Development of a lead cyclic-PDZ-Enhancer drug for Anxiety and Depression

开发用于治疗焦虑和抑郁的先导环 PDZ 增强剂药物

• 批准号: 10015345
• 负责人: JOHN MARSHALL
• 金额: $ 45.26万
• 依托单位: AINGEAL, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10015345
• 关键词: Adult; Affect; Amino Acids; Anesthetics; Animal Model; Antidepressive Agents; Anxiety; Atrophic; Attention; Behavioral; Behavioral Paradigm; Biological Markers; Bipolar Disorder; Brain region; Brain-Derived Neurotrophic Factor; Calmodulin; Chronic; Cognition; Cognitive; Data; Dendritic Spines; Development; Discrimination; Disease; Dose; Down-Regulation; Engineering; Enhancers; Family; Feasibility Studies; Female; Functional disorder; Goals; Half-Life; Hippocampus (Brain); Hour; Human; Immunoblot Analysis; Impairment; Infusion procedures; Injections; Intravenous; Ketamine; Lactams; Lead; Learning; Legal patent; Long-Term Depression; Long-Term Effects; Long-Term Potentiation; Major Depressive Disorder; Measures; Memory impairment; Mental Depression; Modeling; Mood Disorders; Morphology; Motor Activity; Mus; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Nucleus Accumbens; Pathway interactions; Patients; Peptide Hydrolases; Periodicity; Pharmaceutical Preparations; Phase; Phenotype; Phospho-Specific Antibodies; Phosphotransferases; Population; Prefrontal Cortex; Property; Receptor Signaling; Resistance; Safety; Side; Signal Pathway; Signal Transduction; Specificity; Stress; Study models; Sucrose; Synaptic plasticity; System; Tail Suspension; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Treatment Efficacy; Treatment Protocols; Vertebral column; analog; antidepressant effect; aspartate receptor; base; beta-Alanine; blood-brain barrier permeabilization; conditioning; conventional therapy; depression model; depressive behavior; depressive symptoms; design; disability; executive function; fear memory; field study; flexibility; forced swim test; heart damage; life time cost; liver injury; male; mouse model; neurotrophic factor; novel; novel strategies; novel therapeutics; optimal treatments; peptidomimetics; preclinical efficacy; preference; renal damage; social defeat; stability testing; structured data; subcutaneous; treatment effect; treatment-resistant depression; web site

Major depressive disorder is a debilitating mood disorder that affects ~7% of US adults in their lifetime, costing the U.S. economy more than $200 billion a year. Drugs that increase monoaminergic signaling are the mainstay of depression therapy, but have a delayed onset of action and are only effective in about 50% of affected patients. Aberrant brain-derived neurotrophic factor (BDNF) signaling has been proposed to underlie the pathophysiology of major depressive disorder and Bipolar disorder. We have developed a novel family of cyclic peptidomimetic compounds that potentiate the BDNF pathways to produce rapid (within hours) antidepressant effects. Here, we propose a Phase I proof-of- concept and feasibility study for the use of our patented new drug, CN2097, for treating depression. There are three major goals that focus on preclinical efficacy. Aim 1 will test the stability of CN2097 analogues and evaluate toxicity. Aim 2 will evaluate the rapid and long-term effects of treatment with CN2097 in mitigating depressive behaviors using two extensively validated models: Chronic mild stress (CMS) and Chronic social defeat stress (CSDS). Aim 3 will examine the ability of CN2097 to correct impairments in the cellular mechanisms of depression that include signaling, neuronal atrophy and synaptic plasticity.

严重抑郁障碍是一种衰弱的情绪障碍，大约7%的美国成年人会在一生中受到影响， 每年给美国经济造成的损失超过2000亿美元。增加单胺能信号转导的药物 是抑郁症治疗的中流砥柱，但有延迟起效，仅在 约50%的受影响患者。脑源性神经营养因子(BDNF)信号转导异常 提出了严重抑郁障碍和双相情感障碍的病理生理学基础。 我们已经开发了一类新的环肽模拟物，它可以增强BDNF 快速(在数小时内)产生抗抑郁效果的途径。在这里，我们提出了第一阶段的证明- 使用我们的专利新药CN2097治疗抑郁症的概念和可行性研究。 有三个主要目标集中在临床前疗效上。目标1将测试CN2097的稳定性 类似物，并评估毒性。目标2将评估治疗的快速和长期效果 CN2097使用两个广泛验证的模型缓解抑郁行为：慢性 轻度应激(CMS)和慢性社会失败应激(CSDS)。目标3将检验以下能力 CN2097纠正抑郁症细胞机制中的损伤，包括信号传递， 神经元萎缩和突触可塑性。