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: 10412533
• 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/10412533
• 关键词: Affinity; Agonist; American; Anatomy; Animal Model; Animals; Anti-Inflammatory Agents; Award; Behavioral; Binding; Biological; Biomedical Research; Brain; Characteristics; Chemosensitization; Clinical; 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; Levodopa; 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; novel; novel strategies; novel therapeutics; 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.

帕金森病 (PD) 是由多种潜在病理引起的，包括 a-突触核蛋白的积累 含有路易体、多巴胺能神经元丧失以及其他神经递质途径的扰动。 虽然使用前体 L-DOAP 增加多巴胺的产生似乎可以有效减轻帕金森病症状 首先，随着帕金森病的进展，多巴胺能神经元数量持续减少，从而减少了 左旋多巴的有效性以及控制 PD 症状的额外治疗变得必要。 针对帕金森病潜在病理学并阻止其进展的疾病缓解药物具有重要意义 我们的知识差距和未满足的临床需求因此，该应用旨在启动早期实验。 在一系列研究中，可能会导致临床相关的正变构的发展 烟碱乙酰胆碱受体 (nAChR) 调节剂 (PAM) 已知具有神经保护作用、抗 炎症和预知特性，因此有望开发治疗疾病的药物 修改 PD 的属性。 在本提案中，我们利用了主要药效基团 CMPI，我们已将其确定为 (α4)3(β2)2 nAChR 选择性 PAM 及其类似物，用于开发选择性 nAChR PAM 并提供证明- 其体内抗帕金森病功效的概念证据我们提出以下具体目标：1) 鉴定。 与 (α4)3(β2)2 nAChR PAM 一样具有高效力、功效和选择性的 CMPI 类似物 2A) 优化 用于体内帕金森病药物筛选的斑马鱼模型；和 2B) 评估 nAChR PAM 的作用 PD进展的行为、解剖和分子测量。 在实现这些特定目标后，我们期望 CMPI 类似物能够以高亲和力和选择性结合 并增强 (α4)3(β2)2 nAChR 激动剂诱导的反应将得到预期结果。 还提供体内证据支持 α4β2 nAChR PAM 作为一种新策略的药理学优点 拟议的研究项目还将减缓与帕金森病相关的运动和认知能力下降的进程。 优化具有可测量行为的可靠斑马鱼 PD 样表型动物模型的条件， 适合高通量筛选新型治疗化合物的解剖学和生物学读数 该模型将有助于减少为未来动物和人类选择先导化合物的时间和成本。 研究并促进治疗运动症状和认知的新疗法的开发 一旦这些药物变得与帕金森病相关，就会取得进展。 致力于有效的帕金森病治疗并推进美国国立卫生研究院的使命。