Developing GPR37 activators as non-opioid pain therapeutics

开发 GPR37 激活剂作为非阿片类疼痛疗法

• 批准号: 10453930
• 负责人: John A Allen
• 金额: $ 157.35万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10453930
• 关键词: Acute; Acute Pain; Affective; Agonist; Analgesics; Animal Model; Animals; Arrestins; Behavior; Behavioral Paradigm; Biological Assay; Biology; Brain; CD59 Antigen; Cell Line; Cells; Cellular Assay; Chemicals; Chemosensitization; Chronic; Conflict (Psychology); Coupling; Cyclic AMP; Data; Development; Disease; Docking; Dose; Drug Addiction; Drug Design; Fentanyl; G-Protein-Coupled Receptors; GPR37 receptor; GTP-Binding Protein alpha Subunits, Gs; Hypersensitivity; Infection; Inflammation; Inflammatory; Injections; Injury; Interdisciplinary Study; Knock-out; Lead; Lipids; Literature; Maintenance; Mediating; Memory; Molecular; Molecular Target; Motivation; Mus; Neurons; Nociception; Nociceptors; Opioid; Orphan; Outcome Measure; Pain; Pain management; Peptides; Persistent pain; Pharmaceutical Chemistry; Pharmaceutical Preparations; Prevention; Research; Research Activity; Research Personnel; Resolution; Rodent; Self Administration; Sensory; Spinal; Spinal Cord; Spinal cord posterior horn; Spine pain; Structure; Structure-Activity Relationship; Synapses; System; Testing; Therapeutic; Time; Training; Validation; Withdrawal; Work; abuse liability; addiction; assay development; base; cell type; cellular targeting; chemical synthesis; chronic neuropathic pain; chronic pain; chronic pain management; conditioned place preference; counterscreen; database of Genotypes and Phenotypes; design; dorsal horn; drug discovery; ex vivo imaging; excitatory neuron; high throughput screening; in silico; in vivo evaluation; inhibitory neuron; macrophage; multidisciplinary; nerve injury; neural circuit; non-opioid analgesic; novel; novel strategies; pain behavior; painful neuropathy; peptidomimetics; pre-clinical; prevent; receptor; relating to nervous system; remifentanil; response; screening; small molecule; small molecule libraries; targeted treatment; therapeutic target; tissue injury

ABSTRACT Intense nociceptor inputs produce long-term changes in the spinal cord dorsal horn, which resemble the memory engram in the brain. Thus, such long-term changes are suggested to constitute ‘spinal pain memory’ underlying chronic pain. Efforts to develop chronic pain therapies targeting ‘pain memory maintenance’ have been unsuccessful due to our incomplete understanding of mechanisms maintaining this memory. Here we take a conceptually novel approach of triggering endogenous ‘pain memory erasure’ mechanisms for effective prevention and treatment of chronic pain. Based on the literature and our preliminary data demonstrating that activating the spinal G protein-coupled receptor 37 (GPR37) using its putative agonists reverses spinal long- term synaptic potentiation and abolishes/curtails long-lasting pain hypersensitivity in multiple animal models, we propose that spinal GPR37 is the key to erasing spinal pain memory and therefore, its agonists will be promising pain therapeutics effectively prevent/treat chronic pain. This project is to collect preliminary data validating this idea from pain biology, drug addiction, and drug discovery/development perspectives through the following Specific Aims. In Aim 1, using TX14A, a putative peptide agonist for GPR37, we will validate spinal GPR37 as a molecular target for pain therapy and identify cells expressing the receptor to mediate the pain memory erasure effect. Additionally, we will determine if TX14A reverses experimentally induced long-term changes in dorsal horn neuronal responses to afferent inputs. In Aim 2, we will develop a GPR37 cellular assay system and perform a high throughput screening (HTS) testing compounds in small molecule libraries to identify potential druggable GPR37 agonists. Using medicinal chemistry approaches, we will also design, synthesize, and early optimize new small peptide and peptidomimetic small molecules based on TX14A and the GPR37 HTS ‘hits’. In Aim 3, we will develop and optimize preclinical in vivo testing paradigms to streamline the assessment of analgesic efficacy and abuse liability of new GPR37 agonists. The preliminary results obtained through these Aims will lay the groundwork for a subsequent Team Research U19 application responding to RFA-NS-21-015. Specifically, the results of Aims 1-3 will be the basis of the three Research Components in the U19 application: 1) Validation of Therapeutic Target and Underlying Biology, 2) Assay Development, Screening and Optimization, and 3) Development and Validation of Animal Models and/or Outcome Measures.

摘要 强烈的伤害感受器输入在脊髓背角产生长期的变化，类似于 大脑中的记忆印记因此，这种长期的变化被认为构成了“脊髓疼痛记忆” 潜在的慢性疼痛努力开发针对“疼痛记忆维持”的慢性疼痛疗法， 由于我们对维持这种记忆的机制的不完全理解，这里我们以 一种概念上新颖的方法，触发内源性“疼痛记忆擦除”机制， 慢性疼痛的预防和治疗。根据文献和我们的初步数据， 使用其假定的激动剂激活脊髓G蛋白偶联受体37（GPR 37）逆转脊髓长- 在多种动物模型中，我们发现， 我认为脊髓GPR 37是消除脊髓疼痛记忆的关键，因此，它的激动剂将是有希望的 疼痛治疗剂有效地预防/治疗慢性疼痛。这个项目是收集初步数据验证这一点 从疼痛生物学、药物成瘾和药物发现/开发的角度，通过以下几个方面提出了一些想法： 具体目标。在目标1中，使用TX 14 A（GPR 37的推定肽激动剂），我们将验证脊髓GPR 37作为一种抗肿瘤药物。 疼痛治疗的分子靶点，并鉴定表达受体的细胞，以介导疼痛记忆消除 效果此外，我们将确定TX 14 A是否逆转实验诱导的背侧神经元的长期变化。 角神经元对传入输入的反应。在目标2中，我们将开发一个GPR 37细胞检测系统，并进行 高通量筛选（HTS）测试小分子文库中的化合物，以鉴定潜在的可药用化合物 GPR 37激动剂。使用药物化学方法，我们还将设计，合成和早期优化 基于TX 14 A和GPR 37 HTS“命中”的新型小肽和拟肽小分子。在目标3中， 我们将开发和优化临床前体内试验范例，以简化镇痛药的评估， 新GPR 37激动剂的功效和滥用倾向。 通过这些目标获得的初步结果将为随后的团队研究奠定基础 响应RFA-NS-21-015的U19应用程序。具体而言，目标1-3的结果将是这三个目标的基础。 U19申请中的研究组件：1）治疗靶点和基础生物学验证，2） 试验开发、筛选和优化，以及3）动物模型的开发和验证和/或 结果测量。