Developing GPR37 activators as non-opioid pain therapeutics

开发 GPR37 激活剂作为非阿片类疼痛疗法

基本信息

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
项目类别：
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

项目摘要

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.

抽象的强烈的伤害感受器输入会导致脊髓背角发生长期变化，这类似于因此，这种长期变化被认为构成了“脊髓疼痛记忆”。开发针对“疼痛记忆维持”的慢性疼痛疗法的努力已经取得进展。由于我们对维持这种记忆的机制不完全理解，所以没有成功。一种概念新颖的方法，触发内源性“疼痛记忆消除”机制，以有效根据文献和我们的初步数据证明，慢性疼痛的预防和治疗。使用其假定的激动剂激活脊髓 G 蛋白偶联受体 37 (GPR37) 可逆转脊髓长在多种动物模型中，术语突触增强并消除/减少持久的疼痛超敏反应，我们提出脊髓GPR37是消除脊髓疼痛记忆的关键，因此其激动剂将很有前途疼痛疗法有效预防/治疗慢性疼痛该项目旨在收集验证这一点的初步数据。通过以下内容从疼痛生物学、药物成瘾和药物发现/开发的角度提出想法具体目标在目标 1 中，我们将使用 TX14A（一种假定的 GPR37 肽激动剂）验证脊髓 GPR37。疼痛治疗的分子靶标并识别表达受体的细胞以介导记忆疼痛消除此外，我们将确定 TX14A 是否可以逆转实验诱导的背侧长期变化。在目标 2 中，我们将开发 GPR37 细胞检测系统并执行角神经对传入输入的反应。高通量筛选 (HTS) 测试小分子库中的化合物，以识别潜在的可成药药物我们还将利用药物化学方法设计、合成和早期优化 GPR37 激动剂。基于 TX14A 和 GPR37 HTS 的新小肽和拟肽小分子“命中”，我们将开发和优化临床前体内测试范例，以简化镇痛药的评估新型 GPR37 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后续团队研究奠定基础具体而言，U19 申请响应 RFA-NS-21-015，目标 1-3 的结果将成为这三个目标的基础。 U19 申请中的研究组成部分：1) 治疗靶点和基础生物学的验证，2) 测定开发、筛选和优化，以及 3) 动物模型的开发和验证和/或结果措施。