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

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

展开

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（由申请人提供）：帕金森氏病（PD）是一种最常见和严重的神经退行性疾病之一，其特征是大脑中多巴胺能神经元退化，导致衰弱的运动缺陷，例如震颤，刚度，刚度和akinesia，对患者以及社会都有严重影响。左旋多巴（L-DOPA）的多巴胺替代疗法目前是PD的标准药物疗法，但不幸的是，对L-DOPA的持续治疗不可避免地导致严重的运动波动，称为L-DOPA诱导的运动障碍（LID）。 LID在L-DOPA治疗后2 - 3年，在L-DOPA治疗5年后，盖子可能最早发生2 - 3年。一旦确定，预防盖子或降低盖子的治疗选择非常有限。由于盖子缺乏足够的治疗方法，由于LID衰弱的运动效应的严重程度，PD患者在L-DOPA疗法上的生活质量显着下降，并给患者和社会带来了巨大的经济负担。迫切需要采用新的药物治疗方法来治疗盖子，并在可能的情况下，以防止在治疗帕金森氏症状时盖子的发生。多巴胺替代疗法的这些副作用需要研究对PD治疗的非遍及胺能方法，从而减少盖子的发生，或取代L-DOPA和其他多巴胺能治疗以治疗PD症状。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，正在评估几种非多巴胺能方法。但是，其中几种临床阶段药物显示出明显的脱靶作用和PD症状的“恶化”，并且无法改善帕金森氏症或运动障碍分数。因此，需要新的靶标和方法来改善PD的长期治疗。该应用建议研究一个新靶标和一种新的治疗特征，以治疗PD症状，重要的是盖子。我们建议将NociTptin受体NOP作为PD治疗和盖子处理的靶标，并建议开发出有效减少与PD相关的运动缺陷的所需特征的NOP受体配体，以及减少或预防盖子的症状。 NOP受体Nocteptin/Orphanin FQ（N/OFQ）的内源性配体已显示在多巴胺耗竭状态下上调，并导致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的大鼠模型中为帕金森氏症残疾提供保护的概念证明。该提案的目的是使用迭代药物化学发现优化的新型有效NOP配体。受体结合和功能测定中的体外表征；急性给药后，PD和盖子动物模型中的体内PK评估和体内评估。我们的研究将为PD和LID疗法提供这种新颖的治疗方法的批判性验证，还提供了可以进一步开发的潜在新型药物候选者。在这项简短的概念验证研究中，我们验证PD治疗的新型靶标和新型药物概况的翻译方法有可能对高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：帕金森氏病（PD）是最常见和严重的神经退行性疾病之一，发生在60多个人口中的2％中。其主要疗法L-DOPA与持续治疗后不可避免地发生的严重且恶化的症状有关，但对于这种治疗选择非常有限，没有可用的治疗方法。据估计，与没有PD的普通患者相比，PD患者每年的医疗费用花费多约11,000美元。 PD的年成本负担估计为350亿美元，在医疗和药物成本，患者护理和间接成本的生产率损失方面。目前研究的方法似乎都没有临床成功。因此，探索新方法有很大的空间。我们的建议调查了一个针对PD治疗和L-DOPA诱导的运动障碍的新的，相对尚未开发的靶标，并提议开发针对该靶标的新型药物候选者，以验证该靶标对于开发针对PD和Dyskinesias的急需的药物治疗。成功完成我们的研究可能会对PD治疗的结果产生重大影响。