA受体依赖性痛觉过敏。我们由 Shekhar 博士（Anagin 创始人）领导的临床前团队现已证明，即使在条件性恐惧训练发生后（即创伤后），IC87201 和相关类似物 ZL006 也能阻止条件性恐惧的长期编码。与 NMDA 受体拮抗剂不同，这些蛋白质相互作用抑制剂在不损害运动或记忆的情况下有效。因此，破坏信号区室化代表了一种创新方法，可以开发副作用更少的焦虑症新疗法。我们组建了一支具有协同和互补专业知识的合作团队，将在药物发现 (Lai)、开发新型临床前应激和记忆模型 (Shekhar 和 Hohmann)、先导化合物的化学优化 (Thakur) 和靶点验证 (Lai 和 Hohmann) 方面的丰富综合经验结合起来，开展根据两个具体目标提出的工作。该提案的目标 1 将描述我们的先导抑制剂的药代动力学特征和口服功效。然后，目标 2 将使用传统的药物化学方法来设计和开发备用化学品系列，与母体化合物相比，其溶解度和效力均有所提高。这项 SBIR 一期研究的结果将为 nNOS 靶向抑制剂的进一步先导优化和临床前开发奠定基础，作为 II 期 PTSD 的新疗法。这些研究预计将验证信号蛋白区室化的破坏是一种创新且可行的药物开发方法。开发具有新颖化学结构、副作用有限的有效药物疗法，预计将降低不断上升的医疗保健成本，并减轻 PTSD 患者不必要的痛苦。