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

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：
9912345
负责人：
ELENA MOLOKANOVA
金额：
$ 35万
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912345
关键词：
Acute Address Affect Alcohol consumption Alcohols Animals Area Awareness Behavioral Binding Biological Sciences Brain Brain region Chronic Clinical Clinical Research Clinical Trials Cocaine Complex Control Animal Corpus striatum structure Country Coupled Dangerousness Development Diffusion Dimensions Disease model Dose Drug Kinetics Effectiveness Electrophysiology (science)Engineering Epidemic Exhibits FDA approved Fentanyl Formulation Goals Guidelines Hippocampus (Brain)Human Human body Immunohistochemistry In Vitro Individual Intravenous Intraventricular Kidney Literature Liver Mass Spectrum Analysis Measures Memantine Molecular N-Methyl-D-Aspartate Receptors N-Methylaspartate NMDA receptor antagonist Naloxone Nanostructures Neuraxis Neurons Neuropeptides Opioid Opioid user Pharmaceutical Preparations Pharmacology Phase Placebos Plasma Politics Population Pre-Clinical Model Preparation Probability Property Relapse Reporting Reproducibility Route Severities Slice Spleen Stains Substance Use Disorder Symptoms Synapses Synaptic Cleft Testing Therapeutic Agents Therapeutic Effect Time Tissues Toxic effect Treatment Efficacy United States Validation Withdrawal Withdrawal Symptom behavior test cocaine use cohort design economic impact efficacy study experimental study extracellular in vivo nanoGold nanobiologic nanodrug nervous system disorder novel therapeutic intervention novel therapeutics opioid epidemic opioid use opioid use disorder opioid withdrawal patient population pre-clinical preclinical efficacy preference prevent public health relevance receptor relapse risk side effect social socioeconomics success synaptic inhibition therapeutic evaluation

项目摘要

ABSTRACT Opioid use in the United States has been at epidemic proportions for over five 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 across the country. 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. Memantine, an FDA-approved NMDA receptor antagonist, has shown encouraging results as an adjunct to existing opioid use therapies. Its therapeutic efficacy likely derives from its preferential binding to NMDA receptors located outside the synapse, since broad spectrum NMDA receptor antagonists are associated with multiple clinical side effects. Furthermore, pre-clinical literature suggests that extrasynaptic NMDARs are preferentially targeted by cocaine and alcohol, although opioid effects on this receptor population remain unknown. We designed a nanostructured version of memantine (AuM) that physically prevents its binding to synaptic NMDA receptors, but allows activation of extrasynaptic receptors with potency exceeding that of free memantine. In studies performed in different labs, AuM has been demonstrated to exclusive target extrasynaptic NMDA receptors while exhibiting pronounced neuropeptide effects in several neurological disease models. In this proposal we will use a pre-clinical model to evaluate AuM targeting of extrasynaptic NMDA receptors as treatment of opioid withdrawal symptoms, a hallmark of opioid use disorder and a major reason for high rates of relapse among chronic opioid users.

摘要在美国，阿片类药物的使用已经流行了五年多。协调努力在迄今为止，一系列政治、社会意识、临床和研究举措都无法遏制艾滋病发病率的上升。阿片类药物的使用从治疗的角度来看，一些新的疗法，以减轻严重的阿片类药物继续提出减少戒断症状和/或减少复发风险的建议。美金刚，FDA批准的NMDA 受体拮抗剂作为现有阿片类药物使用疗法的辅助治疗，已显示出令人鼓舞的结果。其治疗功效这可能是由于其优先结合位于突触外的NMDA受体，因为广谱NMDA 受体拮抗剂与多种临床副作用有关。此外，临床前文献表明，突触外NMDAR优先被可卡因和酒精靶向，尽管阿片类药物对该受体有影响，人口仍然未知。我们设计了一种纳米结构的美金刚胺（AuM），结合突触NMDA受体，但允许激活突触外受体，其效力超过游离NMDA受体。美金刚。在不同实验室进行的研究中，AuM已被证明专门靶向突触外NMDA 受体，同时在几种神经疾病模型中表现出明显的神经肽作用。在该提案中，我们将使用临床前模型来评估突触外NMDA受体的AuM靶向，阿片类药物戒断症状的治疗，这是阿片类药物使用障碍的标志，也是复发率高的主要原因在长期阿片类药物使用者中。