Selective CB2 Cannabinoid Agonists as Candidate Therapeutics for ALS

选择性 CB2 大麻素激动剂作为 ALS 的候选治疗药物

基本信息

批准号：
7884988
负责人：
Paul L Prather
金额：
$ 4.31万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-15 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7884988
关键词：
AM 1241 Agonist Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Animal Model Anti-Inflammatory Agents Anti-inflammatory Appearance Biochemical Biocompatible Biological Availability CNR1 gene CNR2 gene Cannabinoids Cessation of life Characteristics Clinical Trials Data Development Diagnosis Disease Disease Progression Dose Drug Delivery Systems Drug Kinetics Endocannabinoids Funding Opportunities Future GTP-Binding Proteins Goals Half-Life In Vitro Indoles Injection of therapeutic agent Life Ligands Messenger RNA Metabolic Clearance Rate Modality Motor Motor Neurons Multiple Sclerosis Mus Mutant Strains Mice Neurodegenerative Disorders Onset of illness Paralysed Pathologic Patients Pattern Pharmaceutical Preparations Pharmacologic Substance Relative (related person)Research Route Screening procedure Series Serum Signal Pathway Solubility Spinal Cord Staging Symptoms Testing Therapeutic Tissues Translating Universities aqueous base in vivo intraperitoneal mouse model neuroinflammation neuron loss novel novel therapeutics receptor binding relating to nervous system research study response subcutaneous

项目摘要

Project Summary: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, paralysis and death within 2 to 5 years of diagnosis. Currently, no effective pharmacological agents exist for the treatment of this devastating disease. Neuroinflammation may greatly influence the progression of motor neuron loss during ALS. Cannabinoids produce anti-inflammatory actions via CB1 and CB2 receptors and delay the progression of pathologic conditions characterized by neuroinflammation. In G93A-SOD1 (G93A) mutant mice, the most well-characterized animal model of ALS, we demonstrate that mRNA, receptor binding and function of CB2, but not CB1, receptors are dramatically and selectively upregulated in the spinal cords of G93A mice in a temporal pattern closely paralleling disease progression. More importantly, daily injections of two structurally diverse selective CB2 agonists (AM-1241 and L- 759,633) initiated at symptom onset, markedly maintain motor function and increase the survival interval after disease onset. Therefore, we propose that selective CB2 agonists may represent a novel therapeutic modality for ALS. While CB2 agonists may prove useful for this devastating neurodegenerative disease, their development as pharmaceutical agents has been fundamentally hindered by their relative insolubility in aqueous, or other biocompatible, vehicles. Indeed, several lines of evidence indicate that the actual maximal efficacy of AM-1241 might have been underestimated due to less than optimal drug delivery by the vehicle employed in our preliminary studies. As such, we propose that pharmacokinetic studies are needed to determine the most efficient vehicle, route of administration and/or dose required to produce the maximal efficacy of AM-1241 in G93A mice. The current A1 revision of this R21 application will "identify candidate therapeutics" and "obtain preliminary data on the efficacy of candidate therapeutics" for ALS by conducting the following two Specific Aims: Specific Aim 1 will identify novel CB2 agonists as candidate therapeutics for ALS by screening a series of indole and classic cannabinoid-based CB2 agonists provided by Dr. John W. Huffman (Clemson University, SC) for their ability to slow disease progression and prolong survival of G93A mice. Specific Aim 2 will optimize the therapeutic potential of AM-1241, a CB2 agonist with proven efficacy in the G93A mouse model of ALS. This will be accomplished by employing the vehicle and route of administration demonstrated by pharmacokinetic studies to produce the greatest delivery of AM-1241 to serum and spinal cords. Selective CB2 agonists identified by this project could be the first efficacious drugs for the management of ALS. Most importantly, our long-term goal is to translate results from these studies into a future clinical trial in ALS patients. Project Narrative: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, paralysis and death within 2 to 5 years of diagnosis. Currently, no effective drugs exist for the treatment of this devastating disease. Based on some exciting preliminary evidence, this project will seek to discover new drugs called "CB2 agonists" that could be the first class of effective drugs to prolong the lives of ALS patients.

项目概要：肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征是进行性进展诊断后 2 至 5 年内运动神经元丧失、瘫痪和死亡。目前，尚无有效存在用于治疗这种毁灭性疾病的药物。神经炎症可能极大地影响 ALS 期间运动神经元丢失的进展。大麻素产生通过 CB1 和 CB2 受体发挥抗炎作用，延缓病理进展以神经炎症为特征的病症。在 G93A-SOD1 (G93A) 突变小鼠中，最通过充分表征的 ALS 动物模型，我们证明了 mRNA、受体结合和 CB2（而非 CB1）受体的功能在脊髓中显着且选择性上调 G93A 小鼠的脊髓的时间模式与疾病进展密切相关。更多的重要的是，每天注射两种结构不同的选择性 CB2 激动剂（AM-1241 和 L- 759,633）在症状出现时启动，显着维持运动功能并提高生存率发病后的间隔时间。因此，我们建议选择性CB2激动剂可能代表一种治疗 ALS 的新方法。虽然 CB2 激动剂可能对这种毁灭性的治疗有用神经退行性疾病，它们作为药物制剂的开发已经从根本上由于它们在水性或其他生物相容性载体中的相对不溶性而受到阻碍。确实，有几个证据表明 AM-1241 的实际最大功效可能是由于我们初步使用的车辆未达到最佳药物输送而被低估研究。因此，我们建议需要进行药代动力学研究来确定最产生最大功效所需的有效载体、给药途径和/或剂量 G93A 小鼠中的 AM-1241。此 R21 应用程序的当前 A1 修订版将“确定候选人疗法”和“获得有关 ALS 候选疗法疗效的初步数据” 执行以下两个具体目标：具体目标 1 将确定新型 CB2 激动剂为通过筛选一系列基于吲哚和经典大麻素的 ALS 候选疗法 John W. Huffman 博士（南卡罗来纳州克莱姆森大学）提供的 CB2 激动剂能够减缓疾病进展并延长 G93A 小鼠的生存期。具体目标 2 将优化 AM-1241 的治疗潜力，一种 CB2 激动剂，在 G93A 小鼠模型中已被证明有效肌萎缩侧索硬化症。这将通过使用载体和给药途径来完成药代动力学研究证明 AM-1241 能够最大程度地向血清输送和脊髓。该项目确定的选择性 CB2 激动剂可能是第一个有效的用于治疗 ALS 的药物。最重要的是，我们的长期目标是将结果转化为这些研究将进入未来针对 ALS 患者的临床试验。项目叙述：肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征是进行性进展诊断后 2 至 5 年内运动神经元丧失、瘫痪和死亡。目前，尚无有效存在用于治疗这种毁灭性疾病的药物。基于一些令人兴奋的初步证据，该项目将寻求发现称为“CB2激动剂”的新药，这可能是第一个一类延长 ALS 患者生命的有效药物。