In vitro pharmacology and In vivo neuroprotective effects of CMPI analogues in an optimized Zebrafish model of Parkinsons disease

CMPI 类似物在帕金森病优化斑马鱼模型中的体外药理学和体内神经保护作用

• 批准号: 10624889
• 负责人: Ayman K. Hamouda
• 金额: $ 14.7万
• 依托单位: UNIVERSITY OF TEXAS TYLER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-20 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624889
• 关键词: Affinity; Agonist; American; Anatomy; Animal Model; Animals; Anti-Inflammatory Agents; Award; Behavioral; Binding; Biological; Biomedical Research; Brain; Characteristics; Chemosensitization; Clinical; Cognitive; Cognitive deficits; Communities; Data; Development; Disease; Disease Progression; Dopamine; Drug Screening; Drug Targeting; Effectiveness; Electrophysiology (science); Ensure; Future; Goals; Human; Impaired cognition; In Vitro; Interleukin-1 beta; Isoxazoles; Knowledge; Laboratories; Lead; Lewy Bodies; Ligands; Measurable; Measures; Mission; Modeling; Molecular; Motor; Motor Activity; Mutation Analysis; Neurobehavioral Manifestations; Neurons; Neurotransmitters; Nicotinic Receptors; Oxidopamine; Parkinson Disease; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Production; Property; Reproducibility; Research; Research Project Grants; Research Training; Students; Symptoms; Testing; Texas; Therapeutic; Time; United States National Institutes of Health; Universities; Zebrafish; acetylcholine receptor agonist; alpha synuclein; analog; associated symptom; clinical development; clinically relevant; cost; disease phenotype; dopaminergic neuron; drug development; effective therapy; experimental study; high throughput screening; improved; in vivo; in vivo Model; in vivo evaluation; insight; motor symptom; neuroprotection; novel; novel strategies; novel therapeutics; pharmacologic; pharmacophore; positive allosteric modulator; pre-clinical; programs; response; screening; symptom treatment; therapy outcome; undergraduate student

Parkinson’s Disease (PD) results from multiple underlying pathologies, including accumulation of a-synuclein- containing Lewy bodies, loss of dopaminergic neurons, and perturbation of other neurotransmitter pathways. While increasing dopamine production using the precursor L-DOAP seems effective at reducing PD symptoms at first, the continuous decline in the number of dopaminergic neurons as PD progresses reduces the effectiveness of L-DOPA, and additional therapy to control the PD's symptoms becomes necessary. The lack of disease-modifying drugs that target PD's underlying pathologies and stop its progression represents a significant gap in our knowledge and unmet clinical need. Therefore, this application aims to initiate early step experiments in a continuum of research that is likely to lead to the development of clinically relevant positive allosteric modulators (PAMs) of nicotinic acetylcholine receptors (nAChRs) which are known to have neuroprotective, anti- inflammatory, and precognitive properties and thus hold promise for the development of drugs with disease- modifying properties for PD. In this proposal, we are taking advantage of a lead pharmacophore, CMPI, that we have identified as an (α4)3(β2)2 nAChR-selective PAM and its analogs to develop selective nAChR PAMs and to provide proof-of- concept evidence of their in vivo efficacy against PD. We propose the following specific aims: 1) Identification of CMPI analogs with high potency, efficacy, and selectivity as (α4)3(β2)2 nAChR PAMs; 2A) Optimization of a zebrafish model for in vivo Parkinson’s disease drug screening; and 2B) Assessment of nAChR PAMs effect on behavioral, anatomical, and molecular measures of PD progression. Upon accomplishing these specific aims, we expect that CMPI analogs that bind with high affinity and selectivity to and potentiate agonist-induced responses of (α4)3(β2)2 nAChR will be identified. The anticipated results will also provide in vivo evidence to support the pharmacological merit of α4β2 nAChR PAMs as a novel strategy to slow the progression of motor and cognitive decline associated with PD. The proposed research project will also optimize conditions for a reliable zebrafish PD-like phenotype animal model with measurable behavioral, anatomical, and biological readouts suitable for high throughput screening of novel therapeutic compounds for PD. This model will help reduce the time and cost of selecting lead compounds for future animal and human studies and facilitate the development of novel therapeutics for the treatment of motor symptoms and cognitive decline associated with Parkinson’s disease. Once such drugs become clinically relevant, progress will have been made toward effective PD treatment and advancing the National Institutes of Health mission.

帕金森氏病（PD）是由多种潜在的病变引起的，包括积累A-核蛋白 - 包含路易的身体，多巴胺能神经元的丧失以及其他神经递质途径的扰动。 使用前体L-DOAP增加多巴胺的产生似乎有效减少PD症状 首先，随着PD的进展，多巴胺能神经元的数量不断减少。 L-DOPA的有效性以及控制PD症状的其他疗法是必要的。缺乏 靶向PD的潜在病理并停止其进展的疾病改良药物代表了重要的 我们的知识和未满足的临床需求的差距。因此，该应用程序旨在启动早期步骤实验 在连续研究中可能导致临床相关阳性变构的发展 烟碱乙酰胆碱受体（NACHR）的调节剂（PAMS），该受体已知具有神经保护性，抗 - 炎症性和漂亮的特性，因此有望开发患有疾病的药物 - 修改PD的属性。 在此提案中，我们利用铅药理CMPI的优势，我们已经确定为一个 （α4）3（β2）2 NACHR选择性PAM及其类似物，以发展选择性nACHR PAM并提供证明 其体内效率对PD的概念证据。我们提出以下具体目的：1）识别 具有高效力，效率和选择性的CMPI类似物（α4）3（β2）2 NACHR PAM； 2a）优化 体内帕金森氏病药物筛查的斑马鱼模型；和2b）评估NACHR PAM对 PD进展的行为，解剖和分子测量。 完成这些特定目标后，我们期望具有高亲和力和选择性结合的CMPI类似物 将鉴定出（α4）3（β2）2 NACHR的对和潜在激动剂诱导的响应。预期的结果将 还提供体内证据，以支持α4β2NACHRPAM的药物优点作为一种新的策略 减慢与PD相关的运动和认知下降的进展。拟议的研究项目也将 优化可靠的斑马鱼PD样表型动物模型的条件，可测量的行为， 解剖学和生物学读数适用于新型治疗化合物的高吞吐量筛查 PD。该模型将有助于减少为未来动物和人类选择铅化合物的时间和成本 研究并促进用于治疗运动症状和认知治疗的新型治疗 与帕金森氏病有关的衰落。一旦此类药物在临床上具有相关性，进度就会有 我们是为了有效的PD治疗，并推进了美国国立卫生研究院的任务。