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

• 批准号: 7884989
• 负责人: Paul L Prather
• 金额: $ 1.07万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884989
• 关键词: AM 1241; Agonist; Alzheimer' 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

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.

项目摘要： 肌萎缩性外侧硬化症（ALS）是一种神经退行性疾病，其特征是进行性疾病 运动神经元丧失，瘫痪和死亡诊断2至5年。目前，无效 存在药理学剂来治疗这种毁灭性疾病。神经炎症 可能会极大地影响ALS期间运动神经元丧失的进展。大麻素会产生 通过CB1和CB2受体的抗炎作用，并延迟病理的进展 以神经炎症为特征的条件。在G93A-SOD1（G93A）突变小鼠中，最多 ALS的特征良好的动物模型，我们证明mRNA，受体结合和 CB2的功能，但不是CB1，受体在脊柱中显着和有选择地上调 时间模式中G93A小鼠的绳索紧密平行疾病进展。更多的 重要的是，每天注射两种结构上不同的选择性CB2激动剂（AM-1241和L- 759,633）在症状发作时启动，明显保持运动功能并增加生存率 疾病发作后的间隔。因此，我们建议选择性CB2激动剂可能代表 ALS的一种新颖的治疗方式。虽然CB2激动剂可能对这种破坏性有用 神经退行性疾病，它们作为药物的发展从根本上是 由于它们在水性或其他生物相容性车辆中的相对不溶性所阻碍。确实，有几个 证据线表明AM-1241的实际最大功效可能是 由于我们的初步使用的车辆递送不到最佳药物，因此被低估了 研究。因此，我们建议需要进行药代动力学研究以确定最多 有效的车辆，给药途径和/或剂量可产生最大功效 G93A小鼠中的AM-1241。此R21应用程序的当前A1修订将“确定候选人 治疗学”和“获取有关候选治疗疗法疗效的初步数据” 执行以下两个具体目标：特定目标1将确定新型的CB2激动剂为 通过筛选一系列基于大麻的吲哚和经典大麻素，用于ALS的候选疗法 约翰·W·霍夫曼（John W. G93A小鼠的疾病进展和延长生存率。特定目标2将优化 AM-1241的治疗潜力，一种CB2激动剂，具有在G93A小鼠模型中具有良好功效的CB2激动剂 ALS。这将通过使用车辆和管理途径来实现 通过药代动力学研究证明，产生AM-1241最大递送到血清 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 用于管理ALS的药物。最重要的是，我们的长期目标是翻译 这些研究对ALS患者的未来临床试验进行了研究。项目叙述： 肌萎缩性外侧硬化症（ALS）是一种神经退行性疾病，其特征是进行性疾病 运动神经元丧失，瘫痪和死亡诊断2至5年。目前，无效 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 有效的药物延长ALS患者的寿命。