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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）是一种较为常见和严重的神经退行性疾病，其特征是大脑多巴胺能神经元变性，导致虚弱的运动缺陷，如震颤、强直、运动障碍，对患者和社会都有严重的影响。多巴胺替代疗法左旋多巴（L-Dopa）是目前PD的标准药物治疗，但不幸的是，继续左旋多巴治疗不可避免地导致严重的运动波动，称为左旋多巴诱导的运动障碍（LID）。早在左旋多巴治疗后2-3年就可发生LID，多达80%的患者在左旋多巴治疗5年后发生。有非常有限的治疗选择预防或减少LID一旦建立。由于缺乏足够的治疗方法，左旋多巴治疗的PD患者的生活质量显著下降，并且由于LID的衰弱性运动效应的严重性，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预防LID的发生。多巴胺替代疗法的这些副作用使得我们有必要研究非多巴胺能治疗PD的方法，这些方法可以减少LID的发生，或者替代左旋多巴和其他多巴胺能治疗PD症状。一些非多巴胺能的方法正在临床试验（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）中进行评估。然而，这些临床阶段的药物中有几种显示出明显的脱靶效应和PD症状的“恶化”，并且无法改善帕金森病或运动障碍评分。因此，需要新的靶点和方法来改善PD的长期治疗。该应用程序提出了一个新的靶点和新的治疗方案，以治疗PD症状，重要的是，LID。我们建议研究伤害肽受体NOP作为PD治疗和LID治疗的靶点，并建议开发期望谱的NOP受体配体，有效减少PD相关的运动缺陷，以及减少或预防LID症状。NOP受体的内源性配体nociceptin/orphanin FQ （N/OFQ）已被证明在多巴胺耗尽状态下上调，并有助于PD症状。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PD和LID偏瘫大鼠模型中对帕金森残疾的保护作用的概念证明。本提案的目的是利用迭代药物化学发现优化的新型强效NOP配体；体外受体结合特性及功能测定；PD和LID动物模型急性给药后的体内早期PK评估和体内评估。我们的研究将为这种新的PD和LID治疗方法提供关键的验证，并提供潜在的新型候选药物，可以进一步开发。在这个简短的概念验证研究中，我们的翻译方法验证了PD治疗的新靶点和新药物谱，有可能在高未满足需求和巨大经济负担的领域产生重大影响。