Developing Small-Molecule Probes for Opioid-Induced Glial Activation

开发用于阿片类药物诱导的神经胶质激活的小分子探针

• 批准号: 7943002
• 负责人: Hang Hubert Yin
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943002
• 关键词: Absence of pain sensation; Address; Adverse effects; Animal Model; Animal Testing; Arts; Basic Science; Biology; Blood - brain barrier anatomy; Cellular Assay; Chemicals; Clinical; Complex; Computer Simulation; Crystallization; Dependence; Development; Drug Addiction; Drug Kinetics; Effectiveness; Generations; Goals; In Vitro; Lead; Libraries; Ligands; Light; Link; Literature; Mediating; Membrane; Meperidine; Methadone; Molecular; Morphine; Myelogenous; Neuraxis; Neurobiology; Neuroglia; Neurons; Opiate Addiction; Opiates; Opioid; Outcome; Overdose; Oxycodone; Pain; Pain management; Permeability; Pharmaceutical Preparations; Pharmacological Treatment; Prevention; Property; Proteins; Research; Resolution; Safety; Screening procedure; Signal Pathway; Structure; Structure-Activity Relationship; Technology; Testing; Therapeutic; Validation; Work; addiction; base; clinical efficacy; clinically relevant; computational chemistry; design; drug candidate; drug development; drug discovery; high reward; high risk; improved; in vivo; inhibitor/antagonist; innovation; insight; interest; molecular recognition; novel; novel therapeutics; opioid abuse; prevent; prototype; public health relevance; receptor; receptor function; response; small molecule; toll-like receptor 4; virtual

DESCRIPTION (provided by applicant): The pharmacological treatment of pain has long been limited by the negative side effects of opioids: development of tolerance, dependence, and danger of overdose. A literature has developed linking opiate side effects to their influence on glial cells within the central nervous system (CNS). These effects have been shown to result from toll-like receptor 4 (TLR4)-mediated glial activation, which causes both pain enhancement and opioid tolerance and dependence. As such, there is an urgent need to understand opioid dysregulation via TLR4. The objective of this current proposal is to optimize a small-molecule probe identified from virtual screening, which in turn will be used to study glial activation and its impact on opioid effectiveness. The rationale underlying this research is that optimized small molecule TLR4 inhibitors can serve as highly specific probes to study the molecular mechanism of opioid-induced glial activation. The proposed research is significant because the optimized small molecule agents will preclude the development of novel therapeutics to increase opiate efficacy and safety. The proposed research is innovative because it is the first drug discovery approach attempting to regulate opioid-induced glial activation. The studies are built on a strong collaborative team with expertise that optimizes its chance to effectively bridge the atomic detail of TLR4 activation with the macroscopic pain management inefficiencies of opioid use. In Aim 1, extensive structure-activity relationship studies will be carried out to optimize the lead compound indentified from in silico screening. Established in vitro biophysical and cellular assays will then be used to evaluate synthesized small molecule agents for their potency in blocking TLR4 activation. Crystallization of TLR4 in complex with the small-molecule ligands will be attempted in a parallel effort to elucidate the structural geometry of TLR4 inhibition. These results will shed light on the molecular recognition in the ligand/receptor association, thereby providing insights for the optimization of the first generation small molecule inhibitors. Aim 2 will test the second working hypothesis, that by inhibiting opioid-induced TLR4 activation, glial activation can also be blocked, thus enhancing analgesia as well as reduce tolerance and dependence on opioids. The proposed studies, if successful, are projected to yield significant novel outcome: First, the results will shed light on the mechanism of clinically relevant opioid-induced glial activation. Second, the small molecule antagonists of TLR4 identified from the proposed research will serve as prototypes for potential drug candidates. These inhibitors may be clinically useful in the treatment of opioid side effects, addressing a public heath issue that encompasses opioid addiction, tolerance, and abusing. PUBLIC HEALTH RELEVANCE: The proposed research aims to unravel the mechanism of opioid-induced glial activation that both hinders the ability of opioids to effectively control pain and also importantly contributes to the development of drug addiction and abuse. State-of-the-art technologies will be employed to define, design, create, and test new chemical entities predicted to prevent opioid induced glial activation, thereby optimizing opioid analgesia while preventing negative consequences of clinical opioid use.

描述（由申请人提供）：疼痛的药物治疗长期以来一直受到阿片类药物的负面副作用的限制：产生耐受性、依赖性和过量服用的危险。一篇文献将阿片类药物的副作用与其对中枢神经系统 (CNS) 内神经胶质细胞的影响联系起来。这些效应已被证明是由 Toll 样受体 4 (TLR4) 介导的神经胶质激活引起的，这会导致疼痛增强以及阿片类药物耐受和依赖性。因此，迫切需要通过 TLR4 了解阿片类药物的失调。当前提案的目标是优化通过虚拟筛选确定的小分子探针，该探针反过来将用于研究神经胶质细胞激活及其对阿片类药物有效性的影响。这项研究的基本原理是优化的小分子 TLR4 抑制剂可以作为高度特异性的探针来研究阿片类药物诱导的神经胶质细胞激活的分子机制。拟议的研究意义重大，因为优化的小分子药物将阻碍开发新疗法以提高阿片类药物的功效和安全性。拟议的研究具有创新性，因为它是第一个尝试调节阿片类药物诱导的神经胶质细胞激活的药物发现方法。这些研究建立在一个强大的协作团队的基础上，该团队拥有专业知识，可以优化有效连接 TLR4 激活的原子细节与阿片类药物使用的宏观疼痛管理低效的机会。在目标 1 中，将进行广泛的构效关系研究，以优化通过计算机筛选确定的先导化合物。然后，建立的体外生物物理和细胞测定将用于评估合成小分子药物阻断 TLR4 激活的效力。我们将同时尝试 TLR4 与小分子配体复合物的结晶，以阐明 TLR4 抑制的结构几何形状。这些结果将揭示配体/受体结合中的分子识别，从而为第一代小分子抑制剂的优化提供见解。目标 2 将测试第二个工作假设，即通过抑制阿片类药物诱导的 TLR4 激活，也可以阻止神经胶质细胞的激活，从而增强镇痛作用并减少对阿片类药物的耐受性和依赖性。拟议的研究如果成功，预计将产生重大的新成果：首先，结果将揭示临床相关的阿片类药物诱导的神经胶质细胞激活的机制。其次，从拟议研究中鉴定出的 TLR4 小分子拮抗剂将作为潜在候选药物的原型。这些抑制剂在临床上可用于治疗阿片类药物副作用，解决包括阿片类药物成瘾、耐受和滥用在内的公共卫生问题。 公共健康相关性：拟议的研究旨在揭示阿片类药物诱导的神经胶质激活机制，该机制既阻碍阿片类药物有效控制疼痛的能力，又重要地促进药物成瘾和滥用的发展。将采用最先进的技术来定义、设计、创建和测试预计可防止阿片类药物诱导的神经胶质激活的新化学实体，从而优化阿片类药物镇痛，同时防止临床阿片类药物使用的负面后果。