Evaluation of the therapeutic potential of exclusive antagonists of extrasynaptic NMDA receptors for the treatment of opioid use disorder

评估突触外 NMDA 受体的独家拮抗剂治疗阿片类药物使用障碍的治疗潜力

基本信息

批准号：
10581405
负责人：
ELENA MOLOKANOVA
金额：
$ 83.57万
依托单位：
NEURANO BIOSCIENCE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581405
关键词：
Acute Address Affect Animal Model Animals Anxiety Awareness Behavior Biological Markers Biological Sciences Blinded Brain Brain-Derived Neurotrophic Factor Buprenorphine Chemistry Clinical Control Animal Control Groups Data Death Rate Development Dimensions Dose Drug Targeting Endotoxins Engineering Ensure Enzyme-Linked Immunosorbent Assay Epidemic Evaluation Exhibits Extinction FDA approved Formulation Future Glutamates Goals Guidelines Human Inflammatory Infusion procedures Intranasal Administration Link Maintenance Mediating Memantine Memory Methods Microglia Morphine Morphine Dependence N-Methyl-D-Aspartate Receptors NMDA receptor antagonist Naloxone Opiate Addiction Opioid Opioid Receptor Outcome Pathway interactions Patients Pharmaceutical Preparations Placebos Politics Prevention Probability Process Property Protocols documentation Quantitative Reverse Transcriptase PCR Relapse Reporting Reproducibility Research Research Contracts Rewards Risk Reduction Route Safety Saline Scientist Self Administration Severities Synapses Synaptic Cleft System Testing Therapeutic Therapeutic Effect Time Treatment Efficacy United States United States National Institutes of Health Validation Western Blotting Withdrawal Withdrawal Symptom abuse liability addiction analytical method antagonist behavior test behavioral study cytokine design dosage economic impact effectiveness evaluation efficacy study experience extracellular fighting flexibility improved in vivo manufacturability manufacture mortality risk nanoGold nanoparticle nanotherapeutic neuroinflammation neuroprotection non-opioid analgesic novel novel therapeutic intervention novel therapeutics opioid epidemic opioid mortality opioid use opioid use disorder opioid withdrawal pharmacologic phase 1 study phase 2 study preclinical efficacy preclinical study prevent rational design receptor relapse prevention relapse risk scale up side effect social socioeconomics standard of care success synaptic inhibition therapeutic evaluation treatment group zeta potential

项目摘要

PROJECT SUMMARY Opioid use in the United States has been at epidemic proportions for many years. Concerted efforts across the spectrum of political, social awareness, clinical and research initiatives have so far been unable to curb the rising rates of opioid use and opioid overdose deaths across the USA. From the treatment standpoint, a number of novel therapies to alleviate the severe opioid withdrawal symptoms and/or reduce risk of relapse continue to be proposed. A significant portion of research into potential therapies focuses on testing FDA-approved drugs as potential treatments for opioid use. Such approach relies on the verified scientific rationale and clinically validated drug targets to ensure that these studies will produce efficacious new drugs for opioid use disorder. One of such drugs is memantine, an NMDA receptor antagonist, that has shown encouraging results as an adjunct to existing opioid use therapies. Therapeutics effects of memantine are due to the involvement of glutamatergic pathways in the development and maintenance of opioid addiction, and its clinical tolerability likely derives from preferential inhibition of NMDA receptors located outside the synapse, since broad spectrum NMDA receptor antagonists are associated with serious clinical side effects. However, memantine concentrations must be kept low to take advantage of its preferential antagonism, because at higher (and more therapeutically relevant) concentrations, memantine may inhibit synaptic NMDA receptors and trigger side effects. To resolve this problem, NeurANO Bioscience created a nanoparticle-based (AuM) conjugate comprising several memantine molecules. Due to its dimensions, AuM cannot access the synaptic cleft and synaptic NMDA receptors, but allows activation of extrasynaptic NMDAR receptors with the potency greatly exceeding that of free memantine. During Phase I studies, we discovered that AuM can drastically minimize the opioid withdrawal symptoms, and demonstrated that AuM can be delivered into the brain at therapeutic concentrations using intranasal administration. During proposed Phase II studies, we will proceed with efforts directed at establishing the commercial manufacturability of AuM, determining optimal administration routes and AuM dosage for the treatment of opioid withdrawal symptoms, and exploring AuM therapeutic potential for the prevention of acquisition of opioid dependence and/or relapse. Using the data acquired during Phase II studies, we will develop the efficient strategy to pursue IND-enabling studies for use of exclusive antagonists of extrasynaptic NMDARs in the treatment of OUD.

项目概要多年来，阿片类药物的使用在美国一直处于流行状态。各地齐心协力迄今为止，各种政治、社会意识、临床和研究举措都无法遏制这种情况美国各地阿片类药物使用率和阿片类药物过量死亡率不断上升。从治疗的角度来看，一些缓解严重阿片类药物戒断症状和/或降低复发风险的新疗法仍在不断涌现被提议。潜在疗法研究的很大一部分集中于测试 FDA 批准的药物作为阿片类药物使用的潜在治疗方法。这种方法依赖于经过验证的科学原理和临床验证药物靶点，以确保这些研究将为阿片类药物使用障碍产生有效的新药。其中一种药物是美金刚，一种 NMDA 受体拮抗剂，作为一种药物已显示出令人鼓舞的结果。现有阿片类药物使用疗法的辅助疗法。美金刚的治疗作用是由于参与阿片类药物成瘾发生和维持的谷氨酸途径及其临床耐受性源于对位于突触外部的 NMDA 受体的优先抑制，因为广谱 NMDA 受体拮抗剂与严重的临床副作用相关。然而，美金刚浓度必须保持较低以利用其优先拮抗作用，因为在较高（且更具治疗效果）在相关）浓度下，美金刚可能会抑制突触 NMDA 受体并引发副作用。为了解决这个问题，NeurANO Bioscience 创建了一种基于纳米颗粒 (AuM) 的缀合物，其中包含几个美金刚分子。由于其尺寸，AuM 无法访问突触间隙和突触 NMDA 受体，但可以激活突触外 NMDAR 受体，其效力大大超过游离美金刚。在第一阶段研究中，我们发现 AuM 可以极大地减少阿片类药物戒断症状，并证明 AuM 可以使用以下方法以治疗浓度输送到大脑中：鼻内给药。在拟议的第二阶段研究期间，我们将继续致力于建立 AuM 的商业生产能力，确定最佳给药途径和 AuM 剂量治疗阿片类药物戒断症状，并探索 AuM 预防阿片类药物戒断症状的治疗潜力获得阿片类药物依赖和/或复发。利用第二阶段研究中获得的数据，我们将制定有效的策略来进行 IND 启用研究，以使用突触外的独家拮抗剂 NMDAR 治疗 OUD。