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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.

项目摘要阿片类药物在美国的使用多年来一直处于流行病的比例。协调努力在迄今为止，政治、社会意识、临床和研究举措的范围都无法遏制美国阿片类药物使用率和阿片类药物过量死亡率上升。从治疗的角度来看，缓解严重阿片类戒断症状和/或降低复发风险的新疗法继续被提议。对潜在疗法的研究的很大一部分集中在测试FDA批准的药物上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，以确保这些研究将产生有效的阿片类药物使用障碍的新药。其中一种药物是美金刚胺，一种NMDA受体拮抗剂，作为一种抗抑郁药，辅助现有的阿片类药物使用疗法。美金刚的治疗作用是由于涉及阿片类药物成瘾的发展和维持中的阿片能途径及其临床耐受性可能源于位于突触外的NMDA受体的优先抑制，受体拮抗剂与严重的临床副作用有关。然而，美金刚浓度必须保持低水平以利用其优先拮抗作用，因为在较高的（和更有治疗意义的）相关浓度），美金刚可抑制突触NMDA受体并引发副作用。为了解决这个问题，NeurANO Bioscience创建了基于纳米颗粒（AuM）的缀合物，其包含：几个美金刚分子由于其尺寸，AuM不能进入突触间隙和突触NMDA 受体，但允许激活突触外NMDAR受体的效力大大超过免费美金刚。在I期研究中，我们发现AuM可以大大减少阿片类药物戒断症状，并证明AuM可以在治疗浓度下递送到大脑中，鼻内给药。在拟议的第二阶段研究中，我们将继续努力， AuM的商业可制造性，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。利用第二阶段研究期间获得的数据，我们将制定有效的策略，以进行IND使能研究，以使用突触外受体拮抗剂 NMDAR在治疗OUD中的应用