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Development of Novel Therapies for Levodopa-induced Dyskinesia in Parkinson's Dis

帕金森病左旋多巴诱发的运动障碍新疗法的开发

基本信息

批准号：
7927877
负责人：
Nurulain T Zaveri
金额：
$ 24.14万
依托单位：
ASTRAEA THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7927877
关键词：
Acute Adrenergic alpha-Antagonists Adverse effects Affect Agonist Amantadine Animal Model Area Attenuated Behavioral Biological Assay Brain Buspirone Chronic Clinical Clinical Trials Collaborations Corpus striatum structure Development Dopamine Dopamine D2 Receptor Dopamine Receptor Drug Addiction Drug Costs Dyskinetic syndrome Economic Burden Evaluation Excitatory Amino Acid Antagonists Facilities and Administrative Costs Foxes Future Glutamates Gold Human In Vitro Investigation L-DOPA induced dyskinesia Laboratories Lead Levodopa Libraries Ligands Medical Modeling Motor Muscle Rigidity National Institute of Mental Health Neurodegenerative Disorders Opioid Receptor Outcome Oxidopamine Pain Parkinson Disease Parkinsonian Disorders Patient Care Patients Penetration Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacotherapy Plasma Population Preclinical Drug Evaluation Prevention Prevention therapy Process Psychotropic Drugs Quality of life Rattus Replacement Therapy Rodent Rodent Model Role Screening procedure Series Severities Societies Staging Substantia nigra structure Symptoms System Therapeutic Tremor Validation Work abnormal involuntary movement base cost design disability dopaminergic neuron drug candidate improved in vivo motor deficit nigrostriatal pathway nociceptin nociceptin receptor novel novel strategies novel therapeutic intervention novel therapeutics outcome forecast pre-clinical preclinical study prevent productivity loss programs public health relevance receptor receptor binding scaffold stem success translational approach translational study

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is one of the more common and serious neurodegenerative diseases characterized by degeneration of dopaminergic neurons in the brain, resulting in debilitating motor deficits such as tremor, rigidity, and akinesia, which have a severe impact on the patient as well as society. Dopamine replacement therapy with Levodopa (L-Dopa) is currently the standard pharmacotherapy for PD, but unfortunately, continued therapy with L-Dopa inevitably leads to serious motor fluctuations termed as L-Dopa induced dyskinesia (LID). LID can occur as early as 2-3 years after L-Dopa therapy and in as many as 80% of patients after 5 years of L-Dopa treatment. There are very limited treatment options for the prevention of LID or reduction of LID once established. Because of the lack of adequate treatment for LID, there is a significant decline in the quality of life of PD patients on L-Dopa therapy and a huge economic burden to the patient and to society due to the severity of the debilitating motor effects of LID. New pharmacotherapeutic approaches are urgently needed to treat LID and if possible, to prevent the occurrence of LID while treating Parkinson's symptoms. These side effects of dopamine replacement therapies have necessitated the investigation of nondopaminergic approaches for treatment of PD, that can reduce the occurrence of LID, or replace L-Dopa and other dopaminergic treatments for treating PD symptoms. Several non-dopaminergic approaches are being evaluated in clinical trials (5HT1A agonists, alpha adrenergic antagonists) and in preclinical studies (glutamate antagonists). However, several of these clinical-stage drugs have shown significant off-target effects and 'worsening' of PD symptoms, and have been unable to improve parkinsonism or dyskinesia scores. New targets and approaches are therefore needed to improve the long-term therapy of PD. This application proposes to investigate a new target and a novel therapeutic profile for the treatment of PD symptoms and importantly, for LID. We propose to investigate the nociceptin receptor NOP as a target for PD treatment and treatment of LID, and propose to develop NOP receptor ligands of desired profiles that are effective in reducing motor deficits associated with PD, as well as reducing or preventing symptoms of LID. The endogenous ligand for the NOP receptor, nociceptin/orphanin FQ (N/OFQ) has been shown to be upregulated in dopamine depletion states and contributes to PD symptoms. We propose to develop novel NOP receptor ligands possessing the desired receptor activity, and to investigate the proof of concept that these ligands afford protection against parkinsonian disabilities in hemilesioned rat models of PD and LID. The Aims of this proposal are to discover optimized novel potent NOP ligands using iterative medicinal chemistry; in vitro characterization in receptor binding and functional assays; early in vivo PK assessments and in vivo evaluation in animal models of PD and LID after acute administration. Our studies will provide critical validation of this novel therapeutic approach for PD and LID therapy, and also provide potentially novel drug candidates that can be further developed. Our translational approach to validate this novel target and novel drug profiles for PD treatment, in this short proof-of-concept study, has the potential to have a significant impact in an area of high unmet need and tremendous economic burden. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is one of the more common and serious neurodegenerative diseases and occurs in 2% of the population over 60. Its main therapy, L-Dopa, is associated with severe and worsening symptoms that inevitably occur after continued therapy, but for which there are very limited treatment options and no prevention therapies available. It is estimated that a PD patient spends about $11,000 more per year in medical costs than the average patient without PD. The annual cost burden of PD is estimated at $35 billion, in combined medical and drug costs, patient care and indirect costs of loss of productivity. None of the currently investigated approaches appear to have much clinical success; therefore there is significant room for exploring new approaches. Our proposal investigates a new, relatively unexplored target for PD therapy and L-Dopa induced dyskinesias, and proposes to develop novel drug candidates against this target, to validate this target as being suitable for developing much-needed pharmacotherapies against PD and dyskinesias. Successful completion of our studies has the potential to have a significant impact on the outcome of PD treatment.

描述(申请人提供)：帕金森病(PD)是一种更常见和更严重的神经退行性疾病，其特征是大脑中的多巴胺能神经元变性，导致震颤、僵直和运动障碍等衰弱的运动障碍，对患者和社会都有严重的影响。多巴胺替代疗法联合左旋多巴(L-多巴)是目前治疗帕金森病的标准药物，但遗憾的是，继续使用L-多巴治疗不可避免地会导致严重的运动波动，称为L-多巴诱导的运动障碍(LID)。LID最早可在L-多巴治疗后2-3年发生，高达80%的患者在L-多巴治疗5年后发生。一旦确诊，预防或缩小眼睑的治疗选择非常有限。由于LID缺乏足够的治疗，使用L-多巴疗法的PD患者的生活质量明显下降，LID的衰弱运动效应严重，给患者和社会带来了巨大的经济负担。迫切需要新的药物治疗方法来治疗LID，如果可能的话，在治疗帕金森症状的同时防止LID的发生。多巴胺替代疗法的这些副作用使人们有必要研究治疗帕金森病的非多巴胺能途径，以减少LID的发生，或取代L-多巴和其他多巴胺能疗法来治疗帕金森病症状。临床试验(5HT1a激动剂、α肾上腺素能拮抗剂)和临床前研究(谷氨酸拮抗剂)正在对几种非多巴胺能药物进行评估。然而，这些临床阶段的药物中有几种已经显示出显著的非靶向效应和帕金森病症状的“恶化”，并且无法改善帕金森症或运动障碍的评分。因此，需要新的靶点和方法来改善帕金森病的长期治疗。这项申请提出了一种新的靶点和新的治疗方案，用于治疗帕金森病症状，更重要的是治疗LID。我们建议研究伤害素受体NOP作为帕金森病治疗和LID治疗的靶点，并建议开发具有所需特征的NOP受体配体，以有效地减少与PD相关的运动障碍，以及减轻或预防LID的症状。研究表明，在多巴胺耗竭状态下，NOP受体的内源性配体伤害素/孤儿蛋白FQ(N/OFQ)表达上调，并与帕金森病症状有关。我们建议开发具有所需受体活性的新型NOP受体配体，并研究这些配体在偏侧PD和LID大鼠模型中对帕金森病残疾提供保护的概念证据。这项建议的目的是利用迭代药物化学发现优化的新的有效NOP配体；在受体结合和功能分析中的体外表征；早期体内PK评估和急性给药后PD和LID动物模型的体内评估。我们的研究将为PD和LID治疗这一新的治疗方法提供关键的验证，并提供潜在的新候选药物，可以进一步开发。在这项简短的概念验证研究中，我们验证帕金森病治疗的新靶点和新药概况的翻译方法，有可能在一个高度未满足需求和巨大经济负担的领域产生重大影响。公共卫生相关性：帕金森病(PD)是一种更常见和更严重的神经退行性疾病，在60岁以上的人口中有2%的人会发生帕金森病。其主要疗法L-多巴与持续治疗后不可避免地出现的严重和恶化的症状有关，但对这些症状的治疗选择非常有限，也没有预防疗法可用。据估计，帕金森病患者每年的医疗费用比普通的非帕金森病患者多11,000美元。PD每年的成本负担估计为350亿美元，其中包括医疗和药品成本、病人护理以及生产力损失的间接成本。目前研究的方法中没有一种在临床上有很大的成功，因此有很大的空间来探索新的方法。我们的建议调查了一个相对未被探索的治疗帕金森病和L-多巴诱发的运动障碍的新靶点，并建议开发针对该靶点的新候选药物，以验证该靶点适合于开发急需的治疗帕金森病和运动障碍的药物疗法。我们研究的成功完成有可能对帕金森病的治疗结果产生重大影响。